Let-7 inhibits self-renewal of hepatocellular cancer stem-like cells through regulating the epithelial-mesenchymal transition and the Wnt signaling pathway

Abstract

BackgroundTumor suppressive let-7 miRNAs are universally down-regulated in human hepatocellular carcinoma (HCC) versus normal tissues; however, the roles and related molecular mechanisms of let-7 in HCC stem cells are poorly understood.MethodsWe examined the inhibitory effect of let-7 miRNAs on the proliferation of MHCC97-H and HCCLM3 hepatic cancer cells by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, which was further confirmed by apoptosis and cell cycle studies. The sphere-forming assay was used to study the effects of let-7a on stem like cells. Through western blot, immunofluorescence and the luciferase-reporter assay, we explored the activity of epithelial-mesenchymal transition (EMT) signaling factors in HCC cells. qRT-PCR was applied to detect miRNA expression levels in clinical tissues.ResultsLet-7a effectively repressed cell proliferation and viability, and in stem-like cells, also let-7a decreased the efficiency of sphere formation.in stem-like cells. The suppression of EMT signaling factors in HCC cells contributed to let-7’s induced tumor viability repression and Wnt activation repression. Besides, Wnt1 is critical and essential for let-7a functions, and the rescue with recombinant Wnt1 agent abolished the suppressive roles of let-7a on hepatospheres. In clinical HCC and normal tissues, let-7a expression was inversely correlated with Wnt1 expression.ConclusionsLet-7 miRNAs, especially let-7a, will be a promising therapeutic strategy in the treatment of HCC through eliminating HCC stem cells, which could be achieved by their inhibitory effect on the Wnt signaling pathway.

Analysis of Let-7 Family miRNA in Plasma as Potential Predictive Biomarkers of Diagnosis for Papillary Thyroid Cancer

“…However, there is some evidence that, probably due to unique target preferences, different members of the let-7 family do have different roles, and thus cannot be considered as one. It has been verified that overexpression of different let-7 family members affects cell viability on different levels in hepatocellular carcinoma [34]. Our ROC analysis has shown that structurally related let-7c and let-7f have similar sensitivity and specificity, as do let-7a and let-7d.…”

Targeting Pin1 by inhibitor API‐1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development

“…E; http://onlinelibrary.wiley.com/doi/10.1002/hep.29819/suppinfo), which are sensitive to Pin1/pXPO5‐mediated miRNA biogenesis. Both miR‐122 and let‐7a have the ability to induce cell cycle arrest by increasing cell number in S phase, providing a possible explanation for API‐1‐induced S‐phase block in these cells.…”

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

“…This points to potential tumor-suppressive functions that are lost during cancer development. Overexpression of let-7a in HCC cells decreased cell viability and promoted an epithelial-like phenotype, which decreased sphere formation and prohibited the self-renewal ability of HCC stem-like cells by affecting the Wnt signaling pathway [134]. Furthermore, overexpression of let-7a improved In melanoma, it has been shown that experimental overexpression of let-7a interferes with cancer cell invasiveness via downregulation of integrin β3 [92] (Figure 3).…”