The insights of Let-7 miRNAs in oncogenesis and stem cell potency

Abstract

The ability of the classic tumour-suppressive let-7 family to inhibit carcinogenesis, tumour progression, recurrence and pluripotency of cancer stem cells has generated significant interest in the field of cancer research. Through suppressing and degrading downstream-targeted mRNAs, let-7 affected most aspects of cell biology. It is perplexing how let-7 affects oncogenesis, as the large influx of new miRNAs and other kinds of non-coding RNAs are continuously defined. In this review, we delineate the complex functions of let-7 and discuss the future direction of let-7 research.

Keywords: DNA methylation; Let-7 miRNAs; anti-cancer research; cancer stem cells; clinical application; non-coding RNAs; regulatory loops.

Figure 1

The regulatory functions and mechanisms of let‐7 in cell biology. Let‐7 is involved in multiple intracellular and extracellular functions through targeting and degrading the 3′UTR of certain mRNAs. Moreover, the feedback regulatory loops between let‐7 and its targeted genes constitute a more complicated and interesting network, centering on let‐7. Intracellular let‐7 may be also secreted to affect adjacent cells, exerting multiple effects.

Figure 2

The regulations of self‐renewal and let‐7 involved stem cell generation. Asymmetric division type helps maintain a balance of primary stem cells and differentiated cells, resulting in two unequal daughter cells, one of which resembles the parent stem cell, with another differentiating into distinct cell types. Cell determinants were segregated to the cytoplasm of one daughter cell differently, associated with membranes, and centrosome of other constituents. Symmetric cell division types made stem cells divide symmetrically, producing two stem cell daughters and expanding the stem cell numbers. The stem cells transmit amplifying progenitors, and well differentiated cells could be reprogrammed when they are triggered by cytokines, signals, transcription factors and micro‐environmental niches. Let‐7 could function in influencing some key factors related to division types.

Figure 3

TP53 dominated cell polarity direction. P53 was used as an example to illustrate the functions of genes and signalling pathways in stem cell division, which is regulated mainly by E3 ubiquitin ligase, functioning in Notch signalling. As post‐transcriptional regulators, let‐7 and many miRNAs could probably make similar functions through regulating mRNAs implicated in this process, with specific roles determined in different situations.

Figure 4

Methylation–miRNA regulatory loop. EpimiRNAs regulate whole gene expression patterns and some methylation‐associated regulators, such as DNMTs and TETs, by which epimiRNAs can regulate genomic DNA methylation levels. CpG island methylation status can regulate gene expression containing some miRNAs, such as let‐7a‐3, which can regulate other miRNA family members through DICER.