Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy
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PRIMARY RESEARCH
Cancer Cell International Open Access
Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy Chia‑Chen Hsu1, Yu‑Fu Su1,2, Kuo‑Yang Tsai3,4, Feng‑Chih Kuo5, Chi‑Fu Chiang6, Chu‑Yen Chien1, Ying‑Chen Chen7, Chien‑Hsing Lee5, Yu‑Chiao Wu6, Kun Wang8*, Shyun‑Yeu Liu9* and Yi‑Shing Shieh6,10*
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) mark‑ ers 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 nicotinetreated 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 partici‑ pated in nicotine-induced oral cancer malignancy. Keywords: Gamma synuclein, Nicotine acetylcholine receptor, Oral cancer, Signal transduction Background Oral cancer is the sixth most common type of cancer worldwide and the most common cause of head and neck tumors. Each year more than 500,000 patients are
*Correspondence: [email protected]; [email protected]; [email protected] 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 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 Full list of author information is available at the end of the article
newly diagnosed with oral cancer [1], and more than 90% of these patients have oral squamous cell carcinoma (OSCC) [1, 2]. The overall 5-year survival rate for OSCC is less than 50% [3]. In the past 20 years, although advancements have been made in diagnosis and treatment, the mortality rate for oral cancer has not declined [2]. Investigating molecules that mediate OSCC progression could help enable early diagnosis and effective treatment. Cigarette smoking is a risk factor for o
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