ORIGINAL ARTICLE
Prognostic and clinicopathological implications of expression of Beclin-1 and hypoxia-inducible factor 1α in serous ovarian carcinoma: an immunohistochemical study
1
Pathology Department, Faculty of Medicine, Zagazig University, Egypt
2
Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Zagazig University, Egypt
3
Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
4
General Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
5
Histology and Cell Biology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
6
Obstetrics and Gynecology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Submission date: 2020-04-17
Final revision date: 2020-10-15
Acceptance date: 2020-10-29
Publication date: 2021-05-31
Pol J Pathol 2021;72(1):23-38
KEYWORDS
TOPICS
ABSTRACT
Serous ovarian carcinoma (SOC) is an ovarian cancer with a high fatality rate. Therefore, a lot of researchers have tried to identify novel prognostic biomarkers which might improve the patient prognosis. The aims of the study were to detect the tissue protein expression of Beclin-1 in addition to HIF-1α in SOC patients, to evaluate the relationship between their expression, the clinicopathological parameters, patients’ prognosis, and the relation to chemotherapy resistance in SOC. We evaluated the expression of Beclin-1 in addition to HIF-1α in 60 patients with SOC using immunohistochemistry, followed all patients for about 36 months, analyzed associations between both markers' expression, clinicopathological data, and patients’ prognosis. Beclin-1 expression was related to low grade (p = 0.002), early SOC stage, absence of peritoneal spread (p = 0.006), and absence of lymph nodes, and distant metastases (p = 0.004 and < 0.001 respectively), while HIF-1α expression was associated with higher grade and stage (p = 0.007), and presence of nodal and distant metastases (p < 0.001 and = 0.012 respectively). High Beclin-1 expression and low HIF-1α expression were positively associated with good response to chemotherapy (p = 0.047 and p = 0.022 respectively), a lower recurrence rate after successful therapy (p = 0.006 and < 0.001 respectively), and increased three-year recurrence-free and overall survival rates (p < 0.001). In SOC patients; Beclin-1 is a good prognostic marker, while HIF-1α is a poor prognostic marker.
REFERENCES (43)
1.
Ying H, Qu D, Liu C, et al. Chemo-resistance is associated with Beclin-1 and PTEN expression in epithelial ovarian cancers. Oncol Lett 2015; 9: 1759-1763.
2.
KunduM, Thompson CB. Autophagy: basic principles and relevance to disease. Annu Rev Pathol 2008; 3: 427-455.
3.
Koren I, Kimchi A. Cell biology. Promoting tumorigenesis by suppressing autophagy. Science 2012; 338: 889-890.
4.
Baspinar S, Bircan S, Orhan H, et al. The relation of beclin 1 and bcl2 expressions in high grade prostatic intraepithelial neoplasia and prostate adenocarcinoma: A tissue microarray study. Pathol Res Pract 2014; 210: 412418.
5.
Tong Y, You L, Liu H, et al. Potent antitumor activity of oncolytic adenovirus expressing Beclin1 via induction of autophagic cell death in leukemia. Oncotarget 2013; 4: 860874.
6.
Sun Q, Fan W, Zhong Q. Regulation of Beclin 1 in autophagy. Autophagy 2009; 5: 713-716.
7.
Edinger AL, Thompson CB. Defective autophagy leads to cancer. Cancer Cell 2003; 4: 422-424.
8.
Kang KF, Wang XW, Chen XW, et al. Beclin 1 and nuclear factor-κBp65 are up-regulated in hepatocellular carcinoma. Oncol Lett 2013; 5: 1813-1818.
9.
Wong CC, Kai AK, Ng IO. The impact of hypoxia in hepatocellular carcinoma metastasis. Front Med 2013; 8: 33-41.
10.
Mabjeesh NJ, Amir S. Hypoxia-inducible factor (HIF) in human tumorigenesis. Histol Histopathol 2007; 22: 559-572.
11.
Wilson KG, Tennant AD, McKeating AJ. Hypoxia inducible factors in liver disease and hepatocellular carcinoma: current understanding and future directions. J Hepatol 2014; 61: 1397-1406.
12.
Zhang H, Bosch-Marce M, Shimoda LA, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008; 283:10892–903.
13.
Dong M, Wan X, Yuan ZY, et al. Low expression of Beclin 1 and elevated expression of HIF-1 α define distant metastasis risk and predict poor prognosis of ER- positive, HER2-negative breast cancer. Med Oncol 2013; 30: 355-365.
14.
Prat J. FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2014; 124: 1-5.
15.
Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. 4th ed. International Agency for Research on Cancer, Lyon 2014.
16.
Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures.
18.
Osman NA, Abd El-Rehim DM, Kamal IM. Defective Beclin-1 and elevated hypoxia-inducible factor (HIF)-1α expression are closely linked to tumorigenesis, differentiation, and progression of hepatocellular carcinoma. Tumour Biol 2015; 36: 4293-4299.
19.
Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 2011; 10: 1533-1541.
20.
Cui J, Gong Z, Shen HM. The role of autophagy in liver cancer: molecular mechanisms and potential therapeutic targets. Biochim Biophys Acta 2013; 1836: 15-26.
21.
Cai M, Hu Z, Liu J, et al. Beclin 1 expression in ovarian tissues and its effects on ovarian cancer prognosis. Int J Mol Sci 2014; 15: 5292-5303.
22.
Wu X, Chen J, Cao Q, et al. Beclin 1 activation enhances chemosensitivity and predicts a favorable outcome for primary duodenal adenocarcinoma. Tumor Biol 2013; 34: 713-722.
23.
Fei B, Ji F, Chen X, et al. Expression and clinical significance of Beclin-1 in gastric cancer tissues of various clinical stages. Oncol Lett 2016; 11: 2271-2277.
24.
Miracco C, Cosci E, Oliveri G, et al. Protein and mRNA expression of autophagy gene Beclin-1 in human brain tumours. Int J Oncol 2007; 30: 429-436.
25.
Zhao Y, Chen S, Gou WF, et al. Aberrant Beclin 1 expression is closely linked to carcinogenesis, differentiation, progression, and prognosis of ovarian epithelial carcinoma. Tumour Biol 2014; 35: 1955-1964.
26.
Dong LW, Hou YJ, Tan YX, et al. Prognostic significance of Beclin 1 in intrahepatic cholangiocellular carcinoma. Autophagy 2011; 7: 1222-1229.
27.
Park KJ, Lee SH, Lee CH, et al. Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochem Biophys Res Commun 2009; 382: 726-729.
28.
Furuya D, Tsuji N, Yagihashi A, Watanabe N. Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res 2005; 307: 26-40.
29.
Shi YH, Ding ZB, Zhou J, Qiu SJ, Fan J. Prognostic significance of Beclin 1-dependent apoptotic activity in hepatocellular carcinoma. Autophagy 2009; 5: 380-382.
30.
Wan XB, Fan XJ, Chen MY, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 2010; 6: 395-404.
31.
Tang JY, Fang YY, Hsi E, et al. Immunopositivity of Beclin1 and ATG5 as indicators of survival and disease recurrence in oral squamous cell carcinoma. Anticancer Res 2013; 33: 5611-5616.
32.
Acs G, Xu X, Chu C, Acs P, Verma A. Prognostic significance of erythropoietin expression in human endometrial carcinoma. Cancer 2004; 100: 2376-2786.
33.
Qin J, Liu Y, Lu Y, et al. Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression. Sci Rep 2017; 7: 10592.
34.
Jin Y, Wang H, Liang X, et al. Pathological and prognostic significance of hypoxia-inducible factor 1alpha expression in epithelial ovarian cancer: a meta-analysis. Tumour Biol 2014; 35: 8149-8159.
35.
Zheng SS, Chen XH, Yin X, Zhang BH. Prognostic significance of HIF-1alpha expression in hepatocellular carcinoma: a meta-analysis. PLoS One 2013; 8: e65753.
36.
Shimogai R, Kigawa J, Itamochi H, et al. Expression of hypoxiainducible factor 1alpha gene affects the outcome in patients with ovarian cancer. Int J Gynecol Cancer 2008; 18: 499-505.
37.
Birner P, Schindl M, Obermair A, et al. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000; 60: 4693-4696.
38.
Nakai H, WatanabeY, Ueda H, Hoshiai H. Hypoxia inducible factor 1- alpha expression as a factor predictive of efficacy of taxane/platinum chemotherapy in advanced primary epithelial ovarian cancer. Cancer Lett 2007; 251: 164-167.
39.
Liu T, Zhao L, Hou H, Ding L, et al. Ginsenoside 20(S)-Rg3 suppresses ovarian cancer migration via hypoxia-inducible factor 1 alpha and nuclear factor-kappa B signals. Tumor Biol 2017; 39: 1010428317692225.
40.
Ruscito I, Gasparri ML, Marchetti C, et al. Cediranib in ovarian cancer: state of the art and future perspectives. Tumour Biol 2016; 37: 2833-2839.
41.
Zhang H, Qian DZ, Tan YS, et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci U S A 2008; 105: 19579-19586.
42.
Zagzag D, Nomura M, Friedlander DR, et al. Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. J Cell Physiol 2003; 196: 394-402.
43.
Lee SJ, Kim HP, Jin Y, et al. Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Autophagy 2011; 7: 829-839.
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