Methylation Of Schlafen11 Is A Marker Of Poor Prognosis And Cisplatin Resistance In Colorectal Cancer

Introduction: Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer related death worldwide. Incidence is low at ages younger than 50 years but increases significantly with age. Median age at diagnosis is approximately 70 years in developed countries. However, rapid increases CRC incidence have been noted with the changes in dietary patterns in China. Most sporadic cases have chromosomal instability, an allelic imbalance at several chromosomal loci, chromosomal amplification and translocation. Defects in DNA damage repair and checkpoint control can result in gene mutations and chromosomal instability to promote tumorigenesis. Familial adenomatous polyposis and Lynch syndrome, which are caused by gene mutations in the DNA mismatch repair system, account for less than 5% of all colorectal cancer. Aberrant methylation changes in DNA damage repair genes were reported to be an important mechanism of colorectal cancer development.The Schlafen (SLFN) gene family was first identified by Steven Hedrick’s group in 1998. To date, 10 mouse SLFN genes and 6 human SLFN genes have been identified.SLFN gene products have been demonstrated to be involved in cell biological processes including proliferation, differentiation and immune function. The expression of human Schlafen 11 (SLFN 11) was reported to sensitize cancer cells to DNA damaging agents. The role and epigenetic regulation of SLFN 11 in human colorectal cancer remains to be elucidated.Abstract:Aim: To explore the epigenetic change and the function of Schlafen11 (SLFN11) in human colorectal cancer (CRC).Materials & Methods: Six CRC cell lines and 128 primary CRC samples were used.Six CRC cell lines (RKO, DLD1, SW620, LOVO, Ls180 and DKO (Dnmtl and Dnmt3b double knockout HCT-116 cells) were examined in this study。A total of 128 cases of primary colorectal cancer and five cases of non-cancerous colorectal mucosa were collected. from the Chinese PLA General Hospital in Beijing between May 2009 and November 2013.methylation-specific PCR(MSP)、RT-PCR、bisulfite sequencing、MTT、colony formation and flow cytometry were employed to study the function of SLFN11 in CRC cells.The methylation status of 128 primary CRC samples was analyzed by MSP.Mouse Xenograft model was employed to further study the function of SLFN11 in vivo.MTT and flow cytometry were employed to explore the sensitizing effects of SLFN11 on CRC cells。Results: SLFN11 was methylated in 55.47% (71/128) of primary CRC. The expression of SLFN11 was regulated by promoter region methylation. Methylation of SLFN11 was significantly associated with age, poor 5-year overall survival (OS) and 5-year relapse-free survival (RFS) (all p<0.05). SLFN11 suppressed colorectal cancer cell growth both in vitro and in vivo and sensitized CRC cells to cisplatin.Conclusion: SLFN11 is frequently methylated in human colorectal cancer, and the expression of SLFN11 is regulated by promoter region methylation. Methylation of SLFN11 reduced the sensitivity of CRC cells to cisplatin.