Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

Chen,Siqi; Chen,Siqi; Liu,Zixuan; Liu,Zixuan; Wu,Haixia; Wu,Haixia; Wang,Bo; Wang,Bo; Ouyang,Yuqing; Ouyang,Yuqing; Liu,Junru; Liu,Junru; Zheng,Xiaoyan; Zheng,Xiaoyan; Zhang,Haoke; Zhang,Haoke; Li,Xueying; Li,Xueying; Feng,Xiaofan; Feng,Xiaofan; Li,Yan; Li,Yan; Shen,Yangyang; Shen,Yangyang; Zhang,Hong; Zhang,Hong; Xiao,Bo; Xiao,Bo; Yu,Chunyan; Yu,Chunyan; Deng,Weimin; Deng,Weimin

doi:10.3892/ijmm.2024.5361

Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

Authors:
- Siqi Chen
- Zixuan Liu
- Haixia Wu
- Bo Wang
- Yuqing Ouyang
- Junru Liu
- Xiaoyan Zheng
- Haoke Zhang
- Xueying Li
- Xiaofan Feng
- Yan Li
- Yangyang Shen
- Hong Zhang
- Bo Xiao
- Chunyan Yu
- Weimin Deng
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Affiliations: Department of Immunology, Tianjin Institute of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Diseases and Microenvironment of Ministry of Education of China, Tianjin Medical University, Tianjin 300070, P.R. China, Department of Pathology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, P.R. China, Department of Blood Transfusion, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, Shandong 253000, P.R. China, Department of Laboratory, Shanxi Eye Hospital, Taiyuan, Shanxi 030002, P.R. China, Department of Family Planning, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China, Department of Clinical Laboratory, The Affiliated Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
Published online on: February 27, 2024 https://doi.org/10.3892/ijmm.2024.5361
Article Number: 37
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The effects of adipocyte‑rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte‑rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM‑associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferator‑activated receptor γ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3‑shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARM‑educated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.

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