WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer.

Autor: Tan XY; Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China., Li YT; Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.; Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China., Li HH; Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.; Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China., Ma LX; Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China., Zeng CM; Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China., Zhang TT; Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China., Huang TX; Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China., Zhao XD; Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China., Fu L; Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China. gracelfu@szu.edu.cn.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2023 Oct; Vol. 42 (41), pp. 3062-3074. Date of Electronic Publication: 2023 Aug 26.
DOI: 10.1038/s41388-023-02816-1
Abstrakt: Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/β-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2-SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2-SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2-SOX4 axis may be a potential therapeutic target for gastric cancer treatment.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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