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

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; 20(13); 3434-45. Ó2014 AACR.

Sirtuin 7 in cell proliferation, stress and disease: Rise of the Seventh Sirtuin!

“…A recent study found similar results in colorectal cancer samples (CRCs) [73] . An increased expression of SIRT7 was found in colorectal cancer tissues as well as CRC cell lines (HCT116.DLD1, THC8307, HT29 and SW620).…”

“…SIRT7 overexpressing cells also showed increased motility which was attributed to induction of mesenchymal characters in these cell lines. SIRT7 overexpression decreased E-cadherin and β-catenin expression to cause this transition and increase cell motility [73] (Fig.-4C). A study in head and neck squamous cell carcinomas, reported a decrease in expression levels of all sirtuins including SIRT7 at transcript levels [76].…”

“…SIRT1 has been most extensively studied in context of cancer and its expression pattern has varied in different cancer types [69][70][71][72]. In contrast, SIRT7 has been found to be upregulated in all the cancer types studied so far -Thyroid, node positive breast cancer, Bladder cancer, hepatocellular carcinoma and colorectal cancer; and hence is seen as a potential oncogene [31,[33][34][35]73]. Also in many of these studies reported an increased expression levels in cancerous cell lines compared to their normal counterpart and a knockdown in the expression levels of SIRT7 in these cell lines abrogated their proliferative capacity or oncogenic capacity [22,35,73].…”

SIRT7 Exhibits Oncogenic Potential in Human Ovarian Cancer Cells

“…In recent years, emerging studies have been performed on SIRT7 and provided some potential mechanisms for SIRT7 in promoting cancer development. Researches in hepatocelluar carcinoma and bladder cancer indicated that SIRT7 promoted cancer cell proliferation and was regulated by microRNA, such as miR-125a-5p and miR-125b; a research in colorectal cancer identified that SIRT7 functioned as an oncogene by activation of RAF-MEK-ERK signaling pathway and increased cancer cells motility by epithelial-tomesenchymal transition (EMT) (Han et al, 2013;Kim et al, 2013;Yu et al, 2014). However, the level of SIRT7 in ovarian malignancies and the corresponding consequences of its aberrant regulation have not been discovered.…”

“…Another study proposed that SIRT7 can promote cell survival by suppressing ER stress in a myc-dependent mannner (Shin et al, 2013). In addition, evidence has suggested that SIRT7 was related to maintenance of cellular transformation in malignancies, such as breast, liver, bladder and colorectal cancer; it has an elevated level in cancerous tissues compared with the noncancerous and its levels are associated with tumor progression (Ashraf et al, 2006;Han et al, 2013;Kim et al, 2013;Yu et al, 2014). On the contrary, a comprehensive research on the expression level of SIRT7 in head and neck squamous cell carcinoma showed a significant down-regulation (Lai et al, 2013).…”