Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma.

Lin Lin,Chang Chang,Kuei Kuei,Wang Wang,Lu Lu,Hsu Hsu,Lee Lee

doi:10.3390/jcm8091454

Abstract

Radiotherapy is commonly used to treat patients with oral squamous cell carcinoma (OSCC), but a subpopulation of OSCC patients shows a poor response to irradiation treatment. Therefore, identifying a biomarker to predict the effectiveness of radiotherapy in OSCC patients is urgently needed. In silico analysis of public databases revealed that upregulation of CHRNA5, the gene encoding nicotinic acetylcholine receptor subunit alpha-5, is extensively detected in primary tumors compared to normal tissues and predicts poor prognosis in OSCC patients. Moreover, CHRNA5 transcript level was causally associated with the effective dose of irradiation in a panel of OSCC cell lines. Artificial silencing of CHRNA5 expression enhanced, but nicotine reduced, the radiosensitivity of OSCC cells. Gene set enrichment analysis demonstrated that the E2F signaling pathway is highly activated in OSCC tissues with high levels of CHRNA5 and in those derived from patients with cancer recurrence after radiotherapy. CHRNA5 knockdown predominantly suppressed E2F activity and decreased the phosphorylation of the Rb protein; however, nicotine treatment dramatically promoted E2F activity and increased Rb phosphorylation, which was mitigated after CHRNA5 knockdown in OSCC cells. Notably, the signature combining increased mRNA levels of CHRNA5 and the E2F signaling gene set was associated with worse recurrence-free survival probability in OSCC patients recorded to be receiving radiotherapy. Our findings suggest that CHRNA5 is not only a useful biomarker for predicting the effectiveness of radiotherapy but also a druggable target to enhance the cancericidal effect of irradiation on OSCC.

Highlights

Oral squamous cell carcinoma (OSCC) is the most predominant type of oral cancer and accounts for more than 90% of all oral cancers [1]
Since oral squamous cell carcinoma (OSCC) is included among HNSCCs, we first delineated the association of CHRNA5 expression with tumorigenesis in HNSCC
The transcript levels of CHRNA2 and CHRNA10 were shown to be dramatically decreased in primary tumors compared to normal tissues derived from HNSCC patients (Figure 1B)

Summary

Introduction

Oral squamous cell carcinoma (OSCC) is the most predominant type of oral cancer and accounts for more than 90% of all oral cancers [1]. The five-year survival rate of the newly diagnosed individuals is approximately 57%, and the disease-free survival rate is 58%. The five-year survival rate has improved only slightly, from 50% to 57%, in decades. Oral habits such as betel quid chewing, alcohol consumption, and tobacco smoking have been documented as risk factors for oral cancer [2]. According to the National Comprehensive Cancer Network (NCCN) guidelines, treatment options vary depending on the cancer stage and include surgery, radiotherapy, chemotherapy, and targeted therapy (e.g., cetuximab) [3]. Modern radiotherapy plays an important role in the therapy of advanced head and neck cancers, including OSCC, further studies are needed to identify biomarkers that can precisely predict the effectiveness of radiotherapy in OSCC

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