Function Study Of The Methylation Of NME2 And Acquired Resistance To 5-FU In Colorectal Cancer

Colorectal cancer(CRC)is one of the common malignancies of the gastrointestinal tract,its the third leading cause of cancer-related deaths worldwide.5-fluorouracil(5-FU)-based chemotherapeutic regimens are routinely used for the treatment of patients with CRC.However,recurrence and chemotherapeutic drug resistance limit the survival rates of patients with CRC.DNA methylation participates in diverse cellular processes by regulating the transcription of a large number of genes expression,cell division,apoptosis,cell adhesion and differentiation,and metabolism,thus it might mediate chemoresistance.Using an Illumina Infinium HD Assay,DNA methylation levels in a human 5-FU-resistant HCT-8 CRC cell line(HCT-8/FU)and its progenitor cell line HCT-8 were analysed.A total of 16,580 differentially methylated genes were identified,of which 8885 were hypermethylated and 7695 were hypomethylated in resistant cells.Among these genes,NME2(nucleoside diphosphate kinase 2)exhibited a significant difference in methylation between cell lines and has known the roles on metastasis and prognosis in cancers such as gastric cancer and breast cancer was read through prervious study,so the gene may play a role in acquired resistance in CRC.Using siRNA Knockdown of NME2 restored 5-FU sensitivity in 5-FU-resistant CRC cells,reduced cell survival and increased cell apoptosis;and using Lentivirus to overexpress of NME2 in HCT-8 cells results in the acquisition of resistance to 5-FU,this alteration enhanced HCT-8 cells growth abilities and reduced apoptosis.These findings suggest that NME2 mediates chemoresistance to 5-FU in CRC and that specific NME2 inhibition could optimize 5-FU-based chemotherapy of CRC.