Hypoxia-inducible factor-1α activation in HPV-positive head and neck squamous cell carcinoma cell lines.

Jennifer Knuth,Shachi J Sharma,Boyan K Garvalov,Till Acker,Claudia Holler,Jens P Klussmann,Nora Würdemann,Steffen Wagner,Claus Wittekindt

doi:10.18632/oncotarget.20813

Jennifer Knuth, Shachi J Sharma + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.20813

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Journal: Oncotarget	Publication Date: Sep 11, 2017
Citations: 15	License type: cc-by

Affiliation: University of Giessen

Abstract

PurposeHuman papillomavirus (HPV) is a causative agent for a rising number of head and neck squamous cell carcinomas (HNSCC), which are characterized by distinct tumor biology. Hypoxia inducible-factor (HIF) signaling influences initiation and progression of carcinogenesis and HPV oncoproteins have evolved to highjack cellular pathways for viral reproduction. Therefore, we investigated whether HPV activates HIF-1α expression in HNSCC.Experimental TechniqueHPV-positive and -negative HNSCC cells were examined for adaptive responses to hypoxia. Expression of HIF-1α, prolyl hydroxylase-domain protein 2 (PHD2) and E-cadherin was analyzed by Western blotting, immunofluorescence (IF) microscopy and migration/wound healing assays.ResultsHPV-positive HNSCC cells showed higher HIF-1α and PHD2 protein levels under normoxia and hypoxia. HIF-1α hydroxylation was reduced in HPV-positive HNSCC cell lines under PHD and proteasomal inhibition. In vitro wound healing assays showed impairment of migration and proliferation by HIF-1α pathway activation in HPV-negative cell lines only. In contrast, migration and proliferation in HPV-positive cell lines was impaired by HIF-1α specific siRNA.ConclusionsHPV-positive HNSCC cells show activation of the HIF pathway and adaptation to HIF-1α upregulation, representing potential therapeutic targets in this emerging tumor entity.

Highlights

Human Papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) are considered to be a distinct tumor entity with clinical, pathological and molecular features that essentially differ from HPVnegative head and neck squamous cell carcinomas (HNSCC) [1,2,3]
Hypoxia inducible-factor (HIF)-1α hydroxylation was reduced in Human papillomavirus (HPV)-positive HNSCC cell lines under prolyl hydroxylase domain (PHD) and proteasomal inhibition
Protein expression of HIF-1α and PHD2 was evaluated in two HPV-negative and four HPV-positive HNSCC cell lines cultured under normoxic conditions (Figure 1)

Summary

Introduction

Human Papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) are considered to be a distinct tumor entity with clinical, pathological and molecular features that essentially differ from HPVnegative HNSCC [1,2,3]. Viral oncoproteins interact with many pivotal cellular regulators to induce metabolic remodeling “optimized” for viral replication and nutrient synthesis [5]. HPV oncoproteins are able to stabilize HIF-1α in different cell lines [6,7,8]. The group of hypoxia-inducible factors (HIF), especially HIF-1 plays a major role in supporting tumor metabolism and in cellular adaptation to hypoxic stress [9]. The stability of the HIF-α (HIF-1α and HIF-2α) subunits is regulated by oxygen sensors of the prolyl hydroxylase domain (PHD)

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