Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

Abstract

Background Cancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC. Methods Through analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms. Results Sec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/β-catenin signaling. Mechanistically, Sec62 bound to β-catenin and inhibited the degradation of β-catenin. Sec62 competitively disrupted the interaction between β-catenin and APC to inhibit the β-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m6A-mediated stabilization of Sec62 mRNA. Conclusions Sec62 upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of CRC by binding to β-catenin and enhancing Wnt signalling. Thus, m6A modification-Sec62-β-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.

Total Flavonoids of Rhizoma Drynariae Promotes Differentiation of Osteoblasts and Growth of Bone Graft in Induced Membrane Partly by Activating Wnt/β-Catenin Signaling Pathway

“…Wnt/β-catenin signaling has become an essential pathway for regulating bone formation and bone resorption. However, it is well-known that the aberrant activation of Wnt/β-catenin pathway is the basis of progression of various types of malignant tumors, including colorectal cancer, liver cancer, gastric cancer, lung cancer, breast cancer and so on ( Zhao et al, 2018 ; Zhao et al, 2020 ; Jiang et al, 2021 ; Liu et al, 2021 ; Zheng et al, 2021 ). TFRD could up-regulate the Wnt/β-catenin signaling pathway, which may potentially aggravate the development of cancers in patients or animals in theory.…”

Identification of m6A-Related Biomarkers Associated with Prognosis of Colorectal Cancer

“…CTNNB1 is a key component of the Wnt/β-catenin signaling pathway and was identified as the regulator of m6A modification in hepatoblastoma induced by METTL3 [ 35 ]. Liu et al found that Sec62 is upregulated by the METTL3-mediated m6A modification and promotes the stemness and chemoresistance of CRC by binding to β-catenin and enhancing Wnt signaling [ 36 ]. That might indicate that the WNT/β-catenin pathway should receive more attention in further study.…”

The m6A RNA Modification Quantity and mRNA Expression Level of RNA Methylation-Related Genes in Head and Neck Squamous Cell Carcinoma Cell Lines and Patients

“…Accumulating data indicates the significant role of m 6 A RNA modification in the post-transcriptional regulation of gene expression that determines the proper function of crucial physiological processes. Therefore, disturbances in m 6 A RNA methylation may lead to the development of pathological changes, including cancers [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. HNSCC initiation, progression, and growth are complex molecular processes encompassing genetic and epigenetic alterations.…”