journal article·2025-08Open access

QSOX2‐Mediated Disulfide Bond Modification Enhances Tumor Stemness and Chemoresistance by Activating TSC2/mTOR/c‐Myc Feedback Loop in Esophageal Squamous Cell Carcinoma

Wo‐Ming Chen, Xiao‐Ping Zhang, Xiao Sun, Hai‐Cheng Liu, Yuan‐Yuan Yan, Xue Wei, Yu Liang, Yue Feng, Zhengjie Chen, Yongxu Jia, Chen Jiang, Qian Yan, Lei Li

Advanced Science· Volume 12· Issue 31

Abstract

Abstract Disulfide bond modification is critical in maintaining protein structure and activity, but its roles in regulating tumor stemness and chemoresistance remain underexplored. Here, Quiescin Sulfhydryl Oxidase 2 (QSOX2) is identified, a protein involved in disulfide bond formation, is highly expressed in esophageal squamous cell carcinoma (ESCC), and is associated with poor patient prognosis. Functional analyses demonstrated that QSOX2 overexpression markedly potentiated tumor stemness and further promoted chemoresistance, proliferation, and metastasis of ESCC cells. Mechanistically, QSOX2 enhances disulfide bond formation in TSC Complex Subunit 2 (TSC2), stabilizing TSC2‐Akt interactions, facilitating phosphorylation of TSC2 at the Ser939 by Akt, and further activating mTOR/4E‐BP1/c‐Myc signaling axis. Intriguingly, cancer‐associated fibroblasts‐secreted IGF‐1 upregulates QSOX2 expression via IGF1R/Akt/mTOR/c‐Myc pathway, establishing a positive feedback loop that sustains ESCC cell stemness. Targeting QSOX2 with Ebselen, in combination with mTOR inhibitor Rapamycin and chemotherapy, effectively downregulates c‐Myc expression and induces tumor dormancy in a mouse xenograft model. Therefore, the findings reveal that QSOX2‐mediated disulfide bond modification enhances tumor stemness by activating mTOR signaling, highlighting a promising therapeutic target in ESCC.
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Research context

OpenAlex topics: Endoplasmic Reticulum Stress and Disease · Cancer, Hypoxia, and Metabolism · Fibroblast Growth Factor Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. China

Department of Clinical Laboratory The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 P. R. China

Breast Tumor Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. China

Department of Clinical Oncology The First Affiliated Hospital of Zhengzhou University Zhengzhou 451191 P. R. China

State Key Laboratory of Metabolic Desregulation & Prevention and Treatment of Esphageal Cancer First Affiliated Hospital of Zhengzhou University Zhengzhou University Zhengzhou 451191 P. R. China

State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China

Guangdong Institute of Gastroenterology and Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 P. R. China

Funding

National Natural Science Foundation of China · Basic and Applied Basic Research Foundation of Guangdong Province

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