Th17 cells favor migration and invasiveness of cervical cancer cells under hypoxia in an IGF2BP2-dependent manner

Sep 22, 2026

Hypoxic regions in cervical tumors suppress HPV oncoproteins E6 and E7 through an AKT-dependent mechanism, producing reversible oxygen-dependent growth arrest. During cervical carcinogenesis, Th17 cells expand in tumor tissue; hypoxia promotes Th17 differentiation and their presence associates with AKT-dependent therapy resistance, metastasis, and relapse. Because both hypoxia and Th17 correlate with poor prognosis, this work tests potential synergy. Th17 cells increase glycolytic genes and transporters, enhance glucose uptake, and promote proliferation and migration in hypoxic 2D cultures and invasion in 3D spheroids, mediated by IGF2BP2.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

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Abstract

Introduction

Clinical context of advanced cervical cancer

Hypoxia and Th17 cells in tumor progression

DOI: 10.1002/ijc.70340 RES EARCH A RTICLE Molec u la r C a n cer Bio logy Th17 cells favor migration and invasiveness of cervical cancer cells under hypoxia in an IGF2BP2-dependent manner Selina Gies 1,2 | Maike Pohlers 2 | Tanja Tänzer 2 | Emmanuel Ampofo 3 | Matthias W. Laschke 3,4,5 | Moritz Schäfer 1,2 | Yoo-Jin Kim 6 | Rainer Maria Bohle 6 | Erich-Franz Solomayer 7 | Konrad Wagner 4,8 | Martin Empting 4,8 | Alexandra K. Kiemer 4,5,8 | Barbara Walch-Rückheim 1,2 1Experimental Gynecological Oncology, Gynecology, Faculty of Medicine, University of Augsburg, Augsburg, Germany 2Center of Human and Molecular Biology (ZHMB), Institute of Virology, Saarland University, Homburg, Germany 3Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany 4PharmaScienceHub (PSH), Saarbrücken, Germany 5Center for Gender-Specific Biology and Medicine (CGBM), Saarland University, Saarbrücken, Germany 6Institute of Pathology, Saarland University, Medical Center, Homburg, Germany 7Department of Obstetrics and Gynecology, Saarland University, Medical Center, Homburg, Germany 8Department of Pharmacy, Saarland University, Saarbrücken, Germany Correspondence Barbara Walch-Rückheim, Experimental Gynecological Oncology, Gynecology, Faculty of Medicine, University Hospital Augsburg, Stenglinstraße 2, D-86156 Augsburg, Germany. Email: barbara.walch-rueckheim @[med.uni-augsburg.de](med.uni-augsburg.de) Funding information Dr. Rolf M. Schwiete Stiftung, Grant/Award Number: 2023-012 Abstract Hypoxic regions of cervical cancers mediate suppression of the human papillomavirus (HPV) oncoproteins E6 and E7 in an AKT-dependent manner causing oxygendependent reversible growth arrest of cancer cells. Furthermore, numbers of T-helper (Th)-17 cells increase during cervical carcinogenesis in cancer tissues, Th17 differentiation is favored by hypoxia and their presence is linked with AKT-dependent therapy resistance, metastases and relapse. As both factors, hypoxia and Th17 cells, are associated with poor prognosis of patients, potential synergistic mechanisms between both are not described so far. In this study, we showed that Th17 cells enhance the expression of hypoxia-related glycolytic enzymes and transporters and functionally favor increased glucose uptake, proliferation and migration of 2D cultures of hypoxic cervical cancer cells as well as invasion of 3D spheroids. As the responsible mediator of increased proliferation, migration and invasion, we identified the RNA-binding protein IGF2BP2 by using small interfering RNAs (siRNAs) for IGF2BP2 as well as small Abbreviations: AKT, protein kinase B; BSA, bovine serum albumin; CAIX, carbonic anhydrase IX; CD, cluster of differentiation; CM, conditioned media; CRT, chemoradiotherapy; DAB, 3,30-diaminobenzidine; DAPI, 40 ,60-diamidin-2-phenylindole; DMEM, Dulbecco's modified eagle medium; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial-tomesenchymal transition; FCS, fetal calf serum; FIGO, international federation of gynecology and obstetrics; HIF1A, hypoxia inducible factor 1 subunit alpha; HPV, human papillomavirus; IF, immunofluorescence; IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2; IHC, immunohistochemistry; IL, interleukin; IRS, immunoreactive score; mTORC2, mammalian target of rapamycin complex 1; NBDG, 2-(N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl]amino)-2-deoxyglucose; PBS, phosphate buffered saline; PCR, polymerase chain reaction; PFA, paraformaldehyde; PI3K, phosphoinositide 3-kinases; POX, peroxidase; RFS, recurrence-free survival; ROC, receiver operator characteristics; RPMI, Roswell Park Memorial Institute; SCC, squamous cell carcinomas; siRNA, small interfering RNAs; SLC2A1, solute carrier family 2 member 1; TBS, tris-buffered saline; TE, tris EDTA; Th, T helper cells. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution a

FAQs

How does hypoxia influence HPV oncoprotein activity in cervical cancer cells?

Hypoxic regions suppress HPV oncoproteins E6 and E7 through an AKT-dependent mechanism, leading to oxygendependent reversible growth arrest.

What effects do Th17 cells have on hypoxic cervical cancer models?

Th17 cells enhance expression of hypoxia-related glycolytic enzymes and transporters, increase glucose uptake, and functionally promote proliferation, migration, and invasion in 2D and 3D hypoxic culture systems.

Which mediator links Th17-driven tumor progression under hypoxia?

The RNA-binding protein IGF2BP2 was identified as the responsible mediator, as IGF2BP2 knockdown reduces the increased proliferation, migration, and invasion effects.

Sep 22, 2026

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