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

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Abstract

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.

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Acknowledgements

We thank Dr. Andrew L Kung (Dana-Farber Cancer Institute, USA) for providing pCMVh-HA-ssHIF-1α and the control pCMVh-HA plasmids.

Funding

This research was supported by Grants from the National Natural Science Foundation of China (No.81572852, 81273520), the Great Program of Science Foundation of Tianjin (No. 18JCZDJC33200) and Center Innovation Team Project (KYCXTD0502, KYCXTD0203).

Author information

Author notes

  1. Qiao Yun Guo, Jiang Nan Song and Yu Meng Chen have contributed equally to this work.

Authors and Affiliations

  1. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No.10 Poyang Lake Road, Jinghai District, Tianjin, 301617, China

    Qiao Yun Guo, Hai Ning Yuan, Wen Shu Xue & Yue Wang

  2. School of Pharmacy and Biological Technology, Tianjin Medical College, Tianjin, 300222, China

    Qiao Yun Guo

  3. Department of Gynaecology and Obstetrics, Characteristic Medical Center of Chinese People’s Armed Police Force, No.220, Chenglin Road, Dongli District, Tianjin, 300162, China

    Jiang Nan Song, Yang Sun & Xiao Chen

  4. Department of Gynecology and Obstetrics, Chinese People’s Liberation Army General Hospital, Beijing, 100080, China

    Jiang Nan Song

  5. College of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China

    Yu Meng Chen

  6. Institute of Prevention and Treatment of Dermatosis in Alpine Environment of Plateau, Characteristic Medical Center of Chinese People’s Armed Police Force, Tianjin, 300162, China

    Xiu long Niu

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  1. Qiao Yun Guo
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Contributions

QYG, JNS and YMC conceived the work that led to the acquisition of literatures and drafted the manuscript. Material preparation, data collection and analysis were performed by HNY and WSX. YS and XN provided supervision throughout the study. YW and XC designed the outline of the review, revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yue Wang.

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Guo, Q.Y., Song, J.N., Chen, Y.M. et al. IL-6 regulates epithelial ovarian cancer EMT, invasion, and metastasis by modulating Let-7c and miR-200c through the STAT3/HIF-1α pathway. Med Oncol 41, 155 (2024). https://doi.org/10.1007/s12032-024-02328-2

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