Human DLG1 and SCRIB Are Distinctly Regulated Independently of HPV-16 during the Progression of Oropharyngeal Squamous Cell Carcinomas: A Preliminary Analysis.

Vjekoslav Tomaić,Lucija Lulić,Antonia Jakovčević,Luka Manojlović,Emil Dediol,Lawrence Banks

doi:10.3390/cancers13174461

Abstract

Simple SummaryThe process of HPV-mediated oncogenesis in HNSCCs is not fully understood. DLG1 and SCRIB protein expression levels and localization changes were evaluated in a number of HPV16-positive and HPV-negative OPSCCs and seem to be associated with malignant transformation. Moreover, loss of SCRIB expression inversely correlates with higher grade tumors, and this is much more evident in the presence of HPV16 E6. This could serve as a potential marker in predicting development of OPSCCs.The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell–cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell–cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs.

Highlights

Head and neck squamous cell carcinomas (HNSCCs) are the most common form of head and neck cancers and are the sixth most common cancer worldwide, with more than 930,000 new cases and more than 460,000 deaths in 2020 [1,2]
head and neck squamous cell carcinoma (HNSCC) are roughly divided into two groups based on human papillomavirus (HPV) status: HPV-negative HNSCCs are caused by environmental risks such as smoking or chewing tobacco, and heavy alcohol consumption; while a proportion of HNSCCs are caused by infection with mucosotropic HPVs, predominantly type HPV16 [3]
Since the majority of HPV-positive oropharyngeal squamous cell carcinomas (OPSCC) result from HPV16 infections and Scribble homolog (SCRIB) protein is known to be a preferred HPV16 E6 PDZ domain-containing cellular target [24], we examined possible differences in the expression levels and localization of discs large homolog 1 (DLG1) and SCRIB in HPV16-positive and HPV-negative formalin-fixed paraffin embedded (FFPE) OPSCC samples, with the aim of better understanding the process of HPV-induced carcinogenesis in the HN area

Summary

Introduction

Head and neck squamous cell carcinomas (HNSCCs) are the most common form of head and neck cancers and are the sixth most common cancer worldwide, with more than 930,000 new cases and more than 460,000 deaths in 2020 [1,2]. HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCCs) seem to be two different entities of the same disease; they show differences regarding their biology, therapeutic response, and even survival prognosis, since HPV-positive OPSCCs can result in better survival rates than HPV-negative. This depends on multiple factors [4]. PBM–PDZ domain interactions seem to be important for the viral life cycle, since PBM mutations contribute to a lower number of episomal HPV genomes and reduced cell growth rate Likewise, these interactions play pivotal roles in cellular transformation and cancer development in transgenic mice models [9,10]. These interactions seem to play critical roles in the later stages of development of HPV-induced malignancies [9,10]

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