Th17 cells target the metabolic miR‐142‐5p–succinate dehydrogenase subunit C/D (SDHC/SDHD) axis, promoting invasiveness and progression of cervical cancers

Author:

Pohlers Maike1,Gies Selina1,Taenzer Tanja1,Stroeder Russalina2,Theobald Laura1,Ludwig Nicole3,Kim Yoo‐Jin4,Bohle Rainer Maria4,Solomayer Erich Franz2,Meese Eckart3,Hart Martin3,Walch‐Rückheim Barbara1ORCID

Affiliation:

1. Center of Human and Molecular Biology (ZHMB), Institute of Virology Saarland University Homburg/Saar Germany

2. Department of Obstetrics and Gynecology Saarland University Medical Center Homburg/Saar Germany

3. Institute of Human Genetics Saarland University Homburg/Saar Germany

4. Institute of Pathology Saarland University Medical Center Homburg/Saar Germany

Abstract

During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients. We previously demonstrated that Th17 cells are associated with therapy resistance as well as cervical cancer metastases and relapse; however, the underlying Th17‐driven mechanisms are not fully understood. Here, using microarrays, we found that Th17 cells induced an epithelial‐to‐mesenchymal transition (EMT) phenotype of cervical cancer cells and promoted migration and invasion of 2D cultures and 3D spheroids via induction of microRNA miR‐142‐5p. As the responsible mechanism, we identified the subunits C and D of the succinate dehydrogenase (SDH) complex as new targets of miR‐142‐5p and provided evidence that Th17–miR‐142‐5p‐dependent reduced expression of SDHC and SDHD mediated enhanced migration and invasion of cancer cells using small interfering RNAs (siRNAs) for SDHC and SDHD, and miR‐142‐5p inhibitors. Consistently, patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patient biopsies correlated with increased numbers of Th17 cells. Correspondingly, a combination of weak or negative SDHD expression and a ratio of Th17/CD4+ T cells > 43.90% in situ was associated with reduced recurrence‐free survival. In summary, we unraveled a previously unknown molecular mechanism by which Th17 cells promote cervical cancer progression and suggest evaluation of Th17 cells as a potential target for immunotherapy in cervical cancer.

Funder

Else Kröner-Fresenius-Stiftung

Wilhelm Sander-Stiftung

Publisher

Wiley

Subject

Cancer Research,Genetics,Molecular Medicine,General Medicine,Oncology

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