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Let-7 as biomarker, prognostic indicator, and therapy for precision medicine in cancer

Abstract

Abnormal regulation and expression of microRNAs (miRNAs) has been documented in various diseases including cancer. The miRNA let-7 (MIRLET7) family controls developmental timing and differentiation. Let-7 loss contributes to carcinogenesis via an increase in its target oncogenes and stemness factors. Let-7 targets include genes regulating the cell cycle, cell signaling, and maintenance of differentiation. It is categorized as a tumor suppressor because it reduces cancer aggressiveness, chemoresistance, and radioresistance. However, in rare situations let-7 acts as an oncogene, increasing cancer migration, invasion, chemoresistance, and expression of genes associated with progression and metastasis. Here, we review let-7 function as tumor suppressor and oncogene, considering let-7 as a potential diagnostic and prognostic marker, and a therapeutic target for cancer treatment. We explain the complex regulation and function of different let-7 family members, pointing to abnormal processes involved in carcinogenesis. Let-7 is a promising option to complement conventional cancer therapy, but requires a tumor specific delivery method to avoid toxicity. While let-7 therapy is not yet established, we make the case that assessing its tumor presence is crucial when choosing therapy. Clinical data demonstrate that let-7 can be used as a biomarker for rational precision medicine decisions, resulting in improved patient survival.

Introduction

During carcinogenesis, cells acquire capabilities termed the hallmarks of cancer [1]. Abnormal microRNA (miRNA) regulation has been attributed to all phases of cancer and affects several of the cancer hallmarks [2, 3]. Discovered in C. elegans, let-7 (lethal-7) miRNA family functions as an important regulator of differentiation [4, 5]. In mammals, let-7 is known as the keeper of differentiation, and its abnormal regulation and expression has been associated with cancer initiation and progression [6]. The functions of all members are generally thought to be overlapping because of sequence similarity [7]. Figure 1 includes a diagram of let-7 structure with seed sequence highlighted. Because let-7 targets several oncogenes, its repression in cancer is most often associated with poor patient prognosis [8]. The human genome contains 13 let-7 family members encoding 9 mature miRNAs. Let-7a1, a2, a3 are encoded from different transcripts, producing identical mature sequence; the same is true for let-7f1, f2. With the exception of let-7i and let-7g, which are encoded individually, transcripts of different let-7 members are located in clusters along with other miRNAs [9,10,11,12]. Due to different genomic loci, transcriptional regulation varies between individual let-7 family members. In this review, we discuss let-7′s involvement in patient survival, focusing on its function as diagnostic, prognostic and therapeutic, in isolation as well as in combination with current therapy regimens. We review let-7 effects on cellular phenotype, and explain it by molecular mechanisms. We also discuss instances of let-7 oncogenic functions, differences between regulation and function of different let-7 family members, and its importance for understanding its effect in cancer biology and its therapeutic potential.

Fig. 1
figure1

LIN28/TUT4(7) let-7 binding during post-transcriptional processing. Modified from Nam et al. and Faehnle et al. [111, 112]. CSD and ZFD are abbreviations for cold shock domain and zinc finger domain of LIN28 respectively. LIM and CM are abbreviations of LIN28 interactive module and catalytic module of TUT4(7) respectively. Sequence of mature let-7a demonstrates position of let-7 family members in the stem along with highlighted seed region

Let-7 as tumor suppressor

Use as a screening tool

Levels of let-7 family members can serve as biomarkers to assist with cancer diagnosis, and monitoring. Detecting differential let-7 levels in bodily fluids has the potential to allow early detection of cancer using minimally invasive procedures, minimizing risks associated with biopsy. Increased plasma let-7 levels are seen in patients with breast, prostate, colon, renal, liver, gastric, thyroid, and ovarian cancer [13,14,15,16,17,18,19]. Elevated urine let-7 levels can also be detected in renal cancer [20]. Some studies have also reported decreased serum let-7 levels in colon, lung, prostate, gastric, ovarian, and breast cancers [21,22,23,24,25,26,27,28,29]. Patients with colorectal carcinoma have decreased levels of let-7 in stool samples compared to healthy controls, providing a less invasive tool to aid with diagnosis [22]. These studies, with some apparently contradictory results, point out the need for further study, but the use of serum let-7 appears to be a promising biomarker. For each cancer type, results are consistent. Table 1 provides a summary of abnormal let-7 levels in plasma (liquid biopsy) based on the type of cancer. Plasma let-7 levels have the potential to serve as a monitoring system for therapy, and may predict accelerated reproliferation of lung cancer, which would assist in providing personalized treatment options for patients [30]. Let-7 levels are directly influenced by therapy, illustrated by let-7c in acute promyelocytic leukemia: its levels increase in blasts after chemotherapy, then decrease again upon relapse [31]. Chemoresistant epithelial ovarian cancers, lung cancers, and acute myeloid leukemia have reduced let-7 levels relative to chemo-sensitive cells, resulting in non-response to chemotherapy [32,33,34,35,36,37]. These are examples of ways that monitoring let-7 levels could be used to predict drug response or recurrence. Thus, much more work remains in order to understand the diagnostic value of let-7 levels in blood and urine.

Table 1 Levels of serum let-7 relative to normal control in patients with different types of cancer

Use as a diagnostic tool for therapy selection

Let-7 is repressed in many different types of human cancer. Table 2 summarizes abnormal let-7 expression obtained from patient tumors, obtained by solid biopsy, and cultured cancer cell lines (including cases where let-7 is up-regulated). Mechanisms for loss of let-7 are incompletely understood, however studies in ovarian cancer suggest that let-7 repression is due to genomic deletions and abnormal transcription, rather than loss of processing mechanisms involving Dicer and Drosha [38]. While 31.2% of epithelial ovarian cancers (EOC) demonstrate let-7a3 deletions, only 3.1% had alterations in copy number of let-7i [36, 38]. Abnormal expression of let-7 family members correlates with patient prognosis. Decreased expression of let-7 correlates with aggressive, high-grade tumors, and poor prognosis; accordingly, high let-7 levels are associated with better prognosis and prolonged patient survival [36, 39,40,41,42,43,44,45,46]. Low post-surgical tumor let-7 levels indicate poor prognosis for lung cancer patients, with reduced overall survival [44, 47]. The picture is similar for breast, pancreatic, colorectal, liver, and ovarian cancer (the only exception is let-7b and c in ovarian cancer) [17, 36, 39,40,41,42,43, 45, 46]. Of note, high let-7b levels in high grade serous EOC positively correlate with markers of invasiveness and worse prognosis. Let-7 family members are expressed at lower levels in metastatic sites compared to primary tumor in gastric, breast, liver, and lung cancers [48,49,50,51]. In vivo, let-7 over-expression in breast cancer resulted in reduced lung and liver metastasis, while let-7 repression resulted in increased in metastasis [51, 52]. Therefore, tumor let-7 levels correlate with and can be used as a prediction for distal metastasis. Thus, while important exceptions must be noted, loss of let-7 in most cancers closely correlates with poor prognosis.

Table 2 Levels of let-7 family members relative to normal tissue in different types of human cancer

While let-7 levels in body fluids can possibly assist in diagnosis, let-7 levels in tumors can be used to create a personalized optimal treatment plan including both chemotherapy and radiation. Determining levels of tumor let-7 as well as its targets is expected to be useful to deliver personalized treatment when considering therapy options. Colorectal carcinoma patients with KRAS mutation and with high levels of let-7 can benefit from anti-EGFR therapy, while patients with low levels of let-7 have impaired responses [45]. A study by Lu et al. examined let-7a expression levels and response to chemotherapy in patients treated with platinum-based chemotherapy with or without paclitaxel. The patients in this study were treated between 1991 and 2000 [53]. The platinum/paclitaxel doublet became the first line standard of care in advanced EOC after the publication of results of GOG 111 in 1996 [54]. In the study by Lu and colleagues, patients with ovarian cancer and high let-7a levels have better prognosis than those with low let-7a levels when treated with platinum-based therapy alone, but counterintuitively, high let-7a levels correlate with poor response when platinum is combined with paclitaxel. The reverse was true for patients with low let-7a levels in tumors [53]. These observations lead to the hypothesis that, for patients with high tumor let-7a levels, forgoing paclitaxel results in improved outcomes. Paclitaxel inhibits microtubule polymerization, thus affecting rapidly dividing cells. Let-7 has anti-proliferative functions (described below), providing a possible explanation why patients with high tumor let-7 levels did not respond well to paclitaxel [55]. Therefore, knowledge of tumor let-7a levels is expected to be an important contributor to decisions about chemotherapy. However, this will require careful consideration and further retrospective trials followed by robust clinical trials, as currently doublet platinum based or combination intravenous/intraperitoneal chemotherapy are recommended for advanced ovarian cancer in the front line setting (NCCN Guidelines Ovarian Cancer Version 2.2018 3/14/2018, http://www.nccn.org, accessed 1/6/2019).

However, what is true for ovarian cancer may not apply to other malignancies: breast cancer cell lines that have low let-7 levels respond better to taxol treatment [56]. The discrepancy between results obtained by the studies in ovarian and breast cancer can be attributed to differences in biology of breast and ovarian cancer as well as the study design. While Lu et al. [53] compared clinical data and tumor let-7a levels from ovarian cancer patients that had undergone different courses of treatment, Sun et al. [56] used breast cancer cell lines for in vitro studies. Tumor let-7 levels can also predict response to other therapies. Breast cancer patients with low tumor let-7 levels do not respond to epirubicin; therefore, choosing an alternative therapy may prolong survival [57]. In prostate cancer patients, tumors with decreased let-7c levels are resistant to androgen therapy, and let-7 delivery to tumors provides promising therapy [58]. Table 3 summarizes best therapy options based on let-7 levels in several types of cancer.

Table 3 Therapy of choice based on tumor let-7 levels in different types of cancer

Let-7 replacement as a therapeutic

Tumor delivery of let-7 is a potential therapy, as a strategy for reversing stemness and chemoresistance, in combination with chemotherapy [59]. Let-7 over-expression results in increased sensitivity to chemotherapy and radiation therapy in ovarian cancer, hepatocellular carcinoma, oral squamous carcinoma, breast cancer, lung cancer, and myeloid leukemia, while inhibiting let-7 results in acquisition of resistance [35,36,37, 57, 59,60,61,62,63,64,65].

Higher tumor let-7 levels contribute to an increase in sensitivity to therapy [36, 57, 58]. This decrease in resistance can allow treatment with lower dose of chemotherapy to obtain the same therapeutic benefit. This represents an opportunity to avoid severe side effects of cancer treatments by using lower chemotherapy dosages. The ability to use lower drug dosages to obtain equivalent therapeutic benefit may lead to lower levels of toxicities and chemotherapy related adverse events, allowing for better quality of life for the patients undergoing treatment. Also, there would likely be fewer instances of chemotherapy discontinuation due to lower instances of dose-limiting toxicities.

The feasibility of using let-7 as therapy has been demonstrated by successful in vivo studies. Let-7 overexpression in animal model studies results in reduction of tumor size, metastasis, and prolonged survival [35, 42, 52, 58, 59, 62, 66,67,68]. These results are explained via functional assays in vitro, where let-7 decreases cellular proliferation, migration, and invasion [37, 42, 58, 59, 67,68,69,70,71,72,73]. Let-7 overexpression has been accomplished in pre-clinical murine models via let-7 mimics, demonstrating its efficacy. As miRNA will rapidly degrade in plasma, advanced let-7 delivery methods are required. In order to avoid tissue toxicity and delivery to other cells within tumor stroma, strategies for delivery of mimics specifically to cancer cells must be developed (see below). Dai et al. utilized polyethyleneglycol (PEG) nanoparticles to deliver let-7 together with paclitaxel in vivo, and they observed successful repression of tumor burden without animal toxicity [59].

Molecular aspects governing functional phenotype

The pleiotropic effects of let-7 include repression of oncogenes, suppression of epithelial-to-mesenchymal transition, induction of chemosensitivity, controlling cell signaling pathways, and decreasing cellular proliferation.

Let-7 effect on cancer observed in clinical, in vivo, and in vitro studies can be explained by several functional aspects. One way let-7 acts as a tumor suppressor is via repression of oncogenes resulting in a decrease in stemness [60, 74]. Let-7 levels inversely correlate with percentage of cancer stem cells (CSC), and its overexpression reduces CSC markers nestin and CD133 in glioblastoma and ALDH1 in breast cancer [40, 73]. To determine the presence of cancer stem cells functionally, spheroid (mammosphere in breast cancer) formation and colony formation assays are used. Spheroids are enriched for tumor initiating cells and have lower let-7 levels, and in mammospheres that are allowed to differentiate, let-7 levels increase [52]. Let-7 over-expression inhibits stemness, resulting in reduced sphere formation [40, 52, 60, 64, 73]. Cancer cells with a stem-like phenotype are also able to form colonies, measured as clonogenicity. Up-regulation of let-7 results in decreased clonogenicity [47, 58, 59, 75].

Let-7 targets oncogenes and genes important for tumor initiation and progression including Myc, RAS, E2F1, E2F5, LIN28, ARID3B, PBX3, HMGA2 and long non-coding RNA H19 [42, 59, 70, 76]. Silencing these genes causes the functional tumor suppressive effects mediated by let-7. LIN28A is a well-known pluripotency marker that is present in embryonic stem cells (ESCs) and decreases upon differentiation [77]. In prostate cancer, LIN28 increases aggressiveness and results in increased tumor burden in vivo [78]. ARID3B and HMGA2 transcriptionally activate OCT-4 and SOX2, respectively, both of which are pluripotency factors highly expressed in ESCs [39, 67, 69, 70, 79,80,81]. Repression of H19 results in methylation of promoters of several other genes due to up-regulation of DNMT3b [37, 42, 48, 72, 73, 81, 82]. PBX3 is an oncogene that induces epithelial-to-mesenchymal transition and promotes invasiveness and metastasis of gastric cancer [42, 60, 70, 71, 83]. Thus, let-7 can repress the function of a number of factors that can be recruited in oncogenesis. These examples illustrate the specific effects of let-7 demonstrated to result in functional changes relevant to cancer.

Besides repression of oncogenes, let-7 also plays a role in controlling cell signaling pathways. Overexpression of the let-7 family member miR-98 results in reduced phosphorylation and down-regulation of Akt and Erk, which have been implicated in carcinogenesis [42, 59, 64, 72, 84]. In Ewing’s sarcoma, let-7 directly represses signal transducer and activator of transcription 3 (STAT3) and results in a less aggressive cancer phenotype [85]. The STAT3 pathway regulates genes related to cell cycle and cell survival and is often linked to cancer progression. STAT3 activity correlates with chemo- and radioresistance and poor survival [86]. In breast cancer, let-7 targets estrogen receptors, which activate WNT signaling and promote stemness and cancer aggressiveness [40]. Let-7 down-regulates WNT signalling activity by targeting estrogen receptors in breast cancer and TCF-4 (a transcription factor downstream of WNT) in hepatocellular carcinoma. WNT pathway is a major regulator of cell proliferation, differentiation, and migration, and has been shown to promote tumor growth and contribute to cancer stem cell phenotype [60, 64, 87]. Cumulatively, let-7′s effects on cell signaling pathways impede the aggressive phenotype.

Another way that let-7 exerts tumor suppressive effects is via inhibition of epithelial-to-mesenchymal transition (EMT). EMT is a normal process during embryonic development as well as wound healing. Cancer development and metastasis are associated with abnormal occurrence of EMT in somatic cells. During EMT, epithelial cells gain the ability to invade and metastasize [88]. Reduced let-7 levels correlate with an increase in EMT markers Twist, Snail, vimentin, and N-cadherin, resulting in increased cancer aggressiveness, as assessed by spheroid formation, migration, invasion, mesenchymal appearance, and resistance to chemotherapy [44, 62, 72]. Over-expression of let-7 reduces expression of Snail and N-cadherin, while increasing E-cadherin; these effects are proposed to be via HMGA2 [42, 59].

Let-7 induction of chemosensitivity seen in vitro and in vivo is due to inhibition of LIN28A/B, STAT3, E2F1, IMP1 and chemoresistance genes MDR1, ABCG2, and MMP9 [33, 37, 62, 63, 65, 89]. In EOC, let-7 down-regulates BRCA1, RAD51, PARP, and IGF1, resulting in increased sensitivity to cisplatin, and longer progression free survival and overall survival [34, 59]. BRCA1, RAD51, PARP, and IGF1 proteins contribute to DNA double strand break repair, which is induced by cisplatin. Inhibiting those enzymes decreases the ability of cancer cells to survive [34, 59, 90]. Nanoparticle delivery of let-7 together with paclitaxel results in an increase in sensitivity, resulting in apoptosis [59]. In blood cancers, up-regulation of the let-7 family member miR-98 results in increase of BAX and p21 in acute myeloid leukemia and increased sensitivity to adriamycin [37]. Figure 2 represents overall let-7 tumor suppressive function.

Fig. 2
figure2

Overview of tumor-suppresive let-7 effect on cancer functional phenotype

Let-7 decreases the cellular proliferation rate due to a decreased proportion of cells in S phase of the cell cycle [56, 64, 75, 76, 91, 92]. Let-7 also represses negative regulators of histone H2b monoubiquitylation (H2Bub1). H2Bub1 loss correlates with cancer progression and poor prognosis while up-regulation causes a decrease in number of breast cancer cells in S phase and cell migration [93]. Inhibition of cancer cell growth by let-7 is also due to increased apoptosis via up-regulation of bak and bax and reduced bcl-xL [37, 42, 58, 60, 67]. Table 4 summarizes targets of let-7 family members stating which have been reporter assay-validated.

Table 4 Validated and non-validated direct Let-7 targets

Let-7 as oncogene

Unexpectedly, let-7 can also have detrimental effects. Even though let-7 has been demonstrated to have tumor suppressive effects in various cancer types, emerging data suggest that, counterintuitively, in some cases let-7 may act as an oncogene. Several groups have demonstrated that the let-7a3 locus is highly methylated in normal tissues, but hypomethylated in lung and ovarian tumors, with higher expression of mature let-7a in cancers [94, 95]. Over expression of let-7a3 in lung cancer cells results in increased aggressiveness of cells, assessed via anchorage independent assay and increase in gene expression associated with cell proliferation, as well as down-regulation of genes associated with adhesion, relevant to tumor progression and metastasis [95]. Higher let-7a3, let-7b, and let-7c levels in ovarian and hepatic cancers are correlated with poor prognosis and decreased overall survival [43, 94, 96]. Ma et al. demonstrated that let-7e is increased in and positively affects migration and invasion of esophageal squamous cell carcinoma cells, possibly via targeting ARID3a [97]. Since ARID3a negatively correlates with pluripotency, decreasing it could contribute to stemness [98]. Let-7f and let-7e have been shown to be upregulated in tongue squamous carcinoma, and let-7c, let-7d, and let-7f are upregulated in aggressive relative to non-aggressive tumors [99]. Mir-98 has been shown to increase chemoresistance via indirect repression of mir-152 by targeting Dicer1. Mir-152 controls RAD51 expression, contributing to the poor prognosis of EOC patients with increased levels of mir-98 [100]. In certain in vitro conditions such as starvation, let-7 paradoxically induces expression of HMGA2 [101]. All of these indicate the complexity of the relationship between let-7 and cancer cell aggressiveness, and illustrate the fact that the actions of any miRNA are context dependent. The set of genes expressed in a particular cell determines the available let-7 targets. Thus, it is important that let-7 overexpression treatment strategies be tailored towards individualized clinical scenarios based on specific miRNA expression profiles, as opposed to overarching treatment schemas spanning across multiple malignancy types.

Tumor microenvironment and stroma are also important to consider when developing new therapies. Baer et al. demonstrated that increased let-7 expression in tumor associated macrophages (TAMs) results in conversion into the M2 phenotype. While tumor infiltration by TAMs with M1 phenotype have pro-inflammatory activity and better prognosis, the M2 phenotype is associated with increased angiogenesis and increased tumor burden [102]. Let-7 delivery as a therapeutic regimen therefore has to be specific to cancer cells due to its oncogenic functions in tumor immune cells. Even though a few studies demonstrated let-7 as having oncogenic functions and correlating with poor prognosis, the vast majority of evidence suggests otherwise. Therefore, let-7 remains a potential therapeutic target.

Let-7 regulation

Transcriptional regulation

Let-7 promoters are activated by the stem cell renewal and pluripotency factor OCT-4, and are repressed by the proto-oncogene MYC, some mutant forms of p53, and in cases of cellular stress (e.g. radiation), by wild type p53 [81, 103,104,105]. Let-7 repression by wild type p53 during stress is important when considering choice of therapy. p53 is activated by radiation, and in turn, p53 represses let-7 transcription. Thus, radiotherapy could induce acquired radio-resistance stemming from the of loss of let-7. Lung tumors in which let-7 levels are low correlate with low proliferation levels prior to radiotherapy. These tumors tend to exhibit accelerated reproliferation posttreatment. Thus, tumor let-7 levels in lung cancer patients may inform the clinician whether radiotherapy would be counterproductive in some cases. Because p53 is involved in many cellular processes and acts differently upon different stimuli, more research is needed to study this phenomenon. The epithelial-mesenchymal transition (EMT) factor Twist also represses the let-7 promoter in cooperation with BMI1 [106].

Epigenetic regulation

Abnormal let-7 expression is also due to epigenetic mechanisms. Let-7 is repressed by a single nucleotide polymorphism (SNP) in the let-7i promoter region, correlating with increased susceptibility to cervical squamous cell carcinoma [107]. Let-7 repression is also achieved by inhibiting let-7e promoter demethylation by JARID1B in urothelial cancer, promoter methylation by COX2/PGE2 signaling, and histone modifications of miR-125b in breast cancer [91, 108, 109]. MiR-125b and let-7a2 share the same promoter, suggesting that let-7a2 is repressed by this mechanism as well.

Post-transcriptional regulation

RNA binding proteins LIN28A and LIN28B represent a major post-transcriptional let-7 regulation pathway. LIN28 blocks let-7 maturation with high specificity at pre- and pri- stages [110]. The cold shock domain (CSD) of Lin28 interacts with the pre-E loop, and the CCHCx2 domain with the GGAG motif at the 3′ end of let-7, inhibiting let-7 processing [111]. Let-7 monouridylation by terminal uridyltransferases TUT4(7) stabilizes let-7 precursors for further processing, and LIN28 binding results in polyuridylation, which is a signal for degradation [112]. Figure 1 illustrates simplified let-7 binding by LIN28 and TUT4(7). LIN28B represses let-7 less effectively than LIN28A due to its nuclear localization, where terminal uridyltransferase, a mediator of let-7 repression, is not present [113]. LIN28A is present at high levels during early embryonic development, is progressively lost as cells differentiate, and is absent in somatic cells. It aberrantly increases in cancer, repressing let-7. Elevation of LIN28 has been attributed to loss of transcriptional regulation [78].

Although these two factors, LIN28 and let-7, appear mutually exclusive, there is evidence that they can coexist. Both mature let-7 and LIN28 are present in ESCs, fine-tuning each other [114]. As let-7 and LIN28 co-exist in ESCs, they also coexist in normal fully differentiated cells, the balance of which is important for proper control and function, as illustrated by glucose metabolism: repression of LIN28 and let-7 upregulation results in insulin resistance and impaired glucose metabolism in vivo [115]. It is also important to note that LIN28 function is not exclusively controlled by let-7. Balzer et al. demonstrated let-7 independent LIN28 function during neurogliogenesis [116]. LIN28 plays an important role during terminal differentiation of mouse skeletal muscle and is detected in mouse muscle tissues, demonstrating co-expression with let-7 [104, 117].

Let-7 overexpression also illustrates the precise balance necessary to maintain homeostasis. While loss of let-7 leads to oncogenesis, aberrantly high expression of let-7 also leads to toxicity indicating that homeostasis requires a precise level of expression. Wu et al. demonstrated that let-7 overexpression by 20-fold resulted in liver damage and dysfunction [66]. Based on this observation and co-expression of let-7 with LIN28 in ESCs, LIN28 is considered an important regulator of let-7 even in somatic cells. Furthermore, changes in LIN28 levels may alter normal cellular processes via let-7 repression or up-regulation. Parisi et al. demonstrated let-7 independent LIN28 increase upon exit from pluripotency [118].

Cellular signaling, including NFkB, STAT3, and MAPK-Erk pathways are also involved in let-7 regulation. While MAPK-Erk signaling positively regulates let-7 by inhibition of LIN28, NFkB and STAT3 cause both LIN28A up-regulation and let-7 repression [85, 119, 120]. Tsanov et al. demonstrated LIN28 stabilization via phosphorylation by MAPK-Erk, which had no effect on let-7 levels, in contrast to results obtained by Liu et al. showing MAPK-Erk-mediated let-7 activation. The discrepancy obtained by the two groups is possibly due to differences in biology of the cell types used and experimental procedures. Liu et al. and Tsanov et al. used mouse and human embryonal carcinoma cells respectively [120, 121]; a species difference could explain the conflicting findings. While Liu et al. used a knockin LIN28 mutant to demonstrate the effect of phosphorylation, Tsanov et al. used overexpression of the mutant.

In normal cells, wild type p53 helps maintain let-7 levels by disrupting the inhibitory effect of LIN28 and facilitating loading of mature let-7 onto Ago2. Mutation and loss of p53 in cancer are associated with let-7 repression [122, 123]. ADAR1 (adenosine deaminase acting on RNA), an RNA-binding protein, negatively regulates let-7 biogenesis by altering let-7 secondary structure at DROSHA and Dicer cleavage sites. ADAR1 expression is positively regulated by JAK2 signaling, and is overexpressed in CML and presumably in other cancers where JAK2 signaling is increased [124]. Let-7 is also inhibited post-transcriptionally by (DCAMKL-1) in colorectal cancer [125].

Aside from repression at the level of transcription and post-transcriptional processing, other RNAs can also inhibit let-7. MiR-107 forms complexes with let-7 and increases its degradation [126]. Long non-coding (lnc) RNA H19, linc-ROR, CCR492, and lnc RSU1P2 inhibit let-7 function by acting as sponges. MiR-107 is over-expressed in some breast cancers, linc-ROR in pancreatic ductal adenocarcinoma, and lnc RSU1P2 in cervical cancer, where they contribute to cancer progression and poor prognosis [49, 127,128,129]. In glioblastoma, insulin-like growth factor 2 binding protein 2 (IMP2) blocks let-7 function by binding to miRNA recognition elements of let-7 targets. There is a lack of negative correlation between let-7 and its targets in spheroids due to the protective effect of IMP2. In cancers expressing IMP2, its repression may be necessary together with let-7 up-regulation to obtain the desired tumor suppressive effect [130]. Table 5 lists factors that regulate let-7 at transcriptional, post-transcriptional, and functional levels.

Table 5 Let-7 regulators on transcriptional, post-transcriptional, and functional levels

Differences between individual family members

Functional differences

Since mature miRNA let-7 family members have nearly identical sequences, in general, it is assumed that they function similarly and have common targets, due to off target binding for which miRNAs are notorious. However, there is some evidence that different members of the let-7 family do have different functions, most likely due to unique target preferences, and therefore cannot be considered as one. In hepatocellular carcinoma, it has been demonstrated that overexpression of different let-7 family members affects cell viability to different extents: let-7a has the greatest effect [60]. It has been demonstrated that when over-expressed together, let-7i and let-7g had a greater effect on hepatoma cell division and apoptosis than overexpression of individual miRNAs, suggesting that members of this family may act in synergy to deliver tumor suppressive actions and other physiological functions [131]. Takamizawa et al. demonstrated that while both let-7a and f reduce the ability of lung cancer to form colonies, let-7f is able to do so to a greater extent [47].

Regulatory differences

Since let-7 family members are located in different clusters, transcriptional regulation is different in each case. During neural differentiation, let-7a1, a2, d, f2, and i are active in several cell types and constitutively transcribed, while let-7a3, b, c, e, and g show dynamic transcription. This difference may be due to the number of transcription start sites (TSS) present in their promoter regions. Multiple TSS produces dynamic expression because more transcription factors are involved in regulation [132]. Another way let-7 family members differ from each other is via post-transcriptional regulation. One study has demonstrated that miR-107, which contributes to metastasis of breast cancer by inhibiting let-7, binds to different let-7 members with different efficiency [126]. Different let-7 family members are repressed by LIN28 to different degrees, and in fact let-7a3 bypasses repression by LIN28 altogether due to a different sequence in the preE region of the bulge [133].

Let-7 over-expression has been widely investigated as a therapeutic agent to inhibit progression of many cancers in vitro and in animal models. It is important to consider which mature let-7 family member would be the most beneficial to patient survival before developing it into therapy.

Conclusion and future direction

In this review, we emphasize the importance of miRNA let-7 in cancer. We focus on the potential to use let-7 in precision medicine for screening and diagnosis of cancer, for its prognostic value, and as a therapeutic agent. We review the complex regulation and function of the let-7 family members, and focus on their abnormal regulation in cancer, which leads to abnormal and/or loss of function. let-7 miRNAs have been referred to as tumor suppressors, but it is important to consider that there is evidence to support their oncogenic functions in vitro and in clinical subjects. Our goal is to demonstrate the importance of let-7 during treatment decisions for chemo- and radiotherapy, to enable its use as precision medicine, and to deliver optimal results for patients.

Let-7 remains a promising cancer therapy and warrants more research; but even before all details of its therapeutic use are worked out, tumor let-7 levels can be used to choose the best therapy options for each individual. Low or high tumor let-7 levels can point to the most effective therapy regimens, and its levels in bodily fluids show potential for use as an aid to diagnosis, therapy monitoring, and prognosis.

Many questions remain unanswered. Knowledge of levels of all let-7 family members in each type of cancer can provide a more precise overview of its regulation, and provide more specific diagnostic/prognostic tools. Functional studies may reveal that upregulation of a specific let-7 member offers the most beneficial effect as a therapeutic regimen. Combination of standard therapy with let-7 over-expression has to be well studied in order to avoid toxicity and unwanted interactions. More in vivo models are needed to develop let-7 into a safe and effective therapy regimen that will provide the rationale for clinical trials.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

ABCG2:

ATP Binding Cassette Subfamily G Member 2

ADAR1:

adenosine deaminase 1

AGO2:

argonaute 2

Akt:

protein kinase B

ARID3A:

AT-rich interaction domain 3A

BAX:

BCL2 associated X protein, apoptosis regulator

BCL-xL:

apoptosis inhibiting protein

BRCA1/2:

DNA repair associated protein 1/2

CCR492:

cell-cycle regulated long non-coding RNA

CDK4:

cyclin dependent-kinase 4

COX2:

stem cell factor

CSC:

cancer stem cell

CSD:

cold shock domain

DCAMKL-1:

doublecortin and CaM kinase-like 1

DICER:

ribonuclease

EMT:

epithelial-to-mesenchymal transition

EOC:

epithelial ovarian cancer

ESC:

embryonic stem cell

GHR:

growth hormone receptor

H2Bub1:

histone H2B monoubiquitylation

HMGA2:

high mobility group AT-Hook 2

IGF1:

insulin like growth factor 1

IGF1R:

insulin like growth factor 1 receptor

IGF2BP1:

insulin like growth factor 2 binding protein 1

IGF2BP2:

insulin like growth factor 2 binding protein 2

IMP2:

insulin-like growth factor 2 binding protein 2

JAK2:

janus kinase 2

JARID1B:

jumonji AT-rich interactive domain 1B

LIN28A/B:

LIN28 homolog A/B

Lnc H19:

long non-coding RNA H19

Lnc ROR:

long non-coding RNA regulator of reprogramming

Lnc RSU1P2:

long non-coding RNA Ras suppressor protein 1 pseudogene 2

MDR1:

multi-drug resistance-1

MIRLET7:

miRNA lethal-7

miRNA:

microRNAs

MMP1:

matrix metallopeptidase 1

MMP9:

matrix metallopeptidase 9

MYC:

proto-oncogene protein

N-Cadherin:

neuronal cadherin

NGF:

nerve growth factor

NTN1:

netrin-1

OCT-4:

octamer-4 embryonic gene

P21:

cell cycle regulator

PARP1/2:

poly (ADP-ribose) polymerase 1/2

PEG:

polyethyleneglycol

PGE2:

prostaglandin E2

PLAGL2:

pleiomorphic adenoma gene-like 2

RAD51:

DNA repair protein

SNP:

single nucleotide polymorphism

STAT3:

signal transducer and activator of transcription-3

TAM:

tumor associated macrophage

TCF-4:

transcription factor 4

TSS:

transcription start site

TUT4(7):

terminal uridylyl transferase 4(7)

WNT:

signaling pathway

References

  1. 1.

    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

  2. 2.

    Peng Y, Croce CM (2016) The role of MicroRNAs in human cancer. Signal Transduct Target Ther 1:15004. https://doi.org/10.1038/sigtrans.2015.4

  3. 3.

    Romano G, Veneziano D, Acunzo M, Croce CM (2017) Small non-coding RNA and cancer. Carcinogenesis 38:485–491. https://doi.org/10.1093/carcin/bgx026

  4. 4.

    Copley MR et al (2013) The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nat Cell Biol 15:916–925. https://doi.org/10.1038/ncb2783

  5. 5.

    Reinhart BJ et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906. https://doi.org/10.1038/35002607

  6. 6.

    Bussing I, Slack FJ, Grosshans H (2008) let-7 microRNAs in development, stem cells and cancer. Trends Mol Med 14:400–409. https://doi.org/10.1016/j.molmed.2008.07.001

  7. 7.

    Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition. PLoS Biol 3:e85. https://doi.org/10.1371/journal.pbio.0030085

  8. 8.

    Balzeau J, Menezes MR, Cao S, Hagan JP (2017) The LIN28/let-7 pathway in cancer. Front Genet 8:31. https://doi.org/10.3389/fgene.2017.00031

  9. 9.

    Lee H, Han S, Kwon CS, Lee D (2016) Biogenesis and regulation of the let-7 miRNAs and their functional implications. Protein Cell 7:100–113. https://doi.org/10.1007/s13238-015-0212-y

  10. 10.

    Bloom O et al (2008) Spinophilin participates in information transfer at immunological synapses. J Cell Biol 181:203–211. https://doi.org/10.1083/jcb.200711149

  11. 11.

    Sempere LF et al (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. https://doi.org/10.1186/gb-2004-5-3-r13

  12. 12.

    Emmrich S et al (2014) miR-99a/100–125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFbeta and Wnt signaling. Genes Dev 28:858–874. https://doi.org/10.1101/gad.233791.113

  13. 13.

    Heneghan HM, Miller N, Kelly R, Newell J, Kerin MJ (2010) Systemic miRNA-195 differentiates breast cancer from other malignancies and is a potential biomarker for detecting noninvasive and early stage disease. Oncologist 15:673–682. https://doi.org/10.1634/theoncologist.2010-0103

  14. 14.

    Ogata-Kawata H et al (2014) Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS ONE 9:e92921. https://doi.org/10.1371/journal.pone.0092921

  15. 15.

    Hung C-H et al (2016) Circulating microRNAs as biomarkers for diagnosis of early hepatocellular carcinoma associated with hepatitis B virus. Int J Cancer 138:714–720. https://doi.org/10.1002/ijc.29802

  16. 16.

    Joosse SA, Muller V, Steinbach B, Pantel K, Schwarzenbach H (2014) Circulating cell-free cancer-testis MAGE-A RNA, BORIS RNA, let-7b and miR-202 in the blood of patients with breast cancer and benign breast diseases. Br J Cancer 111:909–917. https://doi.org/10.1038/bjc.2014.360

  17. 17.

    Qattan A et al (2017) Robust expression of tumor suppressor miRNA’s let-7 and miR-195 detected in plasma of Saudi female breast cancer patients. BMC Cancer 17:799. https://doi.org/10.1186/s12885-017-3776-5

  18. 18.

    Ge W et al (2014) Expression of serum miR-16, let-7f, and miR-21 in patients with hepatocellular carcinoma and their clinical significances. Clin Lab 60:427–434

  19. 19.

    Liu WJ et al (2015) Expression of serum let-7c, let-7i, and let-7f microRNA with its target gene, pepsinogen C, in gastric cancer and precancerous disease. Tumour Biol 36:3337–3343. https://doi.org/10.1007/s13277-014-2967-9

  20. 20.

    Fedorko M et al (2017) Detection of let-7 miRNAs in urine supernatant as potential diagnostic approach in non-metastatic clear-cell renal cell carcinoma. Biochem Med (Zagreb) 27:411–417. https://doi.org/10.11613/BM.2017.043

  21. 21.

    Ali S, Almhanna K, Chen W, Phillip P, Sarkar FH (2010) Differentially expressed miRNAs in the plasma may provide a molecular signature for aggressive pancreatic cancer. Am J Transl Res 3:28–47

  22. 22.

    Ghanbari R et al (2015) Simultaneous underexpression of let-7a-5p and let-7f-5p microRNAs in plasma and stool samples from early stage colorectal carcinoma. Biomark Cancer 7:39–48. https://doi.org/10.4137/BIC.S25252

  23. 23.

    Heegaard NH et al (2012) Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer. Int J Cancer 130:1378–1386. https://doi.org/10.1002/ijc.26153

  24. 24.

    Kelly BD et al (2015) A circulating MicroRNA signature as a biomarker for prostate cancer in a high risk group. J Clin Med 4:1369–1379. https://doi.org/10.3390/jcm4071369

  25. 25.

    Tsujiura M et al (2010) Circulating microRNAs in plasma of patients with gastric cancers. Br J Cancer 102:1174–1179. https://doi.org/10.1038/sj.bjc.6605608

  26. 26.

    Silva J et al (2011) Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J 37:617–623. https://doi.org/10.1183/09031936.00029610

  27. 27.

    Zheng H et al (2013) Plasma miRNAs as diagnostic and prognostic biomarkers for ovarian cancer. PLoS ONE 8:e77853. https://doi.org/10.1371/journal.pone.0077853

  28. 28.

    Li X-X et al (2015) Reduced expression levels of let-7c in human breast cancer patients. Oncol Lett 9:1207–1212. https://doi.org/10.3892/ol.2015.2877

  29. 29.

    Dou H, Wang Y, Su G, Zhao S (2015) Decreased plasma let-7c and miR-152 as noninvasive biomarker for non-small-cell lung cancer. Int J Clin Exp Med 8:9291–9298

  30. 30.

    Xie P et al (2016) Sequential serum Let-7 is a novel biomarker to predict accelerated reproliferation during fractional radiotherapy in lung cancer. Clin Lung Cancer 17:e95–e101. https://doi.org/10.1016/j.cllc.2016.03.010

  31. 31.

    Careccia S et al (2009) A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes. Oncogene 28:4034–4040. https://doi.org/10.1038/onc.2009.255

  32. 32.

    Sorrentino A et al (2008) Role of microRNAs in drug-resistant ovarian cancer cells. Gynecol Oncol 111:478–486. https://doi.org/10.1016/j.ygyno.2008.08.017

  33. 33.

    Yin J et al (2017) Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer. PLoS ONE 12:e0172787. https://doi.org/10.1371/journal.pone.0172787

  34. 34.

    Xiao M et al (2017) Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair. J Ovarian Res 10:24. https://doi.org/10.1186/s13048-017-0321-8

  35. 35.

    Cai J et al (2013) Deregulation of let-7e in epithelial ovarian cancer promotes the development of resistance to cisplatin. Oncogenesis 2:e75. https://doi.org/10.1038/oncsis.2013.39

  36. 36.

    Yang N et al (2008) MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res 68:10307–10314. https://doi.org/10.1158/0008-5472.CAN-08-1954

  37. 37.

    Huang Y, Hong X, Hu J, Lu Q (2017) Targeted regulation of MiR-98 on E2F1 increases chemosensitivity of leukemia cells K562/A02. Onco Targets Ther 10:3233–3239. https://doi.org/10.2147/OTT.S126819

  38. 38.

    Zhang L et al (2008) Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. PNAS 105:7004–7009. https://doi.org/10.1073/pnas.0801615105

  39. 39.

    Shell S et al (2007) Let-7 expression defines two differentiation stages of cancer. PNAS 104:11400–11405. https://doi.org/10.1073/pnas.0704372104

  40. 40.

    Sun X et al (2016) Let-7c blocks estrogen-activated Wnt signaling in induction of self-renewal of breast cancer stem cells. Cancer Gene Ther 23:83–89. https://doi.org/10.1038/cgt.2016.3

  41. 41.

    Calatayud D et al (2017) Tissue MicroRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers. Biomark Res 5:8. https://doi.org/10.1186/s40364-017-0087-6

  42. 42.

    Chen KJ et al (2014) Reexpression of Let-7g microRNA inhibits the proliferation and migration via K-Ras/HMGA2/snail axis in hepatocellular carcinoma. Biomed Res Int 2014:742417. https://doi.org/10.1155/2014/742417

  43. 43.

    Tang Z, Ow GS, Thiery JP, Ivshina AV, Kuznetsov VA (2014) Meta-analysis of transcriptome reveals let-7b as an unfavorable prognostic biomarker and predicts molecular and clinical subclasses in high-grade serous ovarian carcinoma. Int J Cancer 134:306–318. https://doi.org/10.1002/ijc.28371

  44. 44.

    Zhao B et al (2014) MicroRNA let-7c inhibits migration and invasion of human non-small cell lung cancer by targeting ITGB3 and MAP4K3. Cancer Lett 342:43–51. https://doi.org/10.1016/j.canlet.2013.08.030

  45. 45.

    Ruzzo A et al (2012) High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease. Oncologist 17:823–829. https://doi.org/10.1634/theoncologist.2012-0081

  46. 46.

    Zhang W et al (2017) Androgen receptor/let-7a signaling regulates breast tumor- initiating cells. Oncotarget 9:3690–3703. https://doi.org/10.18632/oncotarget.23196

  47. 47.

    Takamizawa J et al (2004) Reduced expression of the let-7 MicroRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756. https://doi.org/10.1158/0008-5472.can-04-0637

  48. 48.

    Tang R et al (2016) MiR-let-7a inhibits cell proliferation, migration, and invasion by down-regulating PKM2 in gastric cancer. Oncotarget 7:5972–5984. https://doi.org/10.18632/oncotarget.6821

  49. 49.

    Peng F et al (2017) H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance. Cell Death Dis 8:e2569. https://doi.org/10.1038/cddis.2016.438

  50. 50.

    Ji J et al (2010) Let-7g targets collagen type I α2 and inhibits cell migration in hepatocellular carcinoma. J Hepatol 52:690–697. https://doi.org/10.1016/j.jhep.2009.12.025

  51. 51.

    Qian P et al (2011) Pivotal role of reduced let-7g expression in breast cancer invasion and metastasis. Cancer Res 71:6463–6474. https://doi.org/10.1158/0008-5472.CAN-11-1322

  52. 52.

    Yu F et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123. https://doi.org/10.1016/j.cell.2007.10.054

  53. 53.

    Lu L et al (2011) MicroRNA let-7a: a potential marker for selection of paclitaxel in ovarian cancer management. Gynecol Oncol 122:366–371. https://doi.org/10.1016/j.ygyno.2011.04.033

  54. 54.

    McGuire WP et al (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. NEJM 334:1–6. https://doi.org/10.1056/nejm199601043340101

  55. 55.

    Mitchison TJ (2012) The proliferation rate paradox in antimitotic chemotherapy. Mol Biol Cell 23:1–6. https://doi.org/10.1091/mbc.E10-04-0335

  56. 56.

    Sun X et al (2015) DICER1 regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1. J Cell Mol Med 19:1357–1365. https://doi.org/10.1111/jcmm.12522

  57. 57.

    Wu J et al (2015) Reduced Let-7a is associated with chemoresistance in primary breast cancer. PLoS ONE 10:e0133643. https://doi.org/10.1371/journal.pone.0133643

  58. 58.

    Nadiminty N et al (2012) MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. PLoS ONE 7:e32832. https://doi.org/10.1371/journal.pone.0032832

  59. 59.

    Dai X et al (2016) Combined delivery of Let-7b MicroRNA and paclitaxel via biodegradable nanoassemblies for the treatment of KRAS mutant cancer. Mol Pharm 13:520–533. https://doi.org/10.1021/acs.molpharmaceut.5b00756

  60. 60.

    Jin B et al (2016) Let-7 inhibits self-renewal of hepatocellular cancer stem-like cells through regulating the epithelial-mesenchymal transition and the Wnt signaling pathway. BMC Cancer 16:863. https://doi.org/10.1186/s12885-016-2904-y

  61. 61.

    Weidhaas JB et al (2007) MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res 67:11111–11116. https://doi.org/10.1158/0008-5472.CAN-07-2858

  62. 62.

    Chang CJ et al (2011) Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer. Oncol Rep 26:1003–1010. https://doi.org/10.3892/or.2011.1360

  63. 63.

    Xue F et al (2016) Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression. Onco Targets Ther 9:7253–7261. https://doi.org/10.2147/OTT.S116127

  64. 64.

    Sun H, Ding C, Zhang H, Gao J (2016) Let7 miRNAs sensitize breast cancer stem cells to radiationinduced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway. Mol Med Rep 14:3285–3292. https://doi.org/10.3892/mmr.2016.5656

  65. 65.

    Boyerinas B et al (2012) Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1. Int J Cancer 130:1787–1797. https://doi.org/10.1002/ijc.26190

  66. 66.

    Wu L et al (2015) Precise let-7 expression levels balance organ regeneration against tumor suppression. Elife 4:e09431. https://doi.org/10.7554/eLife.09431

  67. 67.

    Li Y, Zhang X, Chen D, Ma C (2016) Let-7a suppresses glioma cell proliferation and invasion through TGF-beta/Smad3 signaling pathway by targeting HMGA2. Tumour Biol 37:8107–8119. https://doi.org/10.1007/s13277-015-4674-6

  68. 68.

    Esquela-Kerscher A et al (2008) The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 7:759–764. https://doi.org/10.4161/cc.7.6.5834

  69. 69.

    Wang L et al (2016) Let-7a mimic attenuates CCL18 induced breast cancer cell metastasis through Lin 28 pathway. Biomed Pharmacother 78:301–307. https://doi.org/10.1016/j.biopha.2016.01.028

  70. 70.

    Wu A et al (2015) Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma. J Transl Med 13:105. https://doi.org/10.1186/s12967-015-0462-8

  71. 71.

    Xu X, Bao Z, Liu Y, Ji J, Liu N (2017) MicroRNA-98 attenuates cell migration and invasion in glioma by directly targeting pre-B cell leukemia homeobox 3. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-017-0466-4

  72. 72.

    Liu X, Zhang W, Guo H, Yue J, Zhuo S (2016) miR-98 functions as a tumor suppressor in salivary adenoid cystic carcinomas. Onco Targets Ther 9:1777–1786. https://doi.org/10.2147/OTT.S98534

  73. 73.

    Song H et al (2016) Let-7b inhibits the malignant behavior of glioma cells and glioma stem-like cells via downregulation of E2F2. J Physiol Biochem 72:733–744. https://doi.org/10.1007/s13105-016-0512-6

  74. 74.

    Ibarra I, Erlich Y, Muthuswamy SK, Sachidanandam R, Hannon GJ (2007) A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells. Genes Dev 21:3238–3243. https://doi.org/10.1101/gad.1616307

  75. 75.

    Schultz J, Lorenz P, Gross G, Ibrahim S, Kunz M (2008) MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth. Cell Res 18:549–557. https://doi.org/10.1038/cr.2008.45

  76. 76.

    Liu Y, Yin B, Zhang C, Zhou L, Fan J (2012) Hsa-let-7a functions as a tumor suppressor in renal cell carcinoma cell lines by targeting c-myc. Biochem Biophys Res Commun 417:371–375. https://doi.org/10.1016/j.bbrc.2011.11.119

  77. 77.

    Parisi S et al (2017) Lin28 is induced in primed embryonic stem cells and regulates let-7-independent events. FASEB J 31:1046–1058. https://doi.org/10.1096/fj.201600848R

  78. 78.

    Albino D et al (2016) Activation of the Lin28/let-7 axis by loss of ESE3/EHF promotes a tumorigenic and stem-like phenotype in prostate cancer. Cancer Res 76:3629–3643. https://doi.org/10.1158/0008-5472.CAN-15-2665

  79. 79.

    Yang X et al (2010) Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells. Cancer Res 70:9463–9472. https://doi.org/10.1158/0008-5472.CAN-10-2388

  80. 80.

    Chien CS et al (2015) Lin28B/Let-7 regulates expression of Oct4 and Sox2 and reprograms oral squamous cell carcinoma cells to a stem-like state. Cancer Res 75:2553–2565. https://doi.org/10.1158/0008-5472.CAN-14-2215

  81. 81.

    Subramanian M et al (2015) A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis. Oncogene 34:1094–1104. https://doi.org/10.1038/onc.2014.46

  82. 82.

    Zhong T et al (2017) Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene 36:2345–2354. https://doi.org/10.1038/onc.2016.391

  83. 83.

    Wang S, Li C, Wang W, Xing C (2016) PBX3 promotes gastric cancer invasion and metastasis by inducing epithelial-mesenchymal transition. Oncol Lett 12:3485–3491. https://doi.org/10.3892/ol.2016.5305

  84. 84.

    Ning Y, Xu M, Cao X, Chen X, Luo X (2017) Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity. Oncol Rep 38:949–958. https://doi.org/10.3892/or.2017.5709

  85. 85.

    Zhang Z et al (2016) Let-7a suppresses macrophage infiltrations and malignant phenotype of Ewing sarcoma via STAT3/NF-kappaB positive regulatory circuit. Cancer Lett 374:192–201. https://doi.org/10.1016/j.canlet.2016.02.027

  86. 86.

    Bosch-Barrera J, Queralt B, Menendez JA (2017) Targeting STAT3 with silibinin to improve cancer therapeutics. Cancer Treat Rev 58:61–69. https://doi.org/10.1016/j.ctrv.2017.06.003

  87. 87.

    Tabatabai R, Linhares Y, Bolos D, Mita M, Mita A (2017) Targeting the Wnt pathway in cancer: a review of novel therapeutics. Target Oncol. https://doi.org/10.1007/s11523-017-0507-4

  88. 88.

    Bilyk O, Coatham M, Jewer M, Postovit LM (2017) Epithelial-to-mesenchymal transition in the female reproductive tract: from normal functioning to disease pathology. Front Oncol 7:145. https://doi.org/10.3389/fonc.2017.00145

  89. 89.

    Boyerinas B et al (2008) Identification of Let-7-regulated oncofetal genes. Can Res 68:2587–2591. https://doi.org/10.1158/0008-5472.can-08-0264

  90. 90.

    Staropoli N et al (2018) The Era of PARP inhibitors in ovarian cancer: “Class Action” or not? A systematic review and meta-analysis. Crit Rev Oncol Hematol 131:83–89. https://doi.org/10.1016/j.critrevonc.2018.08.011

  91. 91.

    Mitra D, Das PM, Huynh FC, Jones FE (2011) Jumonji/ARID1 B (JARID1B) protein promotes breast tumor cell cycle progression through epigenetic repression of microRNA let-7e. J Biol Chem 286:40531–40535. https://doi.org/10.1074/jbc.M111.304865

  92. 92.

    Gambardella G et al (2017) The impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells. Nat Commun 8:14126. https://doi.org/10.1038/ncomms14126

  93. 93.

    Spolverini A, Fuchs G, Bublik DR, Oren M (2017) let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery. Oncogene. https://doi.org/10.1038/onc.2017.187

  94. 94.

    Lu L, Katsaros D, de la Longrais IA, Sochirca O, Yu H (2007) Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Cancer Res 67:10117–10122. https://doi.org/10.1158/0008-5472.CAN-07-2544

  95. 95.

    Brueckner B et al (2007) The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res 67:1419–1423. https://doi.org/10.1158/0008-5472.CAN-06-4074

  96. 96.

    Shi W et al (2017) Overexpression of microRNA let-7 correlates with disease progression and poor prognosis in hepatocellular carcinoma. Medicine (Baltimore) 96:e7764. https://doi.org/10.1097/md.0000000000007764

  97. 97.

    Ma J et al (2017) ZEB1 induced miR-99b/let-7e/miR-125a cluster promotes invasion and metastasis in esophageal squamous cell carcinoma. Cancer Lett 398:37–45. https://doi.org/10.1016/j.canlet.2017.04.006

  98. 98.

    An G et al (2010) Loss of bright/ARID3a function promotes developmental plasticity. Stem Cells 28:1560–1567. https://doi.org/10.1002/stem.491

  99. 99.

    Hilly O et al (2016) Distinctive pattern of let-7 family microRNAs in aggressive carcinoma of the oral tongue in young patients. Oncol Lett 12:1729–1736. https://doi.org/10.3892/ol.2016.4892

  100. 100.

    Wang Y et al (2018) miR-98-5p contributes to cisplatin resistance in epithelial ovarian cancer by suppressing miR-152 biogenesis via targeting Dicer1. Cell Death Dis 9:447. https://doi.org/10.1038/s41419-018-0390-7

  101. 101.

    Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931–1934. https://doi.org/10.1126/science.1149460

  102. 102.

    Baer C et al (2016) Suppression of microRNA activity amplifies IFN-gamma-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol 18:790–802. https://doi.org/10.1038/ncb3371

  103. 103.

    Wang YD et al (2013) OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis 4:e760. https://doi.org/10.1038/cddis.2013.272

  104. 104.

    Saleh AD et al (2011) Cellular stress induced alterations in microRNA let-7a and let-7b expression are dependent on p53. PLoS ONE 6:e24429. https://doi.org/10.1371/journal.pone.0024429

  105. 105.

    Wang Z et al (2011) MYC protein inhibits transcription of the microRNA cluster MC-let-7a-1–let-7d via noncanonical E-box. J Biol Chem 286:39703–39714. https://doi.org/10.1074/jbc.M111.293126

  106. 106.

    Yang WH et al (2012) RAC1 activation mediates Twist1-induced cancer cell migration. Nat Cell Biol 14:366–374

  107. 107.

    Liu J, Ni S (2017) Association between genetic polymorphisms in the promoters of let-7 and risk of cervical squamous cell carcinoma. Gene. https://doi.org/10.1016/j.gene.2017.11.038

  108. 108.

    Ooki A et al (2017) YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-17-0836

  109. 109.

    Cisneros-Soberanis F, Andonegui MA, Herrera LA (2016) miR-125b-1 is repressed by histone modifications in breast cancer cell lines. Springerplus 5:959. https://doi.org/10.1186/s40064-016-2475-z

  110. 110.

    Viswanathan SR, Daley GQ, Gregory RI (2008) Selective blockade of microRNA processing by Lin28. Science 320:97–100. https://doi.org/10.1126/science.1154040

  111. 111.

    Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P (2011) Molecular basis for interaction of let-7 microRNAs with Lin28. Cell 147:1080–1091. https://doi.org/10.1016/j.cell.2011.10.020

  112. 112.

    Faehnle CR, Walleshauser J, Joshua-Tor L (2017) Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis. Nat Struct Mol Biol 24:658–665. https://doi.org/10.1038/nsmb.3428

  113. 113.

    Piskounova E et al (2011) Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 147:1066–1079. https://doi.org/10.1016/j.cell.2011.10.039

  114. 114.

    Rahkonen N et al (2016) Mature Let-7 miRNAs fine tune expression of LIN28B in pluripotent human embryonic stem cells. Stem Cell Res 17:498–503. https://doi.org/10.1016/j.scr.2016.09.025

  115. 115.

    Zhu H et al (2011) The Lin28/let-7 axis regulates glucose metabolism. Cell 147:81–94. https://doi.org/10.1016/j.cell.2011.08.033

  116. 116.

    Balzer E, Heine C, Jiang Q, Lee VM, Moss EG (2010) LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development 137:891–900. https://doi.org/10.1242/dev.042895

  117. 117.

    Polesskaya A et al (2007) Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes Dev 21:1125–1138. https://doi.org/10.1101/gad.415007

  118. 118.

    Takahashi S, Kobayashi S, Hiratani I (2018) Epigenetic differences between naive and primed pluripotent stem cells. Cell Mol Life Sci 75:1191–1203. https://doi.org/10.1007/s00018-017-2703-x

  119. 119.

    Iliopoulos D, Hirsch HA, Struhl K (2009) An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139:693–706. https://doi.org/10.1016/j.cell.2009.10.014

  120. 120.

    Liu X et al (2017) Extracellular signal-regulated Kinases (ERKs) phosphorylate Lin28a protein to modulate P19 cell proliferation and differentiation. J Biol Chem 292:3970–3976. https://doi.org/10.1074/jbc.C117.775122

  121. 121.

    Tsanov KM et al (2017) LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency. Nat Cell Biol 19:60–67. https://doi.org/10.1038/ncb3453

  122. 122.

    Krell J et al (2016) TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network. Genome Res 26:331–341. https://doi.org/10.1101/gr.191759.115

  123. 123.

    Lee JY et al (2013) Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells. Nucleic Acids Res 41:5614–5625. https://doi.org/10.1093/nar/gkt222

  124. 124.

    Zipeto MA et al (2016) ADAR1 activation drives leukemia stem cell self-renewal by impairing Let-7 biogenesis. Cell Stem Cell 19:177–191. https://doi.org/10.1016/j.stem.2016.05.004

  125. 125.

    Sureban SM et al (2009) Selective blockade of DCAMKL-1 results in tumor growth arrest by a Let-7a MicroRNA-dependent mechanism. Gastroenterology 137:649–659, 659 e641–642, https://doi.org/10.1053/j.gastro.2009.05.004

  126. 126.

    Chen PS et al (2011) miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans. J Clin Invest 121:3442–3455. https://doi.org/10.1172/JCI45390

  127. 127.

    Fu Z et al (2017) Endogenous miRNA Sponge LincRNA-ROR promotes proliferation, invasion and stem cell-like phenotype of pancreatic cancer cells. Cell Death Discov 3:17004. https://doi.org/10.1038/cddiscovery.2017.4

  128. 128.

    Liu Q et al (2017) LncRNA RSU1P2 contributes to tumorigenesis by acting as a ceRNA against let-7a in cervical cancer cells. Oncotarget 8:43768–43781. https://doi.org/10.18632/oncotarget.10844

  129. 129.

    Maldotti M et al (1859) The long intergenic non-coding RNA CCR142 functions as a let-7 competitive endogenous RNA to regulate c-Myc expression. Biochim Biophys Acta 1322–1332:2016. https://doi.org/10.1016/j.bbagrm.2016.06.010

  130. 130.

    Degrauwe N et al (2016) The RNA binding protein IMP2 preserves glioblastoma stem cells by preventing let-7 target gene silencing. Cell Rep 15:1634–1647. https://doi.org/10.1016/j.celrep.2016.04.086

  131. 131.

    Wu L et al (2015) MicroRNA let-7g and let-7i inhibit hepatoma cell growth concurrently via downregulation of the anti-apoptotic protein B-cell lymphoma-extra large. Oncol Lett 9:213–218. https://doi.org/10.3892/ol.2014.2706

  132. 132.

    Gaeta X, Le L, Lin Y, Xie Y, Lowry WE (2017) Defining transcriptional regulatory mechanisms for primary let-7 miRNAs. PLoS ONE 12:e0169237. https://doi.org/10.1371/journal.pone.0169237

  133. 133.

    Triboulet R, Pirouz M, Gregory RI (2015) A single Let-7 MicroRNA bypasses LIN28-mediated repression. Cell Rep 13:260–266. https://doi.org/10.1016/j.celrep.2015.08.086

  134. 134.

    Chung YW et al (2013) Detection of microRNA as novel biomarkers of epithelial ovarian cancer from the serum of ovarian cancer patients. Int J Gynecol Cancer 23:673–679. https://doi.org/10.1097/IGC.0b013e31828c166d

  135. 135.

    Langhe R et al (2015) A novel serum microRNA panel to discriminate benign from malignant ovarian disease. Cancer Lett 356:628–636. https://doi.org/10.1016/j.canlet.2014.10.010

  136. 136.

    Yu S et al (2012) Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab 97:2084–2092. https://doi.org/10.1210/jc.2011-3059

  137. 137.

    Jayaraman M et al (2017) Identification of novel diagnostic and prognostic miRNA signatures in endometrial cancer. Genes Cancer 8:566–576. https://doi.org/10.18632/genesandcancer.144

  138. 138.

    Kang M et al (2017) Concurrent treatment with simvastatin and NF-kappaB inhibitor in human castration-resistant prostate cancer cells exerts synergistic anti-cancer effects via control of the NF-kappaB/LIN28/let-7 miRNA signaling pathway. PLoS ONE 12:e0184644. https://doi.org/10.1371/journal.pone.0184644

  139. 139.

    Kong D et al (2012) Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS ONE 7:e33729. https://doi.org/10.1371/journal.pone.0033729

  140. 140.

    Dahiya N et al (2008) MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS ONE 3:e2436. https://doi.org/10.1371/journal.pone.0002436

  141. 141.

    Yang H et al (2008) MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 68:425–433. https://doi.org/10.1158/0008-5472.CAN-07-2488

  142. 142.

    Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21:1025–1030. https://doi.org/10.1101/gad.1540407

  143. 143.

    Moore JC et al (2013) Post-transcriptional mechanisms contribute to Etv2 repression during vascular development. Dev Biol 384:128–140. https://doi.org/10.1016/j.ydbio.2013.08.028

  144. 144.

    Zhang X et al (2017) MYC is downregulated by a mitochondrial checkpoint mechanism. Oncotarget 8:90225–90237. https://doi.org/10.18632/oncotarget.21653

  145. 145.

    Colas AR et al (2012) Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis. Genes Dev 26:2567–2579. https://doi.org/10.1101/gad.200758.112

  146. 146.

    Pobezinsky LA et al (2015) Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nat Immunol 16:517–524. https://doi.org/10.1038/ni.3146

  147. 147.

    Johnson SM et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647. https://doi.org/10.1016/j.cell.2005.01.014

  148. 148.

    Peng F et al (2017) Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene. https://doi.org/10.1038/onc.2017.368

  149. 149.

    Zhou J et al (2017) Inhibition of LIN28B impairs leukemia cell growth and metabolism in acute myeloid leukemia. J Hematol Oncol 10:138. https://doi.org/10.1186/s13045-017-0507-y

  150. 150.

    Shen G et al (2014) Upstream and downstream mechanisms for the promoting effects of IGF-1 on differentiation of spermatogonia to primary spermatocytes. Life Sci 101:49–55. https://doi.org/10.1016/j.lfs.2014.02.016

  151. 151.

    Liu Y et al (2019) Lin28 promotes dental pulp cell proliferation via upregulation of cyclin-dependent proteins and interaction with let-7a/IGF2BP2 pathways. Biomed Pharmacother 113:108742. https://doi.org/10.1016/j.biopha.2019.108742

  152. 152.

    Wang Y et al (2018) MicroRNA hsa-let-7b suppresses the odonto/osteogenic differentiation capacity of stem cells from apical papilla by targeting MMP1. J Cell Biochem 119:6545–6554. https://doi.org/10.1002/jcb.26737

  153. 153.

    Li S et al (2015) Let-7 microRNAs regenerate peripheral nerve regeneration by targeting nerve growth factor. Mol Ther 23:423–433. https://doi.org/10.1038/mt.2014.220

  154. 154.

    Wang X et al (2019) The microRNAs let-7 and miR-9 down-regulate the axon-guidance genes Ntn1 and Dcc during peripheral nerve regeneration. J Biol Chem 294:3489–3500. https://doi.org/10.1074/jbc.RA119.007389

  155. 155.

    Lin S et al (2012) Let-7b regulates the expression of the growth hormone receptor gene in deletion-type dwarf chickens. BMC Genomics 13:306. https://doi.org/10.1186/1471-2164-13-306

  156. 156.

    Chen KC et al (2011) Negative feedback regulation between microRNA let-7 g and the oxLDL receptor LOX-1. J Cell Sci 124:4115–4124. https://doi.org/10.1242/jcs.092767

  157. 157.

    Lee YT et al (2013) LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo. Blood 122:1034–1041. https://doi.org/10.1182/blood-2012-12-472308

  158. 158.

    Bronevetsky Y, Burt TD, McCune JM (2016) Lin28b regulates fetal regulatory T cell differentiation through modulation of TGF-beta signaling. J Immunol 197:4344–4350. https://doi.org/10.4049/jimmunol.1601070

  159. 159.

    Strubberg AM et al (2018) The zinc finger transcription factor PLAGL2 enhances stem cell fate and activates expression of ASCL2 in intestinal epithelial cells. Stem Cell Rep 11:410–424. https://doi.org/10.1016/j.stemcr.2018.06.009

  160. 160.

    Han X, Zhang JJ, Han ZQ, Zhang HB, Wang ZA (2018) Let-7b attenuates cisplatin resistance and tumor growth in gastric cancer by targeting AURKB. Cancer Gene Ther. https://doi.org/10.1038/s41417-018-0048-8

  161. 161.

    Ooki A et al (2018) YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells. Cancer Res 78:168–181. https://doi.org/10.1158/0008-5472.CAN-17-0836

  162. 162.

    Chou CH et al (2013) Chromosome instability modulated by BMI1-AURKA signaling drives progression in head and neck cancer. Cancer Res 73:953–966. https://doi.org/10.1158/0008-5472.CAN-12-2397

  163. 163.

    Tzatsos A et al (2011) Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells. J Biol Chem 286:33061–33069. https://doi.org/10.1074/jbc.M111.257667

  164. 164.

    Guan H et al (2011) Characterization and functional analysis of the human microRNA let-7a2 promoter in lung cancer A549 cell lines. Mol Biol Rep 38:5327–5334. https://doi.org/10.1007/s11033-011-0683-8

  165. 165.

    Wang DJ, Legesse-Miller A, Johnson EL, Coller HA (2012) Regulation of the let-7a-3 promoter by NF-κB. PLoS ONE. https://doi.org/10.1371/journal.pone.0031240

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Acknowledgements

We acknowledge support from the LLU Center for Health Disparities and Molecular Medicine. EC was supported by the LLU Division of Anatomy. We are grateful to John Powers and Hao Zhu for critical review of the manuscript, and to members of the Unternaehrer lab for helpful discussions.

Funding

This work was supported by Loma Linda University School of Medicine, Grants to Promote Collaboration and Translation, and by the Department of Pathology and Human Anatomy.

Author information

EC and JJU performed the literature review and analyzed the data that informed this review, and drafted the review. All authors contributed to the writing of the review. All authors read and approved the final manuscript.

Correspondence to Juli J. Unternaehrer.

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Keywords

  • microRNA
  • Cancer
  • Gene regulation
  • Biomarker
  • Therapeutics
  • Tumor suppressor