Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas and Paired Normal Mucosae Reveals Cyclin D1 Deregulation and Compensatory Effect of Cyclin D2.

Jiří Novotný,Miluše Hradilová,Michal Kolář,Josipa Grušanović,Roman Kodet,Václav Pačes,Jan Plzák,Tomáš Vomastek,Hynek Strnad,Jana Šáchová,Martin Šteffl,Karel Smetana,Veronika Bandúrová,Martin Chovanec,Lukáš Lacina

doi:10.3390/cancers12040792

Abstract

Aberrant regulation of the cell cycle is a typical feature of all forms of cancer. In head and neck squamous cell carcinoma (HNSCC), it is often associated with the overexpression of cyclin D1 (CCND1). However, it remains unclear how CCND1 expression changes between tumor and normal tissues and whether human papillomavirus (HPV) affects differential CCND1 expression. Here, we evaluated the expression of D-type cyclins in a cohort of 94 HNSCC patients of which 82 were subjected to whole genome expression profiling of primary tumors and paired normal mucosa. Comparative analysis of paired samples showed that CCND1 was upregulated in 18% of HNSCC tumors. Counterintuitively, CCND1 was downregulated in 23% of carcinomas, more frequently in HPV-positive samples. There was no correlation between the change in D-type cyclin expression and patient survival. Intriguingly, among the tumors with downregulated CCND1, one-third showed an increase in cyclin D2 (CCND2) expression. On the other hand, one-third of tumors with upregulated CCND1 showed a decrease in CCND2. Collectively, we have shown that CCND1 was frequently downregulated in HNSCC tumors. Furthermore, regardless of the HPV status, our data suggested that a change in CCND1 expression was alleviated by a compensatory change in CCND2 expression.

Highlights

Head and neck squamous cell carcinomas (HNSCC) are malignant neoplasms that arise from the mucosal epithelial surface of the upper respiratory and digestive tracts
Since the repression of cyclin D1 promotes cell cycle exit, cellular quiescence and, in some cases, cell differentiation [43] and, in HNSCC tumor models, reduces cell growth and survival [44], these findings indicated that a CCND1 decrease may have a positive impact on patient outcome
We examined the expression of cyclin D1 and other D-type cyclins in a new cohort of HNSCC patients

Summary

Introduction

Head and neck squamous cell carcinomas (HNSCC) are malignant neoplasms that arise from the mucosal epithelial surface of the upper respiratory and digestive tracts. The worldwide annual incidence of head and neck cancers is more than 550,000 cases, making HNSCC the sixth-most common cancer in the world [1]. The incidence of this tumor type continues to increase. Early-stage, locally contained disease responds favorably to treatment, presenting very good cure rates of 70–90%. Advanced HNSCC exhibit aggressive loco-regional invasions, frequent second primary tumors and lymph node metastases, while distant metastases are relatively rare. Despite advances in the treatment of HNSCC using molecularly targeted therapies, the five-year survival rate of loco-regional or recurrent/metastatic diseases has remained at 50–60% [3,4]

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