Original article
Differential expression of the sirtuin family in renal cell carcinoma: Aspects of carcinogenesis and prognostic significance

https://doi.org/10.1016/j.urolonc.2017.08.016Get rights and content

Highlights

  • We compared SIRT expression between normal kidney and renal cell carcinoma (RCC) and examined the relationship between SIRT expression and prognosis. SIRT1, SIRT3, and SIRT6 expression was significantly lower in tumor tissues than in normal tissues.

  • SIRT3 expression was significantly associated with longer CSS, after adjusting for age, T stage, Fuhrman grade, Karnofsky performance status, and distant metastases.

  • SIRT1, SIRT3, and SIRT6 may function as tumor suppressors in RCC. SIRT3 is also expected to be a prognostic marker in clear cell RCC."

Abstract

Objectives

Sirtuins (1–7) are evolutionarily conserved NAD-dependent deacetylases that play an important role in carcinogenesis. However, their role in renal cell carcinoma (RCC) remains unclear. The objective of the present study was to examine the role of SIRTs in RCC carcinogenesis and prognosis.

Materials and methods

Paraffin-embedded specimens from 102 patients who underwent extirpative renal surgeries for renal masses between January 2004 and December 2010 were examined. SIRT expression was compared between RCC and adjacent normal kidney tissues by immunohistochemical staining. Survival differences and cancer-specific survival were analyzed with the Kaplan-Meier log-rank test and univariate and multivariate Cox regression analyses, respectively.

Results

SIRT1, SIRT3, and SIRT6 expression was significantly lower in RCC than in normal tissues (P = 0.001, P = 0.006, and P = 0.033, respectively), whereas the expression of other SIRT proteins did not differ significantly between the 2 tissues. SIRT3 expression was significantly associated with longer cancer-specific survival (HR = 0.133, P = 0.047), after adjusting for age, T stage, Fuhrman grade, Karnofsky performance status, and distant metastases. Kaplan-Meier analysis showed that patients with high-SIRT3 expression had relatively better survival than those with low-SIRT3 expression (P = 0.046, log-rank test).

Conclusions

Our results provide preliminary evidence suggesting that SIRT1, SIRT3, and SIRT6 function as tumor suppressors in RCC. In particular, SIRT3 seems to have a favorable influence on the survival of patients with clear cell RCC.

Introduction

Renal cell carcinoma (RCC) accounts for approximately 90% of all kidney malignancies, which in turn account for 2% to 3% of all adult cancers worldwide [1]. RCC is the most lethal urological tumor and the sixth leading cause of cancer-associated mortality in Western countries [1]. To date, much effort has been made to identify a genetic regulator with diagnostic and prognostic potential in RCC. However, the precise role of the sirtuin (SIRT) family of genes is not well reported.

SIRTs constitute a highly conserved gene family found in organisms ranging from bacteria to humans that play key roles in cellular apoptosis, aging, and resistance to metabolic stress [2], [3]. Seven mammalian SIRTs (SIRT1–7) have been identified, and deregulated expression of these genes is involved in the development of various malignancies [4], [5]. The best-characterized member of this family is SIRT1, which is predominantly located in the nucleus [6]. Recent reports suggest a carcinogenic function of SIRT1 in lung, breast, and colon cancers; however, its role as a putative tumor suppressor in different cancer types was also suggested [7], [8], [9]. Less is known about SIRT2. SIRT2, the primary cytoplasmic SIRT, is downregulated in human gliomas, breast cancer, and hepatocellular carcinoma [10], [11]. SIRT3 to SIRT5 are mitochondrial SIRTs that link aging to energy metabolism [12]. SIRT3 is overexpressed in oral cancer and lymph node-positive breast cancer [13], [14]. However, data indicate a suppressive role of SIRT3 in hepatocellular carcinoma [15], lung adenocarcinoma [16], and gastric cancer [17]. SIRT4 plays an important role in insulin regulation, and its activity is downregulated by calorie restriction [18]. The precise role of SIRT4 and SIRT5 in cancer development remains unclear. The remaining 2 SIRTs, SIRT6 and SIRT7, are localized in the nucleus and cytoplasm [6], [19]. SIRT6 is a candidate tumor suppressor, as its expression is significantly decreased in hepatocellular carcinoma [20]. SIRT7 is a positive regulator of RNA polymerase I transcription and is required for cell proliferation and survival [21]. SIRT7 is also upregulated in breast and thyroid cancers [13], [22].

These results indicate that altered expression of SIRTs may contribute to the development of cancer and other clinicopathological conditions. However, few studies have examined the role of the SIRT family in RCC. The present study explored the potential role of the SIRT family in RCC by evaluating the expression of SIRT proteins and their relationship to the clinicopathological features of patients with RCC.

Section snippets

Study population

The clinical, radiologic, and pathologic records of 119 consecutive patients who underwent extirpative surgery for renal tumors between January 2004 and December 2010 were assessed in accordance with the Institutional Review Board guidelines of Gyeongsang National University Hospital. None of the patients had received chemotherapy or radiation therapy before surgical tumor resection. Clinicopathologic data such as sex, age, Karnofsky performance status, Fuhrman grade, and tumor-node-metastasis

Clinicopathological features of the study population

Of the 119 patients enrolled, 17 were excluded from the study because of lack of expression data. The clinical and pathological parameters of the patients are summarized in Table 1. There were 74 (72.5%) men, and the median age of patients was 59 years (interquartile range: 49.75–69.25). Among the 102 RCCs, 24 (23.5%) recurrences or metastases were noted during the median follow-up duration of 73 months (interquartile range: 42.75–96.25).

Evaluation of SIRT expression in normal and tumor tissues

To evaluate the role of SIRT in RCC, the expression of

Discussion

The aim of the present study was to assess the IHC expression of seven SIRTs (SIRT1–7) in human RCC and their relationships with clinicopathological factors and prognostic significance. To the best of our knowledge, this is the first report examining the expression of individual SIRTs and its relationship to prognosis in RCC. SIRT1, SIRT3, and SIRT6 were downregulated in RCC compared with their expression in normal tissues, suggesting that SIRT1, SIRT3, and SIRT6 may act as tumor suppressors in

Conclusion

The SIRT family shows differential expression in RCC tissues. Among the seven SIRTs, SIRT1, SIRT3, and SIRT6 may act as tumor suppressors in RCC. The results of the present study indicate that SIRT3 gene expression is a potential prognostic marker in clear cell RCC.

Acknowledgments

This work was supported by the Biomedical Research Institute fund (GNUHBRIF-2017-0002) from the Gyeongsang National University Hospital and by the National Research Foundation of Korea Grant from the Korean Government (NRF-2017R1A2B4010122).

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