SIRT1 is overexpressed in endometrial adenocarcinoma: a tissue microarray analysis

Silent mating type information regulation 2 homolog-1 (SIRT1) is a member of sirtuin family. Its role in endometrial carcinoma (EC) is controversial and unclear. This study aims to define the SIRT1 immunoexpression pattern in endometrial carcinoma (EC), its relationship with clinicopathological features, and its prognostic significance. A tissue microarray was constructed and contained 71 endometrial carcinomas, 28 endometrial hyperplasia, and 30 normal endometrial tissues. An immunostaining study was completed using anti-SIRT rabbit polyclonal antibody. SIRT1 immunoexpression was scored and analysed. Positive immunostaining was found in 29 of the 71 (40.8%) endometrial carcinomas and in 7 of the 58 (12.1%) nonneoplastic endometrial tissues. SIRT1 immunoexpression findings were not related to age, histological type, tumor size, myometrial invasion, lymphovascular invasion, surgical resection margin, lymph node metastasis, FIGO staging, local recurrence or survival. In endometrial carcinoma, SIRT1 immunoexpression is expressed at greater levels in malignant endometrial tissue than in hyperplastic and normal endometrial tissues. However, no relationship was found between SIRT1 expression and other clinicopathological parameters. More studies are needed to explore the role of SIRT1 in ECs.

Endometrium; Tissue microarray; Immunohistochemistry; SIRT1.

[1] Bray F., Ferlay J., Soerjomataram I., Siegel R. L., Torre L.A., Je-mal A.: “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries”. Ca. Cancer J. Clin., 2018, 68, 394-424.

[2] Bazarbashi S., Al Eid H., Minguet J.: ”Cancer Incidence in Saudi Arabia: 2012 Data from the Saudi Cancer Registry”. Asian Pac. J. Cancer Prev., 2017, 18, 2437-2444.

[3] Khabaz M.N., Abdelrahman A.S., Butt N.S., Al-Maghrabi B., Al-Maghrabi J.: “Cyclin D1 is significantly associated with stage of tumor and predicts poor survival in endometrial carcinoma patients”. Ann. Diagn. Pathol., 2017, 30, 47-51.

[4] Morice P., Leary A., Creutzberg C., Abu-Rustum N., Darai E.: “En-dometrial cancer”. the Lancet, 2016, 387, 1094-1108.

[5] Amant F., Moerman P., Neven P., Timmerman D., Van Limbergen E., Vergote I.: “Endometrial cancer”. the Lancet, 2005, 366, 491-505.

[6] Blander G., Guarente L.: “The Sir2 Family of Protein Deacety-lases”. Annu. Rev. Biochem., 2004, 73, 417-435.

[7] Saunders L.R., Verdin E.: “Sirtuins: critical regulators at the cross-roads between cancer and aging”. Oncogene, 2007, 26, 5489-5504.

[8] Karbasforooshan H., Roohbakhsh A., Karimi G.: “SIRT1 and microRNAs: The role in breast, lung and prostate cancers”. Exp. Cell Res., 2018, 367, 1-6.

[9] Gharabaghi M.A.: “Diagnostic investigation of BIRC6 and SIRT1 protein expression level as potential prognostic biomarkers in patients with non-small cell lung cancer”. the Clinical Respiratory Journal, 2018, 12, 633-638.

[10] Gong J., Wang H., Lou W., Wang G., Tao H., Wen H., et al.: ”Asso-ciations of sirtuins with clinicopathological parameters and prognosis in non-small cell lung cancer”. Cancer Manag. Res., 2018, 2018, 3341-3356.

[11] Chen Y., Wang T., Wang W., Hu J., Li R., He S., et al.: “Prognostic and clinicopathological significance of SIRT1 expression in NSCLC: a meta-analysis”. Oncotarget, 2017, 8, 62537-62544.

[12] Han F., Zhang S., Liang J., Qiu W.: ”Clinicopathological and predictive significance of SIRT1 and peroxisome proliferator-activated receptor gamma in esophageal squaous cell carcinoma: The correlation with EGFR and Survivin”. Pathol Res Pract. 2018, 214, 686-690.

[13] Ma M., Chiu T., Lu H., Huang W., Lo C., Tien W., et al.: “SIRT1 overexpression is an independent prognosticator for patients with esophageal squamous cell carcinoma”. J. Cardiothorac. Surg., 2018, 13,

[14] Huffman D.M., Grizzle W.E., Bamman M.M., Kim J., Eltoum I.A., Elgavish A., et al.: “SIRT1 Is Significantly Elevated in Mouse and Human Prostate Cancer”. Cancer Res., 2007, 67, 6612-6618.

[15] Ruan L., Department of Nephrology, The First Hospital of Hebei Medical University, Shijiazhuang, China, Wang L., Wang X., College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China, He M., et al.: “SIRT1 contributes to neuroendocrine differentiation of prostate cancer”. Oncotarget, 2018, 9, 2002-2016.

[16] Chen H., Jeng Y., Yuan R., Hsu H., Chen Y.: “SIRT1 Promotes Tumorigenesis and Resistance to Chemotherapy in Hepatocellular Carcinoma and its Expression Predicts Poor Prognosis”. Ann. Surg. Oncol., 2012, 19, 2011-2019.

[17] Jiang H., Zhang X., Tao Y., Shan L., Jiang Q., Yu Y., et al.: “Prog-nostic and clinicopathologic significance of SIRT1 expression in hepatocellular carcinoma”. Oncotarget, 2017, 8, 52357-52365.

[18] FESSEL M.R., LIRA C.B., GIORGIO S., RAMOS C.H.I. and CANO M.I.N.: “Sir2-Related Protein 1 fromLeishmania amazonen-sisis a glycosylated NAD+-dependent deacetylase”. Parasitology, 2011, 138, 1245-1258.

[19] Qiu G., Li X., Wei C., Che X., He S., Lu J., et al.: “The Prognostic Role of SIRT1-Autophagy Axis in Gastric Cancer”. Dis. Markers, 2016, 2016, 1-11.

[20] Jang K.Y., Kim K.S., Hwang S.H., Kwon K.S., Kim K.R., Park H.S., et al.: “Expression and prognostic significance of SIRT1 in ovarian epithelial tumours”. Pathology (Phila.), 2009, 41, 366-371.

[21] Mvunta D.H., Miyamoto T., Asaka R., Yamada Y., Ando H., Higuchi S., et al.: “Overexpression of SIRT1 is Associated With Poor Outcomes in Patients With Ovarian Carcinoma”. Applied Immunohistochemistry & Molecular Morphology, 2017, 25, 415-421.

[22] Sung J., Kim R., Kim J., Lee J.: “Balance between SIRT1 and DBC1 expression is lost in breast cancer”. Cancer Sci., 2010, 101, 1738-1744.

[23] Al-Maghrabi J.: “Overexpression of SIRT1 in urothelial carcinoma of the urinary bladder is associated with local recurrence and poor survival”. Saudi Medical Journal, 2019, 40, 541-547.

[24] Zhao G., Cui J., Zhang J., Qin Q., Chen Q., Yin T., et al.: “SIRT1 RNAi knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells”. Gene Ther., 2011, 18, 920-928.

[25] Amin M.B., Amin M.B., Edge S., Greene F., Byrd D.R., Brookland R. K., et al., Pathologic TNM staging of carcinoma and carcinosar-coma of the corpus uteri, AJCC Cancer Staging Manual. 8th Edition New York, Springer, 2017, 2017.

[26] Al-Maghrabi J., Emam E., Gomaa W., Saggaf M., Buhmeida A., Al-Qahtani M., et al.: “c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence”. Bmc Cancer, 2015, 15,

[27] Al-Maghrabi J.: “Cyclooxygenase-2 expression as a predictor of outcome in colorectal carcinoma”. World J. Gastroenterol., 2012, 18, 1793.

[28] Fang Y., Nicholl M.B.: “Sirtuin 1 in malignant transformation: Friend or foe?”. Cancer Lett., 2011, 306, 10-14.

[29] Fang Y., Nicholl M.: “A Dual Role for Sirtuin 1 in Tumorigenesis”. Curr. Pharm. Des., 2014, 20, 2634-2636.

[30] Stünkel W., Campbell R.M.: “Sirtuin 1 (SIRT1)”. J. Biomol. Screen., 2011, 16, 1153-1169.

[31] Bartosch C., Monteiro-Reis S., Almeida-Rios D., Vieira R., Cas-tro A., Moutinho M., et al.: “Assessing sirtuin expression in endometrial carcinoma and non-neoplastic endometrium”. Oncotar-get, 2016, 7, 1144-1154.

[32] Jiang B., Chen J., Yuan W., Ji J., Liu Z., Wu L., et al.: “Prognostic and clinical value of Sirt1 expression in gastric cancer: A systematic meta-analysis”. Journal of Huazhong University of Science and Technology [Medical Sciences], 2016, 36, 278-284.

[33] Cao Y., Li Y., Wan G., Du X., Li F.: “Clinicopathological and prog-nostic role of SIRT1 in breast cancer patients: a meta-analysis”. Int. J. Clin. Exp. Med., 2015, 8, 616-624.

[34] Kang Y., Sun F., Zhang Y., Wang Z.: “SIRT1 acts as a potential tumor suppressor in oral squamous cell carcinoma”. J. Chin. Med. Assoc., 2018, 81, 416-422.

[35] Jeh S.U., Park J.J., Lee J.S., Kim D.C., Do J., Lee S.W., et al.: “Differential expression of the sirtuin family in renal cell carcinoma: Aspects of carcinogenesis and prognostic significance”. Urologic Oncology: Seminars and Original Investigations, 2017, 35, 675.e9-675. e15.

[36] Chung S.Y., Jung Y.Y., Park I.A., Kim H., Chung Y.R., Kim J.Y., et al.: “Oncogenic role of SIRT1 associated with tumor invasion, lymph node metastasis, and poor disease-free survival in triple negative breast cancer”. Clinical & Experimental Metastasis, 2016, 33, 179- 185.

[37] Hong W. G., Pyo J.: “The clinicopathological significance of SIRT1 expression in colon cancer: An immunohistochemical study and meta-analysis”. Pathology - Research and Practice, 2018, 214, 1550-1555.

[38] Zu G., Ji A., Zhou T. and Che N.: “Clinicopathological significance of SIRT1 expression in colorectal cancer: A systematic review and meta analysis”. Int. J. Surg., 2016, 26, 32-37.

[39] Wang C., Yang W., Dong F., Guo Y., Tan J., Ruan S., et al.: “The prognostic role of Sirt1 expression in solid malignancies: a meta-analysis”. Oncotarget, 2017, 8, 66343-66351.

[40] Asaka R., Miyamoto T., Yamada Y., Ando H., Mvunta D. H., Kobara H., et al.: “Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target”. Lab. Invest., 2015, 95, 1363-1373.

[41] LIN L., ZHENG X., QIU C., DONGOL S., LV Q., JIANG J., et al.: “SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis”. Oncol. Rep., 2014, 32, 2831-2835.

[42] Hishida T., Nozaki Y., Nakachi Y., Mizuno Y., Iseki H., Katano M., et al.: “Sirt1, p53, and p38MAPK Are Crucial Regulators of Detrimental Phenotypes of Embryonic Stem Cells with Max Expression Ablation”. Stem Cells, 2012, 30, 1634-1644.

[43] Roth M., Chen W.Y.: “Sorting out functions of sirtuins in cancer”. Oncogene, 2014, 33, 1609-1620.

[44] Matias-Guiu X., Prat J.: “Molecular pathology of endometrial car-cinoma”. Histopathology, 2013, 62, 111-123.

[45] Moore R.L., Dai Y., Faller D.V.: “Sirtuin 1 (SIRT1) and steroid hor-mone receptor activity in cancer”. J. Endocrinol., 2012, 213, 37-48.

[46] Moore R.L., Faller D.V.: ”SIRT1 represses estrogen-signaling, ligand-independent ERalpha-mediated transcription, and cell proliferation in estrogen-responsive breast cells”. J. Endocrinol., 2013, 216, 273-285.

[47] Leeuwen I.V., Lain S.: ”Sirtuins and p53”. Adv. Cancer Res., 2009, 102, 171-195.

[48] Macedo de Oliveira M.V., Andrade J.M.O., Paraíso A.F., Santos S.H.S.: “Sirtuins and Cancer: New Insights and Cell Signaling”. Cancer Invest., 2013, 31, 645-653.

[49] Bosch-Presegue L., Vaquero A.: “The Dual Role of Sirtuins in Cancer”. Genes & Cancer, 2011, 2, 648-662.

[50] Sebastián C., Satterstrom F.K., Haigis M.C., Mostoslavsky R.: “From Sirtuin Biology to Human Diseases: An Update”. J. Biol. Chem., 2012, 287, 42444-42452.

[51] Song N., Surh Y.: “Janusfaced role of SIRT1 in tumorigenesis”. Ann. N. Y. Acad. Sci., 2012, 1271, 10-19.