IL-6 regulates epithelial ovarian cancer EMT, invasion, and metastasis by modulating Let-7c and miR-200c through the STAT3/HIF-1α pathway

• Published in: Medical oncology (Northwood, London, England) Vol. 41; no. 6; p. 155
• Main Authors: Guo, Qiao Yun, Song, Jiang Nan, Chen, Yu Meng, Yuan, Hai Ning, Xue, Wen Shu, Sun, Yang, Niu, Xiu long, Wang, Yue, Chen, Xiao
• Format: Journal Article
• Language: English
• Published: New York Springer US 14.05.2024; Springer Nature B.V
• Subjects: Animals; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; Cell Line, Tumor; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Hematology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Internal Medicine; Medicine; Medicine & Public Health; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; MicroRNAs - genetics; Neoplasm Invasiveness - genetics; Neoplasm Metastasis; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; Oncology; Original Paper; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pathology; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Let-7c and miR-200c; Epithelial ovarian cancer (EOC); IL-6/STAT3/HIF-1α; EMT; Invasion and metastasis
• ISSN: 1559-131X; 1357-0560; 1559-131X
• DOI: 10.1007/s12032-024-02328-2

Interleukin-6 (IL-6) and hypoxia-inducible factor-1α (HIF-1α) play important roles in epithelial-mesenchymal transformation (EMT) and tumor development. Previous studies have demonstrated that IL-6 promotes EMT, invasion, and metastasis in epithelial ovarian cancer (EOC) cells by activating the STAT3/HIF-1α pathway. MicroRNA (miRNA) is non-coding small RNAs that also play an important role in tumor development. Notably, Let-7 and miR-200 families are prominently altered in EOC. However, whether IL-6 regulates the expression of Let-7 and miR-200 families through the STAT3/HIF-1α signaling to induce EMT in EOC remains poorly understood. In this study, we conducted in vitro and in vivo investigations using two EOC cell lines, SKOV3, and OVCAR3 cells. Our findings demonstrate that IL-6 down-regulates the mRNA levels of Let-7c and miR-200c while up-regulating their target genes HMGA2 and ZEB1 through the STAT3/HIF-1α signaling in EOC cells and in vivo. Additionally, to explore the regulatory role of HIF-1α on miRNAs, both exogenous HIF blockers YC-1 and endogenous high expression or inhibition of HIF-1α can be utilized. Both approaches can confirm that the downstream molecule HIF-1α inhibits the expression and function of Let-7c and miR-200c. Further mechanistic research revealed that the overexpression of Let-7c or miR-200c can reverse the malignant evolution of EOC cells induced by IL-6, including EMT, invasion, and metastasis. Consequently, our results suggest that IL-6 regulates the expression of Let-7c and miR-200c through the STAT3/HIF-1α pathway, thereby promoting EMT, invasion, and metastasis in EOC cells.