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Int J Med Sci. 2020 Jan 1;17(1):112-124. doi: 10.7150/ijms.35133. eCollection 2020.

Comparative Gene Expression Profiling of Tobacco-Associated HPV-Positive versus Negative Oral Squamous Carcinoma Cell Lines.

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Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Italy.
Medical Statistics Unit, University of Campania Luigi Vanvitelli, Naples, Italy.
Anatomic Pathology Unit, Department of Clinic and Experimental Medicine; University of Foggia, Italy.
Section of Clinic Pathology, Riuniti Hospital, Foggia, Italy.


Background: HPV-positive oral squamous cell carcinomas (OSCCs) are specific biological and clinical entities, characterized by a more favorable prognosis compared to HPV-negative OSCCs and occurring generally in non-smoking and non-drinking younger individuals. However, poor information is available on the molecular and the clinical behavior of HPV-positive oral cancers occurring in smoking/drinking subjects. Thus, this study was designed to compare, at molecular level, two OSCC cell lines, both derived from drinking and smoking individuals and differing for presence/absence of HPV infection. Methods: HPV-negative UPCI-SCC-131 and HPV16-positive UPCI-SCC-154 cell lines were compared by whole genome gene expression profiling and subsequently studied for activation of Wnt/βCatenin signaling pathway by the expression of several Wnt-target genes, βCatenin intracellular localization, stem cell features and miRNA let-7e. Gene expression data were validated in head and neck squamous cell carcinoma (HNSCC) public datasets. Results: Gene expression analysis identified Wnt/βCatenin pathway as the unique signaling pathway more active in HPV-negative compared to HPV-positive OSCC cells and this observation was confirmed upon evaluation of several Wnt-target genes (i.e., Cyclin D1, Cdh1, Cdkn2a, Cd44, Axin2, c-Myc and Tcf1). Interestingly, HPV-negative OSCC cells showed higher levels of total βCatenin and its active form, increase of its nuclear accumulation and more prominent stem cell traits. Furthermore, miRNA let-7e was identified as potential upstream regulator responsible for the downregulation of Wnt/βCatenin signaling cascade since its silencing in UPCI-SCC-154 cell resulted in upregulation of Wnt-target genes. Finally, the analysis of two independent gene expression public datasets of human HNSCC cell lines and tumors confirmed that Wnt/βCatenin pathway is more active in HPV-negative compared to HPV-positive tumors derived from individuals with smoking habit. Conclusions: These data suggest that lack of HPV infection is associated with more prominent activation of Wnt/βCatenin signaling pathway and gain of stem-like traits in tobacco-related OSCCs.


Wnt/βCatenin pathway; oral squamous carcinoma; stemness; tobacco

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