HOTAIR/miR-1277-5p/ZEB1 axis mediates hypoxia-induced oxaliplatin resistance via regulating epithelial-mesenchymal transition in colorectal cancer

The hypoxic microenvironment contributes to the chemoresistance of many malignant tumors including colorectal cancer (CRC). Accumulating studies have indicated that long non-coding RNAs (lncRNAs) play important roles in chemotherapy resistance. In this study, we aimed to determine the effect of lncRNAs in hypoxia-mediated resistance in CRC and its potential mechanism. Here, we discovered that hypoxia-induced oxaliplatin resistance and HOX transcript antisense RNA (HOTAIR) expression was increased in hypoxia-treated CRC cell lines and CRC tumors. Knockdown of HOTAIR by siRNA reduced the viability and proliferation of CRC cells treated with oxaliplatin and reversed hypoxia-induced resistance. Mechanically, we found that HOTAIR modulates zinc finger E-box binding homeobox 1 (ZEB1) expression by negative regulations of miR-1277-5p. When miR-1277-5p was silenced, knockdown of HOTAIR was unable to reduce the oxaliplatin resistance in CRC cells. In mouse models of CRC, HOTAIR knockdown markedly inhibited the tumor growth when treated with oxaliplatin. Thus, HOTAIR/miR-1277-5p/ZEB1 axis appears a promising therapeutic target for improving the oxaliplatin efficacy in CRC.

Automated summary

This study discovered that HOTAIR, a long non-coding RNA, is upregulated in hypoxia-treated colorectal cancer (CRC) cells and tumors. Knockdown of HOTAIR reversed the hypoxia-induced resistance to the chemotherapy drug oxaliplatin in CRC cells by inhibiting the expression of ZEB1 through negative regulation of miR-1277-5p. In mouse models, HOTAIR knockdown significantly inhibited tumor growth when treated with oxaliplatin. These findings suggest that the HOTAIR/miR-1277-5p/ZEB1 axis may serve as a potential therapeutic target for improving oxaliplatin efficacy in CRC.