ANGPTL4 accelerates ovarian serous cystadenocarcinoma carcinogenesis and angiogenesis in the tumor microenvironment by activating the JAK2/STAT3 pathway and interacting with ESM1

Yu-kun Li; An-bo Gao; Tian Zeng; Dan Liu; Qun-feng Zhang; Xiao-min Ran; Zhen-zi Tang; Yan Li; Jue Liu; Ting Zhang; Gang-qing Shi; Wen-chao Zhou; Wen-da Zou; Juan Peng; Juan Zhang; Hui Li; Juan Zou

doi:10.1186/s12967-023-04819-8

Journal of Translational Medicine (Jan 2024)

ANGPTL4 accelerates ovarian serous cystadenocarcinoma carcinogenesis and angiogenesis in the tumor microenvironment by activating the JAK2/STAT3 pathway and interacting with ESM1

Yu-kun Li,
An-bo Gao,
Tian Zeng,
Dan Liu,
Qun-feng Zhang,
Xiao-min Ran,
Zhen-zi Tang,
Yan Li,
Jue Liu,
Ting Zhang,
Gang-qing Shi,
Wen-chao Zhou,
Wen-da Zou,
Juan Peng,
Juan Zhang,
Hui Li,
Juan Zou

Affiliations

Yu-kun Li: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
An-bo Gao: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Tian Zeng: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Dan Liu: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Qun-feng Zhang: The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China
Xiao-min Ran: Department of Gynecologic Oncology, School of Medicine, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya, Central South University
Zhen-zi Tang: Department of Gynecologic Oncology, School of Medicine, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya, Central South University
Yan Li: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Jue Liu: The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China
Ting Zhang: The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China
Gang-qing Shi: The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China
Wen-chao Zhou: The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China
Wen-da Zou: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Juan Peng: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Juan Zhang: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Hui Li: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University
Juan Zou: Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University

DOI: https://doi.org/10.1186/s12967-023-04819-8
Journal volume & issue: Vol. 22, no. 1
pp. 1 – 20

Abstract

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Abstract Background Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. Methods The expression of ANGPTL4 was confirmed by bioinformatics and IHC in OC. The potential molecular mechanism of ANGPTL4 was measured by RNA-sequence. We used a series of molecular biological experiments to measure the ANGPTL4-JAK2-STAT3 and ANGPTL4-ESM1 axis in OC progression, including MTT, EdU, wound healing, transwell, xenograft model, oil red O staining, chick chorioallantoic membrane assay and zebrafish model. Moreover, the molecular mechanisms were confirmed by Western blot, Co-IP and molecular docking. Results Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving JAK2-STAT3 signaling pathway activation. The interaction between ANGPTL4 and ESM1 promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. Conclusion Our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1.

Published in Journal of Translational Medicine

ISSN: 1479-5876 (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Medicine
Website: https://translational-medicine.biomedcentral.com/

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