Identification of miRNomes in Human Liver and Hepatocellular Carcinoma Reveals miR-199a/b-3p as Therapeutic Target for Hepatocellular Carcinoma

Abstract

The full scale of human miRNome in specific cell or tissue, especially in cancers, remains to be determined. An in-depth analysis of miRNomes in human normal liver, hepatitis liver, and hepatocellular carcinoma (HCC) was carried out in this study. We found nine miRNAs accounted for ∼88.2% of the miRNome in human liver. The third most highly expressed miR-199a/b-3p is consistently decreased in HCC, and its decrement significantly correlates with poor survival of HCC patients. Moreover, miR-199a/b-3p can target tumor-promoting PAK4 to suppress HCC growth through inhibiting PAK4/Raf/MEK/ERK pathway both in vitro and in vivo. Our study provides miRNomes of human liver and HCC and contributes to better understanding of the important deregulated miRNAs in HCC and liver diseases.

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…Since the downregulation of let-7c and miR-200b and the upregulation of miR-222 were found extensively in HCC cells [40][41][42] , the fact that most HCC cells remain a2d1-negative led us to propose that miR-222 could rescue the effects of let-7c/miR-200b down-regulation on the expression of PBX3 and a2d1 in HCC cells. To test this hypothesis, we overexpressed miR-222 in Huh7 cells with let-7c and miR-200b knocked down simultaneously by respective Tud RNAs.…”

MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers

“…Recently, compelling evidence has shown that miRNAs exert significant impacts on the migration, invasion and metastasis of human cancers, and even demonstrates that miRNAs have the therapeutic potential. 34 However, only a few miRNAs (miR-218, 15 miR-516a-3p, 16 miR-107, 35 Let-7f 18 ) have been reported to be involved in the metastasis of GC. So identifying more miRNAs related to GC metastasis is important for clarifying the complicated mechanisms underlying GC metastasis.…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…Elevating levels of miR-199a reduce the amount of cells in G1 phase of the cell cycle with subsequent reduction of invasive potential, and increase the susceptibility to hypoxia and the sensitivity of doxorubicin-induced apoptosis. Probably, the action of this miRNA is on Discoidin domain receptor-1 (DDR1) tyrosine kinase, a protein that increases the cell invasiveness (Shen et al, 2010) and perhaps also on CD44, increasing the sensitivity of neoplastic cells to doxorubicin (Henry et al, 2010), and PAK4, a protein that inhibits the PAK4/Raf/MEK/ERK cascade by reducing cell proliferation (Hou et al, 2011). Furthermore, Song and colleagues showed that miR199a modulates the survival and cell proliferation by targeting Frizzled type 7 receptor (FZD7), the most important Wnt receptor involved in cancer development and progression .…”