The Role And Mechanism Of RAR? In The Development Of Colorectal Cancer

Colorectal cancer(CRC)is the third most common cancer and the third leading cause of cancer-related morbidity and mortality around the world.Due to difficulty in early diagnosis,the majority of patients are not diagnosed until the late stage.So,it is urgent to find molecular targets in the diagnosis and treatment of CRC.Previous studies have shown that retinoic acid receptor ?(RAR?)plays important roles in the progression of several cancers such as leukemia,breast cancer,and lung cancer.However,its exact functions and molecular mechanisms in human CRC progression remain unclear.In this study,we study the roles and mechanisms of RARa in the development of CRC.In the present study,we demonstrated that RAR? protein was frequently overexpressed in human CRC specimens and CRC cell lines,and expressed both in cytoplasm and nucleus.The clinical data showed that RAR? overexpression was significantly associated with poor differentiation,pathological types and clinical stage.RARa knockdown decreased cell survival,proliferation,and colony formation in vitro and tumorigenic potential in nude mice,whereas RARa overexpression increased cell survival,proliferation,and colony formation in vitro.In addition,RARa knockdown inhibited CRC cell migration and invasion and enhanced drug sensitivity of CRC cells to 5-FU,L-OHP and VCR.Further studies showed that RARa knockdown inhibited cell cycle progression at G1 phase through upregulation of cell cycle inhibitor p21,and downregulation of cyclinD1.Molecular mechanism studies revealed RAR? promotes CRC progression at least by two aspects.On one hand,RAR? served as a transcriptional repression protein,and was recruited to the p21 promoter and synergistically inhibited p21 expression.One the other hand,RAR?enhanced GSK3?/?-catenin pathway by direct interaction with GSK3?,and thus regulated the expression of target genes such as CyclinD1.Taken together,our results signified the importance of RAR? in CRC cells growth and tumorigenesis,migration and invasion and drug resistance from the clinical samples,cell and animal model levels.Furthermore,RAR? promotes CRC progression through suppressing p21 transcription and enhancing GSK3?/?-catenin signaling.RARa might become a potential molecular target for the treatment of CRC.