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

1
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University (TMU), Taipei 11031, Taiwan
2
Department of Otolaryngology, TMU Hospital, TMU, Taipei 11031, Taiwan
3
Graduate Institute of Clinical Medicine, College of Medicine, TMU, Taipei 11031, Taiwan
4
Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
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Department of Neurology, School of Medicine, College of Medicine, TMU, Taipei 11031, Taiwan
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Department of Neurology, Vertigo and Balance Impairment Center, Shuang Ho Hospital, TMU, New Taipei City 23561, Taiwan
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Department of Urology, Division of Surgery, Cardinal Tien Hospital, Xindian District, New Taipei City 23148, Taiwan
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Department of Breast Surgery and General Surgery, Division of Surgery, Cardinal Tien Hospital, Xindian District, New Taipei City 23148, Taiwan
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Department of Radiation Oncology, TMU Hospital, TMU, Taipei 11031, Taiwan
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Department of Otolaryngology, Shuang-Ho Hospital, TMU, New Taipei City 23561, Taiwan
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Department of Otolaryngology, School of Medicine, College of Medicine, TMU, Taipei 11031, Taiwan
12
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, TMU, Taipei 11031, Taiwan
13
Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, TMU, Taipei 11696, Taiwan
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(9), 1454; https://doi.org/10.3390/jcm8091454
Received: 31 July 2019 / Revised: 28 August 2019 / Accepted: 10 September 2019 / Published: 12 September 2019
(This article belongs to the Section Otolaryngology)
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. View Full-Text
Keywords: radiotherapy; oral squamous cell carcinoma; CHRNA5; nicotinic acetylcholine receptor; E2F radiotherapy; oral squamous cell carcinoma; CHRNA5; nicotinic acetylcholine receptor; E2F
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MDPI and ACS Style

Lin, C.-H.; Lee, H.-H.; Kuei, C.-H.; Lin, H.-Y.; Lu, L.-S.; Lee, F.-P.; Chang, J.; Wang, J.-Y.; Hsu, K.-C.; Lin, Y.-F. Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma. J. Clin. Med. 2019, 8, 1454. https://doi.org/10.3390/jcm8091454

AMA Style

Lin C-H, Lee H-H, Kuei C-H, Lin H-Y, Lu L-S, Lee F-P, Chang J, Wang J-Y, Hsu K-C, Lin Y-F. Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma. Journal of Clinical Medicine. 2019; 8(9):1454. https://doi.org/10.3390/jcm8091454

Chicago/Turabian Style

Lin, Che-Hsuan, Hsun-Hua Lee, Chia-Hao Kuei, Hui-Yu Lin, Long-Sheng Lu, Fei-Peng Lee, Jungshan Chang, Jia-Yi Wang, Kai-Cheng Hsu, and Yuan-Feng Lin. 2019. "Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma" Journal of Clinical Medicine 8, no. 9: 1454. https://doi.org/10.3390/jcm8091454

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