Abstract
Metastasis is the major reason for the death of patients suffering from malignant diseases such as human hepatocellular carcinoma (HCC). Among the complex metastatic process, resistance to anoikis is one of the most important steps. Previous studies demonstrate that microRNA-26a (miR-26a) is an important tumor suppressor that inhibits the proliferation and invasion of HCC cells by targeting multiple oncogenic proteins. However, whether miR-26a can also influence anoikis has not been well established. Here, we discovered that miR-26a promotes anoikis of HCC cells both in vitro and in vivo. With a combinational analysis of bioinformatics and public clinical databases, we predicted that alpha5 integrin (ITGA5), an integrin family member, is a putative target of miR-26a. Furthermore, we provide experimental evidence to confirm that ITGA5 is a bona fide target of miR-26a. Through gain- and loss-of-function studies, we demonstrate that ITGA5 is a functional target of miR-26a-induced anoikis in HCC cells. Collectively, our findings reveal that miR-26a is a novel player during anoikis and a potential therapeutic target for the treatment of metastatic HCC.
Highlights
Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers with continuously rising incidence and a 5-year survival rate of less than 12% [1, 2]
To further confirm whether miR-26a is associated with metastasis of HCC, a normalized Gene Expression Omnibus (GEO) dataset (GSE6857) was analyzed
Our results suggest that reduction of ITGA5 levels has similar effects on the HCC cells to miR-26a overexpression, further confirming that ITGA5 may act as a downstream functional mediator www.impactjournals.com/oncotarget of miR-26a during tumor cell anoikis
Summary
Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers with continuously rising incidence and a 5-year survival rate of less than 12% [1, 2]. The aberrant high activity of multiple signaling pathways, including integrin signaling pathway has been demonstrated to be required www.impactjournals.com/oncotarget to prevent anoikis in tumor cells [7, 8]. Blockage of anti-anoikis activity of tumor cells has been shown to be beneficial for the treatment of metastatic diseases [6, 7]. 18 α and 8 β subunits associate in various combinations to form 24 integrins. They transmit signals to exert a stringent control on cell survival, proliferation, adhesion and migration [9]. Recently, it has been demonstrated that the aberrantly high activation of integrins plays a critical role for metastasis of human hepatocellular carcinoma cells [10]
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