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Overexpression of Sirt7 Exhibits Oncogenic Property and Serves As a Prognostic Factor in Colorectal Cancer

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Overexpression of Sirt7 Exhibits Oncogenic Property and Serves As a Prognostic Factor in Colorectal Cancer Published OnlineFirst April 25, 2014; DOI: 10.1158/1078-0432.CCR-13-2952 Clinical Cancer Human Cancer Biology Research Overexpression of Sirt7 Exhibits Oncogenic Property and Serves as a Prognostic Factor in Colorectal Cancer Hongyan Yu1, Wen Ye1, Jiangxue Wu1, Xiangqi Meng1, Ran-yi Liu1, Xiaofang Ying1, Yi Zhou1, Hui Wang1, Changchuan Pan2, and Wenlin Huang1,3 Abstract Purpose: Sirtuins play an important role in cancer development. Sirt7, as a member of this family, is frequently overexpressed in certain carcinomas, but the oncogenic mechanism is seldom reported. In this study, Sirt7 was characterized for its role in colorectal cancer aggressiveness and underlying molecular mechanisms. Experimental Design: Quantitative PCR, Western blotting, and immunohistochemistry were performed to study Sirt7 expression in a cohort of colorectal cancer tissues and non-tumor tissues and cells. A series of in vitro and in vivo assays was performed to elucidate the function of Sirt7 in colorectal cancer and its underlying mechanisms. Association between the Sirt7 signature and survival was examined using Kaplan–Meier analysis and log-rank tests. Results: The Sirt7 protein level significantly correlated with tumor stage (P ¼ 0.029), lymph node metastasis (P ¼ 0.046), and poor patient survival (P < 0.05). Sirt7 knockdown significantly inhibited colorectal cancer cell proliferation, colony formation, and motility. Ectopic Sirt7 expression promoted colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Moreover, Sirt7 enhanced MAPK pathway activity concomitantly with p-ERK and p-MEK upregulation. In Sirt7-overexpressing cells, the mesenchymal markers vimentin and fibronectin were upregulated, and the epithelial markers E-cadherin and b-catenin were downregulated, which was linked to enhanced invasion by colorectal cancer cells. Conclusion: Our findings suggest that Sirt7 plays an important role in the development and progression of human colorectal cancer and functions as a valuable marker of colorectal cancer prognosis. Clin Cancer Res; 1–12. Ó2014 AACR. Introduction Colorectal cancer is one of the three leading causes of cancer mortality worldwide (1). Despite the innovative fi 1 Authors' Af liations: Sun Yat-sen University Cancer Center; State Key therapeutic strategies applied in colorectal cancer, the prog- Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou; 2Medical Oncology, Sichuan Cancer Hos- nosis has not significantly changed in the last 20 years. In pital and Institute, Second People's Hospital of Sichuan Province, past decades, studies have reported alternative factors Chengdu; and 3CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science, involved in colorectal cancer pathogenesis, including genet- Beijing, PR China ic mutations in certain oncogenes or tumor suppressor Note: Supplementary data for this article are available at Clinical Cancer genes (KRAS, APC, DCC, Smad-2, and Smad-4) and changes Research Online (http://clincancerres.aacrjournals.org/). in the p53, b-catenin, TGF-b, and WNT transduction path- ways (2, 3). These findings suggest that colorectal carcino- Current address for X. Ying: Department of Radiotherapy, Hubei Cancer Hospital, Wuhan 430000, PR China; and current address for H. Wang: State genesis results from an accumulation of genetic alterations. Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer How these genetic changes precisely cause the clinical Institute, Shanghai Jiao Tong University School of Medicine, Shanghai characteristics observed in individual patients with colorec- 200032, PR China. tal cancer is unclear; consequently, the mechanisms under- Corresponding Authors: Wenlin Huang, State Key Laboratory of Oncol- ogy in South China, Sun Yat-sen University Cancer Center, No. 651 lying colorectal cancer development and progression Dongfeng East Road, Guangzhou 510060, PR China. Phone: 86-20- remain poorly understood. Sirtuins are homologous with 8734-3146; Fax: 862087343146; E-mail: [email protected]; and yeast sirtuin silent information regulator 2 (Sir2), which Changchuan Pan, Medical Oncology, Sichuan Cancer Hospital and Insti- tute, Second People's Hospital of Sichuan Province, Chengdu 610000, PR was originally described as a transcriptional silencing reg- China. Phone: 862885420660; Fax: 862885420660; E-mail: ulator of mating-type loci, telomeres, and ribosomal DNA [email protected] (4, 5) and extends the yeast lifespan (6). Sir2 was soon doi: 10.1158/1078-0432.CCR-13-2952 found to be an NAD-dependent histone deacetylase Ó2014 American Association for Cancer Research. (HDAC)(7). Sirtuins, also designated as class III histone www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst April 25, 2014; DOI: 10.1158/1078-0432.CCR-13-2952 Yu et al. study also revealed the key functions of Sirt7 in activating Translational Relevance and promoting colorectal cancer growth, epithelial–mes- Colorectal cancer is one of the three leading causes of enchymal transition (EMT), which may have implica- cancer mortality worldwide. Recurrence and metastasis tions for colorectal cancer metastasis. Thus, we propose are common lethal outcomes of colorectal cancer that Sirt7 is a promising target in colorectal cancer curative resection. Thus, a better understanding of the therapy. molecular mechanisms underlying colorectal cancer progression is conducive to the development of targeted Materials and Methods therapy. In this study, we reveal a novel role of Sirtuin7 Patients (Sirt7) in promoting colorectal cancer growth by acti- Tumorous and adjacent non-tumorous colorectal tissues vating the MAPK signal pathway and enhancing colo- were collected from 131 patients (median age, 56 years; rectal cancer invasiveness and metastasis by promoting 55.6% male) at the Cancer Center of Sun Yat-sen University epithelial–mesenchymal transition for the first time. We (Guangzhou, China) between September 1999 and Decem- also find that overexpression of Sirt7 in colorectal cancer ber 2005. The samples contained matched tumors (per- is associated with lymph node metastasis and TNM stage centage of tumor cells 70%) and corresponding normal in patients with colorectal cancer. Taken together, these mucosal tissue (>5 cm laterally from the edge of the cancer- results implicate Sirt7 as a new effective therapeutic ous region); all the patients who had a single primary lesion target for intervention of the progression of colorectal and no neoadjuvant therapy before operation were includ- cancer. ed in the study. The patients were followed-up once every 3 months during the first 2 years, once every 6 months during þ the third and fourth year, and once a year from the fifth year deacetylases, are NAD -dependent deacetylases that target postoperatively, respectively. All patients were contacted by non-histone and histone proteins and are implicated in the phone or with questionnaire to check upon their health control of a wide range of biologic processes, including status and the last censor date was May 1, 2012. The apoptosis, stress responses, cell cycle, DNA repair, metab- patients who did not have the followed-up information olism, and senescence (8). were excluded from this study. Informed consent was The importance of sirtuins is demonstrated by their role obtained from each patient, and the study protocol was in several major human pathologies, including cancer, approved by the Ethics Committee of the Sun Yat-sen cardiovascular disease, diabetes, and neurodegeneration University Cancer Center Institutional Board. Colorectal (9). In mammals, the sirtuin family comprises 7 proteins cancer diagnosis was confirmed by histologic examina- (Sirt1–Sirt7) with considerably different functions and cat- tion. The TNM classification of our study is according to alytic activities (10). The most studied sirtuin that is most the sixth edition of AJCC/UICC; 15 patients were graded closely related to yeast Sir2 is Sirt1. Little is known about the as stage I, 59 patients as stage II, 42 patients as stage III, biologic function of the other 6 sirtuins (4, 11–13). and 15 patients as stage IV. Sirt7, which is primarily located in the nucleus, binds to the ribosomal RNA (rRNA) gene and is relevant to the Cell culture reactivation of rDNA transcription following mitosis The human colorectal cancer cell lines HT29, SW480, (14). Sirt7 participates in the activation of RNA polymer- DLD-1, SW620, and HCT116; the human embryonic kid- ase I transcription and may play a role in controlling ney cell lines 293T; and the normal colon epithelial cell line rRNA expression (15). Furthermore, certain studies have FHC were obtained from the American Type Culture Col- reported that Sirt7 is overexpressed in thyroid and breast lection. THC8307 and GP293 cells were obtained from our cancer tissues compared with normal tissues (16, 17), own laboratory collection. The colorectal cancer cell lines, suggesting that Sirt7 has an oncogenic role. In addition, the GP293 and 293T cells, were grown in DMEM, and the Sirt7 is located on chromosome 17q25.3, which is FHC cells were grown in DMEM:F12 (containing 10 ng/mL involved in various malignancies, including colorectal cholera toxin, 0.005 mg/mL insulin, 0.005 mg/mL trans- cancer (18). Barber and colleagues also found that Sirt7 ferrin, and 100 ng/mL hydrocortisone)
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