Th17 cells target the metabolic miR-142-5p-SDHC/SDHD axis promoting invasiveness and progression of cervical cancers

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 supporting cervical cancer progression are not fully understood as yet. In this study, we found that Th17 cells promote migration and invasion of cervical cancer cells in 2D cultures and 3D spheroids. We demonstrated that Th17 cells induced the expression of miR-142-5p in cervical cancer cells supporting their migration and invasiveness. 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 cells reduced the expression of SDHC and SDHD that was dependent on miR-142-5p. Functional downstream analysis with inhibitors of miR-142-5p and siRNA knock down of SDHC and SDHD revealed that Th17-induced miR-142-5p-mediated reduced expression of SDHC and SDHD was responsible for enhanced migration and invasion of cervical cancer cells. Consistently, cervical cancer patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patients' biopsies significantly correlated with increased numbers of Th17 cells, advanced tumor stage and lymph node metastases. 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 novel 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.