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Downregulated SIRT6 and Upregulated NMNAT2 Are Associated with the Presence, Depth and Stage of Colorectal Cancer

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Downregulated SIRT6 and Upregulated NMNAT2 Are Associated with the Presence, Depth and Stage of Colorectal Cancer ONCOLOGY LETTERS 16: 5829-5837, 2018 Downregulated SIRT6 and upregulated NMNAT2 are associated with the presence, depth and stage of colorectal cancer JIA QI1, CHUNHUI CUI1, QUANWEN DENG2, LIFENG WANG3, RIHONG CHEN1, DUANYANG ZHAI1, LANG XIE1 and JINLONG YU1 1Department of General Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280; 2Department of Pharmacy, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515; 3Department of Gastroenterology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, P.R. China Received July 22, 2016; Accepted January 8, 2018 DOI: 10.3892/ol.2018.9400 Abstract. Colorectal cancer (CRC) is an important cause of preliminary study demonstrated that the increased expres- morbidity and mortality worldwide, and is difficult to detect sion of NMNAT2 and reduced expression of SIRT6 may be in its early stages. Diagnostic and prognostic biomarkers associated with the progression of CRC. The downregulation are required, which may also be the basis for improving the of SIRT6 may promote the expression of NMNAT2. Further targeted therapy for CRC. Sirtuin 6 (SIRT6) is a member of the studies are indicated on the role of NMNAT2 and SIRT6 as sirtuin family of gene regulators, which have specific functions potential diagnostic and prognostic biomarkers and as targets in genomic stability, gene transcription and energy metabolism for therapy in CRC and other malignant tumors. in tumorigenesis. Nicotinamide mononucleotide adenylyl- transferase 2 (NMNAT2) is a metabolic enzyme which can Introduction be deacetylated by sirtuins. In this study, tissue samples from 29 patients with histologically confirmed CRC of varying grade Colorectal cancer (CRC) is one of the most common types of and stage were studied for SIRT6 and NMNAT2 expression by solid tumor, with ~1.2 million new confirmed diagnoses of western blotting and reverse transcription-quantitative poly- CRC annually worldwide and with 55% of cases occurring merase chain reaction. Immunohistochemistry was performed in economically developed countries (1). Changes in lifestyle, for SIRT6 and NMNAT2 expression in 113 paired (CRC and population growth and the aging population have made CRC adjacent) tissue sections. SIRT6 protein and mRNA expression an increasingly global health problem (2). Patients with CRC levels were significantly reduced in CRC tissues; NMNAT2 have a poor prognosis; 15% of patients present with metastases protein and mRNA expression levels were significantly at the time of initial diagnosis, and ~35% of patients diagnosed increased in CRC tissues (P<0.01). A negative correlation with CRC ultimately develop metastasis (3,4). Despite the between the expression of SIRT6 and NMNAT2 in CRC recent use of neoadjuvant chemotherapy (NCT) or NCT in tissue samples was identified (r=‑0.246, P<0.01). The reduced combination with targeted agents, which has resulted in an expression of SIRT6 and increased expression of NMNAT2 improvement in the overall survival rate, CRC remains one were associated with the tumor depth invasion, stage, differ- of the leading causes of cancer mortality, with >600,000 entiation grade (SIRT6 only) and the presence of lymph node mortalities occurring due to CRC annually worldwide (5,6). metastasis (P<0.05). In conclusion, the findings of the present Identifying specific molecules associated with CRC may facilitate the development of diagnostic and prognostic biomarkers, and more specific targets for therapy, in order to further improve the clinical outcome of patients with CRC. Correspondence to: Dr Jinlong Yu, Department of General The sirtuins (SIRTs) are a conserved family of nico- Surgery, Zhujiang Hospital of Southern Medical University, tinamide adenine dinucleotide (NAD)-dependent histone 253 Industrial Avenue, Guangzhou, Guangdong 510280, deacetylases composed of seven SIRT isoforms (SIRT1-7) in P. R. Ch i na mammalian genomes (7,8) The nuclear protein SIRT6 is a E-mail: [email protected] member of the SIRT family, which has been demonstrated to exert diverse cancer-associated functions, including in Abbreviations: CRC, colorectal cancer; NAD, nicotinamide adenine dinucleotide; NMNAT2, nicotinamide mononucleotide genomic stability, DNA repair, gene transcription repression adenylyltransferase 2; SIRT6, sirtuin 6 and stress resistance, by multiple molecular mechanisms (9). SIRT6 is a chromatin-bound factor that promotes genomic Key words: colorectal carcinoma, nicotinamide mononucleotide integrity by de-acetylating histone H3 lysine 9 (H3K9) and adenylyltransferase 2, sirtuin 6 56; SIRT6‑mediated histone de‑acetylation contributes to the repair of DNA double-strand breaks (10-12). SIRT6 may act as a chromatin-bound factor to protect cells from genomic 5830 QI et al: SIRT6 AND NMNAT2 IN COLORECTAL CANCER instability, including in non-transformed cells (13,14). SIRT6 The 113 patients included 65 males and 48 females aged has also been reported to function at the gene expression between 30 and 91 years, with a median age of 64 years. level via the recruitment of transcription factors, including Patients were classified into four stages (stage I, 36; stage II, NF-κB and c-Jun, and may deacetylate H3K9 at the site of 30; stage III, 29; and stage IV, 18) according to the Union for gene promoters (15,16) A previous study identified SIRT6 International Cancer Control Tumor-Node-Metastasis (TNM) as a novel molecular mechanism for controlling energy staging system (25). Tumors were graded according to the metabolism in cancer cells (17). In 2012, the Cancer Cell World Health Organization system (26) as well differentiated Line Encyclopedia reported that the SIRT6 gene is deleted (n=18), moderately differentiated (n=87) or poorly differenti- in 35% of the 1,000 human cancer cell lines recorded in their ated (n=8). The following clinical data were also recorded and database, including in 29% of CRC cell lines (18). However, analyzed in the study: Tumor size, depth of invasion, lymph the role of SIRT6 in CRC and the molecular mechanisms by node metastasis and distant metastasis. The histological diag- which it acts as a regulator of cancer-associated metabolism nosis, classification and tissue sampling was performed by two remain unknown. experienced senior pathologists. Nicotinamide mononucleotide adenylyltransferase From the surgically resected colectomy specimens, 2 (NMNAT2) is an isoform of NMNAT, which catalyzes a pathologists sampled tumor tissue as well as adjacent normal vital step in the synthesis of NAD (19). NMNAT2 is a sensitive colorectal tissue that was confirmed to be free from infiltration enzyme marker for NAD levels that reflects the intracellular by CRC and located >5 cm beyond the tumor margin. Fresh redox equilibrium and cellular energy state, acting as a tissue samples that were sampled following resection were sensor for cells with a high energy demand, including cancer frozen in liquid nitrogen and stored at ‑80˚C until analysis was cells (20,21). Although the associated biological mechanism performed. remains largely unknown, there is increasing evidence that NMNAT2 promotes the survival of cancer cells by acceler- Reverse transcription‑quantitative polymerase chain reaction ating glycolysis (22). SIRT6 controls the expression of multiple (RT‑qPCR) analysis of gene transcription. A total of 29 glycolytic genes, including HIF-1α (23). samples of tissue RNA was extracted with TRIzol reagent Given the evidence of the possible roles for SIRT6 and (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, NMNAT2 in human cancer, including of SIRT6 in the control USA) and RNA concentration was measured by using a of energy metabolism by acting either as a substrate for, or NanoDrop 1000 spectrophotometer (Thermo Fisher Scientific, regulator of, NMNAT2 (24), the present study was performed Inc., Penfield, NY, USA). PrimeScript RT master mix (Takara to determine the expression of SIRT6 and NMNAT2 in Bio, Inc., Otsu, Japan) was added to synthesize the first strand different grades and stages of CRC. of cDNA using the Reverse Transcription system (Promega Corporation, Madison, WI, USA) according to the manufac- Materials and methods turer's protocol. RT-qPCR was performed using the 7500 FastReal-Time Ethical statement. All patients included in this study were Two‑step PCR system (Applied Biosystems; Thermo Fisher informed of the study protocol and requirements, and provided Scientific, Inc.) with the SYBR-Green qPCR master mix signed informed consent to participate in the study. The study, (Takara, Tokyo, Japan). The amplification protocol commenced including the protocols for collection of tissue specimens with a 30‑sec pre‑denaturation step at 95˚C, followed by and analysis of clinical information, was approved by the 40 cycles of denaturation at 95˚C for 5 sec, and annealing Institutional Review Board of Nanfang Hospital and Zhujiang and extension at 60˚C for 34 sec. Subsequent verification of Hospital of the Southern Medical University (Guangzhou, product specificity was conducted in the melting stage, ending China). with inactivation at 95˚C for 15 sec. Quantitative gene expression data were normalized to the Inclusion and exclusion criteria. All patients included in the expression level of GAPDH and the analysis of each sample present study met the following criteria: i) A histologically was performed in triplicate. The primers for human genes confirmed diagnosis of primary CRC; ii) treatment with were designed by PrimerBank
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