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

Abstract

Background: The 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.Methods: CRC 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.Results: According 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.Conclusions: Overexpression 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.

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

“…The targeting of miR-199b-3p to cysteine-rich transmembrane BMP regulator 1 (CRIM1) inhibits Wnt/β-catenin signaling and reverses resistance to cetuximab in colorectal cancer [ 100 ]. Both the ubiquitin-conjugating enzyme 2 proteins UBE2S and UBE2M can activate the Wnt/β-catenin signaling pathway, promoting resistance to olaparib in ovarian cancer and 5-FU resistance in colorectal cancer, respectively [ 101 , 102 ].…”

Centrosomes and associated proteins in pathogenesis and treatment of breast cancer

“…CDC25 exists in three primary isoforms: CDC25A, CDC25B, and CDC25C ( 244 , 245 ). The G1/S transition is mostly regulated by CDC25A, the G2/M transition is regulated by CDC25B and the G2/M checkpoint is dependent on CDC25C ( 58 – 60 ). A vital component in the proper progression of the cell cycle, including the control of centrosomes and chromosomes, is the cell cycle regulator CDC25A ( 61 ) ( Table 1 ).…”

“…Furthermore, CDC25A regulates apoptosis, highlighting the complexity of its role in cellular functioning ( 61 ). CDC25A dysregulation, however, has been linked to a number of malignancies, including breast cancer ( 58 – 60 ) ( Table 1 ). CDC25A has been shown to be overexpressed in HER2-positive and TNBC subtypes ( 246 – 248 ).…”

The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer

“…In contrast, elevated expression levels can induce DNA damage repair and promote drug resistance formation (Yan et al 2019 ). UBE2M plays a role in resistance to 5-FU by regulating the expression of β-catenin (Xu et al 2020 ).…”