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RORγ Hijacks HIF1α to Promote Peritoneal Metastasis of Gastric Cancer
Published version of a preprint
Abstract
Peritoneal metastasis (PM) is the most common and lethal form of metastasis in gastric cancer, highlighting an urgent need for treatment strategies. In this study, we identified retinoic acid receptor–related orphan receptor gamma (RORγ) as a key driver of PM in gastric cancer tumors. Integrative bioinformatics and IHC analyses revealed aberrant upregulation of RORγ in gastric cancer tumors, particularly in metastatic lesions. Functionally, elevated RORγ promoted gastric cancer cell adaptation to hypoxia and accelerated PM formation in vivo. The hypoxic microenvironment in gastric cancer stimulated RORγ expression, which in turn enhanced hypoxia-inducible factor 1α (HIF1α) stability, establishing a positive feedforward loop. Mechanistically, RORγ interacted with HIF1α and protected it from binding to proline hydroxylase domain 3 and von Hippel-Lindau, resulting in markedly decreased HIF1α hydroxylation and ubiquitylation and increased HIF1α accumulation, nuclear translocation, and transactivation. The RORγ–HIF1α complex bound to and activated target genes involved in the hypoxic response and epithelial-to-mesenchymal transition, thereby driving gastric cancer tumor growth and PM. Disruption of the RORγ–HIF1α interaction using RORγ antagonists markedly promoted HIF1α degradation and diminished its function. Importantly, in multiple gastric cancer xenograft models, RORγ inhibition effectively blocked tumor growth and PM while sensitizing tumors to chemotherapy. Thus, this study uncovers a mechanism of hypoxia-mediated metastasis through a RORγ–HIF1α reciprocal regulatory loop and offers a potential therapeutic option against PM in advanced cancer. Significance: RORγ drives peritoneal metastasis in gastric cancer and can be targeted to block metastatic progression, suggesting that RORγ inhibition could serve as a therapeutic strategy for advanced gastric cancer.
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Metadata
- Authors
- Wang, Q., Zhong, L., Wang, X., Zhang, Z., Cai, G., Gu, Z., Yang, B., Zhou, H., Li, H., Chan, F. L., Zhang, Q., Huang, Z., Liu, P., Wang, H., Shen, L., Han, F., & Wang, J.
- Affiliations
- Sun Yat-sen University (CN)
- University of Electronic Science and Technology of China (CN)
- Peking University Cancer Hospital (CN)
- Chinese University of Hong Kong (HK)
- University of Macau (MO)
- Corresponding author
- Wang, Junjian
- ORCID
- Venue
- Cancer Research
- Published
- 2025-10-23
- Volume
- 86
- Issue
- 3
- Pages
- 642-660
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W4415483394
- Cited by
- 0
- References
- 60
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- The National Natural Science Foundation of China (82273956, 82304520)
- The China Postdoctoral Science Foundation (2023M734065)
- The Science and Technology Planning Project of Guangdong Province (2023A0505010013)
- The Guangdong Basic and Applied Basic Research Foundation (2025A1515011034, 2022B1515130008)
- The Key Research and Development Plan of Guangzhou City (202206080007)
- Guangdong-Hong Kong Technology Cooperation Funding Scheme 2021, Innovation and Technology Fund (GHP/093/21GD)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Gastric Cancer Management and Outcomes
- Keywords
- RORγ, HIF-1α, peritoneal carcinomatosis, gastric cancer, hypoxia, tumor microenvironment, VHL, epithelial-mesenchymal transition, chemosensitization, metastasis treatment
- MeSH terms
- Animals, Humans, Mice, Inbred BALB C, Mice, Nude, Peritoneal Neoplasms, Stomach Neoplasms, Gene Expression Regulation, Neoplastic, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Nuclear Receptor Subfamily 1, Group F, Member 3, Epithelial-Mesenchymal Transition, Tumor Microenvironment
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