Biochemical and Biophysical Research Communications
Aberrant expression of SIRT3 is conversely correlated with the progression and prognosis of human gastric cancer
Introduction
Gastric cancer (GC) ranks the second mortality of cancer in the worldwide [1]. Both exogenous and endogenous factors contribute to its development and progression. It has been recognized that multiple genetic and epigenetic alteration or abnormality occurs in the development of GC [2]. In this regard, loss or altered function of tumor suppressor genes plays a critical role in GC etiology.
Sirtuins are NAD+-dependent histone deacetylases (HDAC) and widely expressed in normal tissues in mammary animals. Seven members have been identified in human, including Sirt1–7, and play essential roles in cellular physiology, including cell metabolism, cell cycle, cell division and transcriptional regulation. Furthermore, they are also involved in the pathogenesis of series of diseases such as metabolic diseases [3], neurodegenerative diseases [4], cardiovascular diseases [5] and aging [6].
Human SIRT3 is a full-length 44-kD protein and localized mainly in cell mitochondrial. It has the capacity to activate fat oxidation, amino-acid metabolism and electron transport via interaction with various substrates [7], [8], [9].
Recently, it has been demonstrated that various types of clinical carcinomas, including hepatocellular carcinoma [10], [11], breast carcinoma [12], lung NSC [12], [13], medulloblastoma [12], neck carcinoma and prostate carcinoma [13], [14] displayed decreased levels or deletion of SIRT3 and SIRT3−/− mice were more susceptible to develop mammary tumors compared with the wide type cohorts, suggesting that SIRT3 may function as a mitochondrial tumor suppressor [15], [16], [17]. However, its role in the pathogenesis of gastric cancer is still unclear.
In this study, we investigated the expression of SIRT3 and its correlation with the disease progress and prognosis of gastric cancer. Our data showed that there was significantly decreased expression of SIRT3 protein and mRNA levels in the tissues of 64.0% GC patients. Notably, the expression level of SIRT3 was closely correlated with the tumor infiltration, tumor differentiation and tumor stage. Furthermore, our retrospective analysis of 65 GC patients showed that patients with high SIRT3 expression survived much longer than those with low SIRT3 expression. Taken together, our data demonstrate a critical role for SIRT3 in the progress and prognosis of clinical GC.
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Patients and tissue samples
All the patients were diagnosed according to the 6th edition of AJCC cancer staging manual. The matched fresh tissue samples of primary gastric cancer and adjacent normal tissues from the same patient used for western blot and Real-Time PCR were collected from 25 GC patients, including 18 male and 7 female with a mean age of 61.8 ± 12.5 years, undergoing surgical resection at Longgang District Central Hospital of Shenzhen and Shenzhen People’s Hospital (Shenzhen, China) from 2011 to 2012. All
Expression of SIRT3 is decreased or completely absent in human GC tissues
It was previously shown that SIRT3 could function as either oncogene or tumor suppressor gene. To assess if SIRT3 was involved in the pathogenesis of gastric cancer, we firstly detected the expression of SIRT3 in 25 GC patients using western blot assay. All the GC patients were newly diagnosed and did not receive any treatment before surgical resection. Interestingly, western blot revealed that 64.0% of patients with GC (16/25) had significant reduction of SIRT3 compared with the adjacent
Discussion
SIRT3 has been reported to be correlated with a panel of human tumors, such as hepatocellular carcinoma, breast carcinoma, medulloblastoma, lung NSCO and varian carcinoma, where SIRT3 was obviously deleted [18].
These data have indicated that SIRT3 might function as a mitochondrial tumor suppressor. However, SIRT3 seems to also function as an oncogene in several tumors (e.g. oral carcinoma). SIRT3 was overexpressed in oral squamous cell carcinoma (OSCC) cell lines and down-regulation of SIRT3
Acknowledgments
We thank Dr. Hui Che (The University of Hong Kong) for her technical support. This work was supported by Grants provided from the Scientific Foundation of Shenzhen (No. 201102116).
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These authors contribute equally to this work.