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

Autor: Kunqi Su, Chunfeng Zhang, Yang Jiang, Xiaojuan Du, Xiaoyan Sun, Xiaofeng Liu, Chenyu Hu, Baocai Xing, Lijun Wang, Min Lu
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Colorectal cancer
Mice
Nude
Biology
medicine.disease_cause
03 medical and health sciences
m6A modification
0302 clinical medicine
SEC62
Downregulation and upregulation
Cancer stem cell
Cell Line
Tumor
medicine
Animals
Humans
Wnt Signaling Pathway
neoplasms
Chemosensitivity
beta Catenin
RC254-282
Mice
Inbred BALB C
Research
Wnt signaling pathway
Membrane Transport Proteins
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Sec62
medicine.disease
Xenograft Model Antitumor Assays
digestive system diseases
CRC
Oxaliplatin
030104 developmental biology
HEK293 Cells
Oncology
Apoptosis
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Catenin
Cancer research
Neoplastic Stem Cells
Female
Fluorouracil
Carcinogenesis
Colorectal Neoplasms
Wnt/β-catenin signaling
Zdroj: Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-17 (2021)
Journal of Experimental & Clinical Cancer Research : CR
ISSN: 1756-9966
Popis: 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.
Databáze: OpenAIRE
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