RASSF10 suppresses colorectal cancer growth by activating P53 signaling and sensitizes colorectal cancer cell to docetaxel
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Jing Guo1, Yage Yang1,2, Yunsheng Yang1, Enqiang Linghu1, Qimin Zhan3, Malcolm V. Brock4, James G. Herman4, Bingyong Zhang5, Mingzhou Guo1
1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, P.R.China
2Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R.China
3State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, P.R.China
4Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231, U.S.A
5Department of Gastroenterology and Hepatology, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R.China
Mingzhou Guo, e-mail: [email protected]
Bingyong Zhang, e-mail: [email protected]
James G. Herman, e-mail: [email protected]
Keywords: RASSF10, DNA methylation, P53 signaling, colorectal cancer, epigenetics
Received: August 24, 2014 Accepted: December 07, 2014 Published: December 27, 2014
RASSF10 has previously been reported to be frequently methylated in a number of malignancies. To understand the importance of RASSF10 inactivation in colorectal carcinogenesis, eight colorectal cancer cell lines, 89 cases of primary colorectal cancer and 5 cases of normal colorectal mucosa were examined. Methylation specific PCR, western blot, siRNA, gene expression array and xenograft mice were employed. The expression of RASSF10 was regulated by promoter regional methylation in colorectal cancer cells. RASSF10 was methylated in 60.7% (54/89) of primary colorectal cancers and was positively associated with tumor stage (p < 0.05) and metastasis (p < 0.05). Restoration of RASSF10 led to inhibition of colorectal cancer cell proliferation in vitro and in vivo and increased apoptosis. Gene expression arrays discovered RASSF10 inhibition of MDM2 expression as a mediator of these effects, which was confirmed with RT- PCR and western blot. RASSF10 was shown to activate P53 signaling in RKO and HCT116 cells after UV exposure, and sensitized these cells to docetaxel. In conclusion, our study demonstrates RASSF10 is frequently methylated in human colorectal cancer leading to loss of expression. RASSF10 normally suppresses human colorectal cancer growth by activating P53 signaling in colorectal cancer, and restored expression sensitizes colorectal cancer to docetaxel.
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