Downregulation of SIRT4 Expression Is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma

作者：Nakahara Yujiro; Yamasaki Makoto^*; Sawada Genta; Miyazaki Yasuhiro; Makino Tomoki; Takahashi Tsuyoshi; Kurokawa Yukinori; Nakajima Kiyokazu; Takiguchi Shuji; Mimori Koshi; Mori Masaki; Doki Yuichiro

来源：Oncology, 2016, 90(6): 347-355.

DOI：10.1159/000445323

• Esophageal squamous cell carcinoma
• SIRT4
• Glutamine metabolism
• Prognostic marker
• Distant recurrence

Objective: SIRT4, a mitochondria-localized sirtuin, represses glutamine metabolism by inhibiting glutamate dehydrogenase (GDH). The current study aimed to evaluate the clinical and biological significance of SIRT4 in esophageal squamous cell carcinoma (ESCC). Methods: The study comprised 172 patients with surgically resected ESCC in two independent cohorts. SIRT4 mRNA expression was analyzed in Cohort 1 (n = 79) and SIRT4 protein expression in Cohort 2 (n = 93). The association of SIRT4 expression with clinicopathological parameters and prognosis was assessed. Furthermore, the biological role of SIRT4 in ESCC cell lines was examined. Results: SIRT4 expression was not correlated with any clinicopathological parameters in both cohorts. In Cohort 1, low-SIRT4-expression cases had poorer overall survival than high-SIRT4-expression cases (p = 0.016). In Cohort 2, SIRT4-negative cases had poorer overall survival and disease-free survival than SIRT4-positive cases (p = 0.011 and 0.0026). Multivariate analysis revealed that SIRT4 expression was an independent prognostic factor for overall survival (HR = 2.06, p = 0.038). The rate of distant recurrence was significantly higher in SIRT4-negative cases than in SIRT4-positive cases (39.4 vs. 7.4%; p = 0.0023). In vitro, SIRT4 knockdown significantly increased GDH activity and promoted cell proliferation and migration. Conclusion: SIRT4 is a potential prognostic biomarker in ESCC.

• 出版日期2016