Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

Chia-Chen Hsu; Yu-Fu Su; Kuo-Yang Tsai; Feng-Chih Kuo; Chi-Fu Chiang; Chu-Yen Chien; Ying-Chen Chen; Chien-Hsing Lee; Yu-Chiao Wu; Kun Wang; Shyun-Yeu Liu; Yi-Shing Shieh

doi:10.1186/s12935-020-01401-w

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

Cancer Cell Int. 2020 Jul 10:20:300. doi: 10.1186/s12935-020-01401-w. eCollection 2020.

Authors

Chia-Chen Hsu¹, Yu-Fu Su^{1

2}, Kuo-Yang Tsai^{3

4}, Feng-Chih Kuo⁵, Chi-Fu Chiang⁶, Chu-Yen Chien¹, Ying-Chen Chen⁷, Chien-Hsing Lee⁵, Yu-Chiao Wu⁶, Kun Wang⁸, Shyun-Yeu Liu⁹, Yi-Shing Shieh^{6

10}

Affiliations

¹ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 114 Taiwan.
² Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan.
³ Department of Oral and Maxillofacial Surgery, Changhua Christian Hospital, Changhua, 500 Taiwan.
⁴ College of Nursing and Health Science, Da-Yeh University, Changhua, 515 Taiwan.
⁵ Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan.
⁶ Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, No.161, Sec.6, Min-Chuan East Rd., Nei-Hu, Taipei, 114 Taiwan.
⁷ Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei, 114 Taiwan.
⁸ Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
⁹ Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan, 710 Taiwan.
¹⁰ Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, 114 Taiwan.

Abstract

Background: The mechanisms of neuronal protein γ-synuclein (SNCG) in the malignancy of oral squamous cell carcinoma (OSCC) are not clear. This study tested the hypothesis that SNCG is involved in nicotine-induced malignant behaviors of OSCC. The effect of nicotine on SNCG expression and epithelial-to-mesenchymal transition (EMT) markers were examined.

Methods: Short hairpin RNA (shRNA) and an antagonist specific for α7-nicotine acetylcholine receptors (α7-nAChRs) were used to examine the role of α7-nAChRs in mediating the effects of nicotine. Knockdown of SNCG in nicotine-treated cells was performed to investigate the role of SNCG in cancer malignancy. The in vivo effect of nicotine was examined using a nude mouse xenotransplantation model.

Results: Nicotine increased SNCG expression in a time- and dose-dependent manner. Nicotine treatment also increased E-cadherin and ZO-1 and decreased fibronectin and vimentin expression. After specific knockdown of α7-nAChRs and inhibition of the PI3/AKT signal, the effect of nicotine on SNCG expression was attenuated. Silencing of SNCG abolished nicotine-induced invasion and migration of OSCC cells. The xenotransplantation model revealed that nicotine augmented tumor growth and SNCG expression.

Conclusion: Nicotine upregulated SNCG expression by activating the α7-nAChRs/PI3/AKT signaling that are participated in nicotine-induced oral cancer malignancy.

Keywords: Gamma synuclein; Nicotine acetylcholine receptor; Oral cancer; Signal transduction.