HPV16 E6 Oncogene Contributes to Cancer Immune Evasion by Regulating PD-L1 Expression through a miR-143/HIF-1a Pathway

Sep 21, 2026

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Human Papillomaviruses are linked to cervical cancer, with most cases driven by high-risk HPV16 and HPV18. Viral oncogenes E6/E7 integrate into host genomes and reshape cellular functions and molecular expression. This study used integrated HPV16 cell lines, then knocked out E6 via CRISPR/Cas9 delivered by lentiviral vectors to assess PD-L1, HIF-1a, and miR-143 expression. E6 knockout increased miR-143 while reducing HIF-1a and PD-L1, supporting an E6-driven PD-L1 immune-evasion pathway via a miR-143/HIF-1a axis.

LanguageEnglish

CategoryResearch & Report

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viruses Article HPV16 E6 Oncogene Contributes to Cancer Immune Evasion by Regulating PD-L1 Expression through a miR-143/HIF-1a Pathway Georgios Konstantopoulos 1,†, Danai Leventakou 2,†, Despoina-Rozi Saltiel 1, Efthalia Zervoudi 3, Eirini Logotheti 1, Spyros Pettas 1, Korina Karagianni 1, Angeliki Daiou 1, Konstantinos E. Hatzistergos 1, Dimitra Dafou 1, Minas Arsenakis 1, Amanda Psyrri 4,* and Christine Kottaridi 1, * Citation: Konstantopoulos, G.; Leventakou, D.; Saltiel, D.-R.; Zervoudi, E.; Logotheti, E.; Pettas, S.; Karagianni, K.; Daiou, A.; Hatzistergos, K.E.; Dafou, D.; et al. HPV16 E6 Oncogene Contributes to Cancer Immune Evasion by Regulating PD-L1 Expression through a miR-143/HIF-1a Pathway. Viruses 2024, 16, 113. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/v16010113](10.3390/v16010113) Academic Editor: Daniel DiMaio Received: 29 December 2023 Accepted: 11 January 2024 Published: 12 January 2024 Corrected: 22 November 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; [konstanto@bio.auth.gr](konstanto@bio.auth.gr) (G.K.); [dessalton@bio.auth.gr](dessalton@bio.auth.gr) (D.-R.S.); [eirinilg@bio.auth.gr](eirinilg@bio.auth.gr) (E.L.); [spyrospg@bio.auth.gr](spyrospg@bio.auth.gr) (S.P.); [korinagk@bio.auth.gr](korinagk@bio.auth.gr) (K.K.); [angeldaiou@bio.auth.gr](angeldaiou@bio.auth.gr) (A.D.); [kchatzistergos@bio.auth.gr](kchatzistergos@bio.auth.gr) (K.E.H.); [dafoud@bio.auth.gr](dafoud@bio.auth.gr) (D.D.); [arsenaki@bio.auth.gr](arsenaki@bio.auth.gr) (M.A.) 2 2nd Department of Pathology, University General Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; [dleventakou@med.uoa.gr](dleventakou@med.uoa.gr) 3 Research Unit—Oncology Unit, University General Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; [t.zervoudi@hotmail.com](t.zervoudi@hotmail.com) 4 Section of Medical Oncology, Department of Internal Medicine, Attikon University Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece * Correspondence: [dpsyrri@med.uoa.gr or psyrri237@yahoo.com](dpsyrri@med.uoa.gr or psyrri237@yahoo.com) (A.P.); [ckottaridi@bio.auth.gr](ckottaridi@bio.auth.gr) (C.K.)† These authors contributed equally to this work. Abstract: Human Papillomaviruses have been associated with the occurrence of cervical cancer, the fourth most common cancer that affects women globally, while 70% of cases are caused by infection with the high-risk types HPV16 and HPV18 . The integration of these viruses’ oncogenes E6 and E7 into the host’s genome affects a multitude of cellular functions and alters the expression of molecules. The aim of this study was to investigate how these oncogenes contribute to the expression of immune system control molecules, using cell lines with integrated HPV16 genome, before and after knocking out E6 viral gene using the CRISPR/Cas9 system, delivered with a lentiviral vector. The molecules studied are the T-cell inactivating protein PD-L1, its transcription factor HIF-1a and the latter’s negative regulator, miR-143 . According to our results, in the E6 knock out (E6KO) cell lines an increased expression of miR-143 was recorded, while a decrease in the expression of HIF-1a and PD-L1 was exhibited. These findings indicate that E6 protein probably plays a significant role in enabling cervical cancer cells to evade the immune system, while we propose a molecular

FAQs

What was the main aim of the study?

To investigate how HPV16 E6 and E7 oncogenes contribute to the expression of immune control molecules, focusing on PD-L1 regulation.

How did the researchers evaluate the role of HPV16 E6?

They used integrated HPV16 cell lines and knocked out the E6 viral gene using CRISPR/Cas9 delivered with a lentiviral vector.

What molecular changes were observed after E6 knockout?

E6 knockout increased miR-143 expression and decreased HIF-1a and PD-L1 expression.

Sep 21, 2026

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