| Colorectal cancer(colorectal cancer,CRC)is one of the malignant tumors with high incidence and mortality worldwide.With the aging of China’s population,the improvement of living standard that leads to the change of diet structure,the risk of colorectal cancer is increasing year by year.Traditional physical resection has limited efficacy and low survival rate for advanced patients.Therefore,the development of safe and effective targeted therapy drugs has become one of the focuses of colorectal cancer research.Overexpression of steroid receptor coactivator 1(SRC-1)and aberrant activation of the Hedgehog(Hh)signaling pathway are associated with various tumorigenesis.However,the significance of SRC-1 in CRC and its contribution to the activation of Hh signaling are unclear.Here,we identified a conserved Hh signaling signature positively correlated with SRC-1 expression in CRC based on TCGA database.SRC-1 deficiency significantly inhibited the proliferation,migration and invasion of both human and mouse CRC cells,and SRC-1 knockout significantly suppressed AOM/DSS-induced CRC in mice.Mechanistically,SRC-1 promoted the expression of GLI2,a major downstream transcription factor of Hh pathway,and cooperated with GLI2 to enhance multiple Hh-regulated oncogene expression,including Cyclin D1,Bcl-2,and Slug,and promoted the progression of CRC.Pharmacological blockages of SRC-1 with bufalin retarded the proliferation,migration and invasion of human CRC cells by inhibiting the SRC-1-Hedgehog axis.Together,our studies uncover that inhibition of SRC-1 affects Hh signaling pathway and attenuates CRC tumorigenesis,offering an attractive strategy for CRC treatment.The purpose of this study is to prove that targeting of SRC-1 effectively inhibits the occurrence and development of colorectal cancer and find the main mechanism of its tumor inhibition,providing strong evidence for its clinical use as a potential treatment for colorectal cancer. |
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