| Abstract:Hepatocellular carcinoma (HCC) is one of the most common human cancers in the world, particularly in China. It ranks as the second leading cause for cancer death of men and the sixth of women worldwide. Although its mortality decreased along with the advancement of surgical resection, the long-term prognosis remains unsatisfactory. For example, the5-year survival rate is only30to40%in HCC patients after surgical resection, mainly due to the high recurrence and metastasis rate. Therefore, it is of great importance to clarify the molecular mechanisms of the carcino-genesis and progression process of HCC.MicroRNAs (miRNAs) are a class of small, endogenously expressed, well-conserved noncoding RNA molecules with18-25nucleotides (nt). They play important regulatory roles by targeting mRNAs for cleavage or translational repression. Given that more than50%of miRNAs are located in cancer-associated genomic regions or in fragile sites, miRNAs may play an important role in cancer pathogenesis. Indeed, aberrant miRNA expression has been demonstrated in HCC, which contributes to carcinogenesis and cancer development by promoting oncogene expression or by inhibiting tumor suppressor genes.Previously, we have found a specific subtype of HCC, which was characterized as solitary large hepatocellular carcinoma (SLHCC). Accordingly, we classified HCC into3independent subtypes:SLHCC, small HCC (SHCC) and nodular HCC (NHCC). Further study had confirmed that SLHCC had unique clinical and pathological chara-cteristics, and its metastasis potential was comparable with SHCC, but significantly lower than NHCC. After hepatic resection, SLHCC exhi-bited a similar long-time overall and disease-free survival with SHCC, but was much better than NHCC.Thus, to further demonstrate whether miRNAs can be served as promising prognostic markers for HCC and dissect their implication in HCC invasion and metastasis, we profiled miRNA expressions by analysis of840mammalian miRNAs in hepatocellular carcinoma from30HCC samples. miR-140-5p was identified to be significantly down-regulated in HCC tissues as compared with that of adjacent nontumorous liver tissues (ANLTs, P<0.05). However, miR-140-5p displayed similar expression levels between SLHCC and SHCC, but much lower levels of miR-140-5p was noted in NHCC (P<0.05). By comparing the expression profiles of miRNAs in different HCC subtypes, we identified miR-140-5p as a HCC related miRNA. We found that miR-140-5p was significantly decreased in HCC tissues and all of six liver cancer cell lines (P<0.05). In addition, its expression levels were correlated with multiple nodules, vein invasion, capsular formation, and differentiation, as well as overall and disease-free survival of HCC (P<0.05). We also found that miR-140-5p suppressed HCC cell proliferation and HCC metastasis in vivo and in vitro. Multi-pathway reporter arrays suggested that miR-140-5p inhibited TGF-β and MAPK/ERK signaling. TGFBR1and FGF9were then characterized as the direct targets for miR-140-5p as manisfested by that ectopic miR-140-5p expression suppressed TGFBR1and FGF9expressions. Silencing TGFBR1and FGF9by siRNA resembled phenotype resulted from ectopic miR-140-5p expression, while overexpression of TGFBR1and FGF9attenuated the effect of miR-140-5p on HCC growth and metastasis. Together, our data elucidated a tumor suppressor role for miR-140-5p in HCC development and progression with therapeutic potential. Our correlation studies in clinical HCC samples further suggest that miR-140-5p could be a valuable biomarker for HCC prognosis. |
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