Abstract
AGO1 is a major component of RNA-induced silencing complexes and plays a crucial role in solid tumors. The aim of our study was to investigate AGO1 functions in hepatocellular carcinoma (HCC). Using small interfering RNA, AGO1 functions were investigated in HCCLM3 cell lines. Cell proliferation, immigration, and invasion significantly decreased after AGO1 depletion using MTT, wound-healing, and transwell assay. The associated proteins in the epithelial–mesenchymal transition (EMT) and the activation of its signal pathways were measured using western blot. After AGO1 depleted, increased E-cadherin and decreased N-cadherin, Vimentin, Snail, and Zeb1 were founded. In its upstream pathway, the phosphorylation of ERK1/2(Thr202/Tyr204), Smad2(S425/250/255), and Smad4 were significantly inhibited. Meanwhile, inhibitor of ERK1/2(LY3214996) significantly inhibited the growth and migration of the AGO1 cells. The nuclear importing of Smad4 was blocked and furthermore, the transcription of Snail was also influenced for the decrease of combination between Smad4 and the promotor region of Snail. After Snail was overexpressed, the invasion of HCCLM3 cells was significantly rescued. Immunohistochemistry in tissue microarrays consisting of 200 HCC patients was used to analyze the associations between AGO1 expression and prognosis. Intratumoral AGO1 expression was an independent risk factor for overall survival (P = 0.008) and recurrence-free survival (P < 0.001). In conclusion, AGO1 may promote HCC metastasis through TGF-β pathway, and AGO1 may be a reliable prognostic factor in HCC.
Highlights
Liver cancer is the second leading cause of cancer death worldwide and in less-developed countries and the sixth leading cause of cancer death in more-developed countries among men
Dicer is downregulated in hepatocellular carcinoma (HCC) intratumoral tissues, and we have shown that Hiwi is associated with HCC metastatic potential and prognosis in patients with HCC16,19
Systematic study concerning the role of AGO1 in HCC progression and prognosis has not been reported, with a large number of patients and long-term follow-up
Summary
Liver cancer is the second leading cause of cancer death worldwide and in less-developed countries and the sixth leading cause of cancer death in more-developed countries among men. During 2012, an estimated 782 500 new liver cancer cases and 745 500 deaths occurred worldwide, with China alone accounting for about 50% of the total number of cases and deaths. Most (70–90%) primary liver cancers occurring worldwide are hepatocellular carcinoma (HCC)[1,2]. The high postsurgical recurrence rate is a major problem, HCC patients undergoing curative resection have a poor outcome.
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