Overexpression of SIRT1 is Associated With Poor Outcomes in Patients With Ovarian Carcinoma

Abstract

Sirtuin 1 (SIRT1), originally identified as a longevity gene, regulates DNA repair and metabolism by deacetylating target proteins such as p53. SIRT1 plays a key role in the pathophysiology of metabolic diseases and neurodegenerative disorders, and is considered to protect against age-related diseases including cancer. In contrast, SIRT1 may be oncogenic because its overexpression has been detected in many cancers. The aim of the present study was to clarify the expression and the role of SIRT1 in ovarian carcinoma (OvCa). The expression of SIRT1 was evaluated immunohistochemically in 16 cases of normal ovaries, 35 cases of endometriosis with/without carcinoma, and 68 cases of OvCa (endometrioid, 16; clear cell, 20; mucinous, 16; serous, 16). Staining results were evaluated semiquantitatively by the Immunoreactive Scoring System, and the relationships with clinicopathologic features and outcomes of patients were analyzed. The expression of SIRT1 was higher in endometrioid, mucinous, and clear-cell carcinomas than in the inclusion cysts of normal ovaries, but not in serous carcinoma (P=0.038). The expression of SIRT1 on OvCa did not correlate with age, stage, location of metastasis, or capsular penetration. However, elevated SIRT1 expression was a significant predictor of shorter survival in univariate (P=0.038) and multivariate (P=0.037) survival analyses, regardless of the tumor stage. Results of the present study suggest a positive role for SIRT1 in the development of OvCa and its potential as a novel therapeutic target.

microRNA-494 is a potential prognostic marker and inhibits cellular proliferation, migration and invasion by targeting SIRT1 in epithelial ovarian cancer

“…Furthermore, SIRT1 expression level was associated with increased overall survival rate in SIRT1-positive serous carcinoma (43). A previous study demonstrated that SIRT1 was upregulated in EOC tissues compared with is expression in matched NATs (44). This study revealed that SIRT1 contributed to EOC cell growth and metastasis.…”

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

“…SIRT1 is over-expressed in a majority of ovarian cancers [13,14], implying a role of SIRTs in ovarian tumorigenesis. HighexpressionofSIRT1isalso associated with malignant transformation of human ovarian tissue [15] and with ovarian carcinoma with poor prognosis [16]. Therefore, SIRT1 inhibition appears to be a good strategy to overcome cancer drug resistance and improve therapy.…”

“…It has been suggested that a decline in energy metabolism may play an important role in activating the cell death pathway and dysregulation of pyruvate kinase M2 (PKM2), which favor both carcinogenesis and the Warburg effect [17]. Previous study demonstrated that SIRT1 overexpression is associated with poor outcome and chemo-resistance in ovarian cancer of epithelial origin over-expression, and one of the mechanisms may involve the dysregulation of energy metabolism and stress response [16,18].…”

The Role and Application of Sirtuins and mTOR Signaling in the Control of Ovarian Functions

“…For example, polycystic ovarian syndrome is associated with decreased expression of SIRT1 [17]. High expression of SIRT1 is associated with malignant transformation of human ovarian tissue [18] and with poor outcomes in patients with ovarian carcinoma [19]. Despite the potential usefulness of SIRTs for diagnostics of ovarian dysfunctions, SIRTs other than SIRT1 do not seem to have been studied from this viewpoint.…”

“…Furthermore, mTOR (like SIRTs) may mediate FSH action on ovarian cells; FSH affected mTOR in rat [38] and porcine [26] granulosa cells, while synthetic mTOR inhibitors prevented the stimulatory influence of FSH and induce the inhibitory effect of FSH on proliferation, apoptosis, and steroidogenesis in porcine granulosa cells [26]. Natural mTOR inhibitor (rapamycin) treatment promoted apoptosis in healthy porcine ovarian cells [13], suppressed follicular growth and maturation in rodents [19,32], and increased the risk of oligomenorrhea in humans [39]. Resveratrol, the other mTOR blocker and activator of SIRTs, was able to induce apoptosis/atresia in porcine ovarian follicles [13].…”