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Open AccessArticle

An Integrated Genomic Strategy to Identify CHRNB4 as a Diagnostic/Prognostic Biomarker for Targeted Therapy in Head and Neck Cancer

by Yi-Hsuan Chuang 1,†, Chia-Hwa Lee 2,3,4,†, Chun-Yu Lin 1,5,6,†, Chia-Lin Liu 7, Sing-Han Huang 1, Jung-Yu Lee 1, Yi-Yuan Chiu 1, Jih-Chin Lee 1,8,* and Jinn-Moon Yang 1,5,6,9,10,*
1
Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 300, Taiwan
2
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
3
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
4
Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
5
Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan
6
Center for Intelligent Drug Systems and Smart Bio-devices, National Chiao Tung University, Hsinchu 300, Taiwan
7
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 110, Taiwan
8
Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 110, Taiwan
9
Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
10
Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cancers 2020, 12(5), 1324; https://doi.org/10.3390/cancers12051324
Received: 6 May 2020 / Accepted: 19 May 2020 / Published: 22 May 2020
Although many studies have shown the association between smoking and the increased incidence and adverse prognosis of head and neck squamous cell carcinoma (HNSCC), the mechanisms and pharmaceutical targets involved remain unclear. Here, we integrated gene expression signatures, genetic alterations, and survival analyses to identify prognostic indicators and therapeutic targets for smoking HNSCC patients, and we discovered that the FDA-approved drug varenicline inhibits the target for cancer cell migration/invasion. We first identified 18 smoking-related and prognostic genes for HNSCC by using RNA-Seq and clinical follow-up data. One of these genes, CHRNB4 (neuronal acetylcholine receptor subunit beta-4), increased the risk of death by approximately threefold in CHRNB4-high expression smokers compared to CHRNB4-low expression smokers (log rank, p = 0.00042; hazard ratio, 2.82; 95% CI, 1.55–5.14), former smokers, and non-smokers. Furthermore, we examined the functional enrichment of co-regulated genes of CHRNB4 and its 246 frequently occurring copy number alterations (CNAs). We found that these genes were involved in promoting angiogenesis, resisting cell death, and sustaining proliferation, and contributed to much worse outcomes for CHRNB4-high patients. Finally, we performed CHRNB4 gene editing and drug inhibition assays, and the results validate these observations. In summary, our study suggests that CHRNB4 is a prognostic indicator for smoking HNSCC patients and provides a potential new therapeutic drug to prevent recurrence or distant metastasis. View Full-Text
Keywords: head and neck squamous cell carcinoma (HNSCC); smoking; nicotine; prognostic biomarker; drug repurposing head and neck squamous cell carcinoma (HNSCC); smoking; nicotine; prognostic biomarker; drug repurposing
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Chuang, Y.-H.; Lee, C.-H.; Lin, C.-Y.; Liu, C.-L.; Huang, S.-H.; Lee, J.-Y.; Chiu, Y.-Y.; Lee, J.-C.; Yang, J.-M. An Integrated Genomic Strategy to Identify CHRNB4 as a Diagnostic/Prognostic Biomarker for Targeted Therapy in Head and Neck Cancer. Cancers 2020, 12, 1324.

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