Overexpression of UBE2M through Wnt/β-Catenin signaling is associated with poor prognosis and chemotherapy resistance in colorectal cancer.

Abstract

BackgroundThe expression of ubiquitin-conjugating enzyme E2 M (UBE2M) is elevated in colorectal carcinoma (CRC). However, the underlying mechanisms and effects of UBE2M on the prognosis and drug resistance in CRC have not been investigated.MethodsCRC specimens and adjacent normal tissues were collected from 74 patients. The expression of UBE2M was measured by quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Multivariable cox regression analysis was used to analyze the risk factors for overall survival in clinical CRC patients. Human colorectal cancer cell lines HCT116 and SW480 were transfected with specific UBE2M small interfering ribonucleic acid (siRNA) or plasmid to either suppress or increase the expression of UBE2M for in vitro experiments. Also, chemotherapy-resistant HCT116 and SW480 cells were established by being treated with increasingly higher concentrations of fluorouracil (5-FU) or oxaliplatin. XAV-939 was used as a wingless/integrated-beta-catenin (Wnt/β-catenin) signaling inhibitor.ResultsAccording to quantitative real-time PCR and immunohistochemistry, the expression of UBE2M was elevated in CRC tissues compared to normal tissues. Based on cox regression analysis, the overexpression of UBE2M was a risk factor for overall survival of CRC patients. The expression of UBE2M was notably high in 5-FU- and oxaliplatin-resistant cells in in vitro experiments. Also, cells transfected with specific UBE2M siRNA or plasmid induced lower resistance to 5-FU and higher resistance to oxaliplatin. Finally, the expression of β-catenin was correlated with the expression of UBE2M in transfected cells and treatment with XAV939 decreased the degree of drug resistance in chemotherapy-resistant HCT116 cells.ConclusionsOverexpression of UBE2M in CRC specimens contributes to a decreased overall survival of patients and mediates 5-FU and oxaliplatin resistance in CRC cells via the Wnt/β-catenin signaling pathway.