miR-125/Pokemon auto-circuit contributes to the progression of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a type of human malignant tumor occurring in hepatic tissues with high mortality. Patients benefit little from current therapeutic modalities, at least partially due to the lack of complete elucidation of molecular network regulating HCC. miR-125 and Pokemon are well-recognized tumor suppressor and oncogenes for HCC, respectively. However, the underlying mechanism by which the two genes exert their functions and the relationship between miR-125 and Pokemon is still unexplored yet. In this study, we found that there is an inverse association between miR-125 and Pokemon expression levels in HCC specimen and cell lines. Online database mining indicated that there are three putative mRNA recognition elements (MREs) of miR-125 within 3' untranslated region (3'UTR) of Pokemon. MREs of miR-125 confer the expression of luciferase with a miR-125-dependent fashion. The alteration in miR-125 abundance regulates the expression of Pokemon at both protein and mRNA levels. Overexpression of Pokemon is able to abrogate the inhibitory effect of miR-125 on HCC progression. Further study showed that Pokemon inhibits the expression of miR-125 by binding of recognition sites within its promoter. In conclusion, we found that there is an auto-regulatory circuit consisting of miR-125 and Pokemon, which promotes the progression of HCC and may be a promising therapeutic target in clinical HCC treatment.

Molecular mechanisms governing microRNA-125a expression in human hepatocellular carcinoma cells

“…Few miRNAs have been shown to play an oncosuppressive role in HCC 39 , 40 . Among them, miR-125a inhibits cell proliferation, angiogenesis and cell migration by downregulating the expression of sirtuin-7 34 , vascular endothelial growth factor A, matrix metalloproteinase-11 35 , Zbtb7a 41 , and c-RAF 42 . Targeting of Bcl2 and caspase 3 may also be relevant for the antiangiogenic activity 43 of the miRNA.…”

Epithelialization of mouse ovarian tumor cells originating in the fallopian tube stroma

“…Our finding is consistent with the report by Chen et al [ 22 ] that cancer cells harboring Dicer1 hotspot mutants that had lost 5p miRNA biogenesis, showed increased proliferation rate and upregulated expression of cell cycle promoting genes compared to cancer cells with wild-type Dicer1 , suggesting the tumor-suppressing effect of Dicer1 in wild-type cells. Similar to the Dicer1 hotspot mutant cells, the Dicer-Pten DKO mouse tumor cells showed significant reduced expression of miRNAs such as let-7 and miR-125 (Figure 3B ), which have been shown to harbor tumor suppressor functions [ 22 , 41 ].…”

miR125-Centered ceRNETs in Breast Cancer. Clinical, Molecular and Ethical Aspects in Personalized Medicine

“…In hepatocellular carcinoma (HCC) it has been shown that the ectopic expression of miR-125a inhibits proliferation and metastasis by targeting MMP11 and VEGF [133], while others showed that ectopic expression of miR-125b reduces the cellular proliferation and cell cycle progression of HCC cells by targeting Mcl-1 and IL6R [134]. In another study the authors showed that miR-125b suppresses human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2 [135]. Additional miR-125 interactors in HCC had been identified in the years, including Pokemon [136], TRAF6 [137], hexokinase II [138] and FOXM1 [139].…”