Synergistic AHR Binding Pathway with EMT Effects on Serous Ovarian Tumors Recognized by Multidisciplinary Integrated Analysis

Kuo-Min Su; Hong-Wei Gao; Chia-Ming Chang; Kai-Hsi Lu; Mu-Hsien Yu; Yi-Hsin Lin; Li-Chun Liu; Chia-Ching Chang; Yao-Feng Li; Cheng-Chang Chang

doi:10.3390/biomedicines9080866

Synergistic AHR Binding Pathway with EMT Effects on Serous Ovarian Tumors Recognized by Multidisciplinary Integrated Analysis

Biomedicines. 2021 Jul 22;9(8):866. doi: 10.3390/biomedicines9080866.

Authors

Kuo-Min Su^{1

2}, Hong-Wei Gao³, Chia-Ming Chang^{4

5}, Kai-Hsi Lu⁶, Mu-Hsien Yu^{1

2}, Yi-Hsin Lin², Li-Chun Liu^{2

7}, Chia-Ching Chang², Yao-Feng Li³, Cheng-Chang Chang^{1

2}

Affiliations

¹ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan.
² Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
³ Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
⁴ School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
⁵ Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
⁶ Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei 112, Taiwan.
⁷ Division of Obstetrics and Gynecology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 105, Taiwan.

Abstract

Epithelial ovarian cancers (EOCs) are fatal and obstinate among gynecological malignancies in advanced stage or relapsed status, with serous carcinomas accounting for the vast majority. Unlike EOCs, borderline ovarian tumors (BOTs), including serous BOTs, maintain a semimalignant appearance. Using gene ontology (GO)-based integrative analysis, we analyzed gene set databases of serous BOTs and serous ovarian carcinomas for dysregulated GO terms and pathways and identified multiple differentially expressed genes (DEGs) in various aspects. The SRC (SRC proto-oncogene, non-receptor tyrosine kinase) gene and dysfunctional aryl hydrocarbon receptor (AHR) binding pathway consistently influenced progression-free survival and overall survival, and immunohistochemical staining revealed elevated expression of related biomarkers (SRC, ARNT, and TBP) in serous BOT and ovarian carcinoma samples. Epithelial-mesenchymal transition (EMT) is important during tumorigenesis, and we confirmed the SNAI2 (Snail family transcriptional repressor 2, SLUG) gene showing significantly high performance by immunohistochemistry. During serous ovarian tumor formation, activated AHR in the cytoplasm could cooperate with SRC, enter cell nuclei, bind to AHR nuclear translocator (ARNT) together with TATA-Box Binding Protein (TBP), and act on DNA to initiate AHR-responsive genes to cause tumor or cancer initiation. Additionally, SNAI2 in the tumor microenvironment can facilitate EMT accompanied by tumorigenesis. Although it has not been possible to classify serous BOTs and serous ovarian carcinomas as the same EOC subtype, the key determinants of relevant DEGs (SRC, ARNT, TBP, and SNAI2) found here had a crucial role in the pathogenetic mechanism of both tumor types, implying gradual evolutionary tendencies from serous BOTs to ovarian carcinomas. In the future, targeted therapy could focus on these revealed targets together with precise detection to improve therapeutic effects and patient survival rates.

Keywords: aryl hydrocarbon receptor; borderline ovarian tumors; differentially expressed genes; epithelial ovarian cancers; epithelial–mesenchymal transition; gene ontology; integrative analysis.

Abstract

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