Tan Xiang-Yu, Li Yu-Ting, Li Hua-Hui, Ma Li-Xiang, Zeng Chui-Mian, Zhang Tian-Tian, Huang Tu-Xiong, Zhao Xiao-Di, Fu Li
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.
Oncogene. 2023 Oct;42(41):3062-3074. doi: 10.1038/s41388-023-02816-1. Epub 2023 Aug 26.
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.
胃癌（GC）的特点是对当前治疗具有强烈的化学抗性，这归因于肿瘤起始和进展过程中癌症干细胞（CSCs）高度异质性和不成熟的表型。分泌型WNT2配体调节多种癌症通路，并且已被证明是胃肠道肿瘤的潜在治疗靶点；然而，其在胃CSCs（GCSCs）中的作用仍不清楚。在此，我们发现WNT2的过表达增强了干性特性，从而促进GCSCs中的化学抗性和致瘤性。机制上，WNT2受其转录因子SOX4的正向调控，反过来，SOX4被经典的WNT2/FZD8/β-连环蛋白信号通路上调，形成一个自动调节的正反馈环，导致GCSCs自我更新和致瘤性的维持。此外，在临床GC标本中，WNT2和SOX4的同时过表达与较差的生存率和化疗反应性降低相关。在GCSC衍生的小鼠异种移植模型中，使用特异性单克隆抗体阻断WNT2可显著破坏GCSCs中的WNT2-SOX4正反馈环，并在与化疗药物5-氟尿嘧啶和奥沙利铂协同作用时增强化疗疗效。总体而言，本研究确定了一种新的WNT2-SOX4正反馈环作为GCSCs诱导化疗药物抗性的机制，并表明WNT2-SOX4轴可能是胃癌治疗的潜在治疗靶点。
