Oncogenic retinoic acid receptor γ knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/β-catenin pathway

Retinoic acid receptor gamma (RAR gamma), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma. However, little is known about the regulatory mechanism of the RAR gamma expression in colorectal cancer (CRC) progression. In the present study, we found that RAR gamma was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in CRC specimens. Tissue microarrays showed that RAR gamma indicated vital clinical significance in CRC. RAR gamma knockdown neither affected CRC cell proliferation nor blocked the cell cycle of CRC cells. However, RAR gamma knockdown increased the sensitivity of CRC cells to chemotherapeutics through downregulation of multi-drug resistance 1(MDR1). Further studies suggested that RAR gamma knockdown resulted in downregulation of MDR1, in parallel with suppression of the Wnt/beta-catenin pathway. Moreover, a significantly positive association between RAR gamma and MDR1 was demonstrated in CRC tissue microarrays. Collectively, these results suggested that overexpression of RAR gamma contributed to the multidrug chemoresistance of CRC cells, at least in part due to upregulation of MDR1 via activation of the Wnt/beta-catenin pathway, indicating that RAR gamma might serve as a potential therapeutic target for chemoresistant CRC patients.