Decreased semaphorin 3A expression is associated with a poor prognosis in patients with epithelial ovarian carcinoma

Jiang,Haiyan; Qi,Lei; Wang,Feiran; Sun,Zhichao; Huang,Zhongwei; Xi,Qinghua

doi:10.3892/ijmm.2015.2142

Decreased semaphorin 3A expression is associated with a poor prognosis in patients with epithelial ovarian carcinoma

Authors:
- Haiyan Jiang
- Lei Qi
- Feiran Wang
- Zhichao Sun
- Zhongwei Huang
- Qinghua Xi
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Medical College, Nantong University, Nantong, Jiangsu 226019, P.R. China
Published online on: March 17, 2015 https://doi.org/10.3892/ijmm.2015.2142
Pages: 1374-1380

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Semaphorin 3A (SEMA3A) was initially identified to play an important role in axonal guidance. Recently, SEMA3A has also been considered as a candidate tumor suppressor, since it is often downregulated in numerous types of cancer, including prostate cancer, breast cancer and glioma. However, the biological role of SEMA3A in ovarian cancer is not clear. In the present study, the expression of SEMA3A in ovarian cancer and normal ovarian epithelial tissues was detected by immunofluorescence, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting, and the associations between the expression of SEMA3A with the development of ovarian cancer, clinicopathological characteristics and survival were also analyzed. Results from immunofluorescence, RT‑qPCR and western blotting showed that SEMA3A is significantly downregulated in epithelial ovarian carcinoma compared to normal ovarian epithelial specimens (P<0.05). The expression levels of SEMA3A were lower in the cancer tissues with III/IV stage [the International Federation of Gynecology and Obstetrics (FIGO) stage], poor histological grade, lymph node metastasis and distant metastasis compared to that in the cancer tissues with I/II stage (FIGO), well histological grade, or without lymph node metastasis and distant metastasis (P<0.05). A decreased expression of SEMA3A is associated with a poor prognosis (P<0.001). The present findings suggest that decreased SEMA3A expression may be associated with the development of epithelial ovarian carcinoma, and therefore, SEMA3A may be a valuable prognostic marker, as well as a potential molecular therapy target for ovarian cancer patients.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	Teoh D and Secord AA: Antiangiogenic agents in combination with chemotherapy for the treatment of epithelial ovarian cancer. Int J Gynecol Cancer. 22:348–359. 2012. View Article : Google Scholar : PubMed/NCBI
3	Usha L, Sill MW, Darcy KM, et al: A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol Oncol. 121:455–461. 2011. View Article : Google Scholar : PubMed/NCBI
4	Wu H, Yao L, Mei J and Li F: Development of synthetic of peptide-functionalized liposome for enhanced targeted ovarian carcinoma therapy. Int J Clin Exp Pathol. 8:207–216. 2015.PubMed/NCBI
5	Kannan K, Coarfa C, Chao PW, et al: Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma. Proc Natl Acad Sci USA. Mar 2–2015.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
6	Gurler H, Yu Y, Choi J, Kajdacsy-Balla AA and Barbolina MV: Three-dimensional collagen type I matrix up-regulates nuclear isoforms of the microtubule associated protein tau implicated in resistance to Paclitaxel therapy in ovarian carcinoma. Int J Mol Sci. 16:3419–3433. 2015. View Article : Google Scholar : PubMed/NCBI
7	Morris LG, Veeriah S and Chan TA: Genetic determinants at the interface of cancer and neurodegenerative disease. Oncogene. 29:3453–3464. 2010. View Article : Google Scholar : PubMed/NCBI
8	Cao L, Liu X, Lin EJ, et al: Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell. 142:52–64. 2010. View Article : Google Scholar : PubMed/NCBI
9	Chilton JK: Molecular mechanisms of axon guidance. Dev Biol. 292:13–24. 2006. View Article : Google Scholar : PubMed/NCBI
10	Dickson BJ: Molecular mechanisms of axon guidance. Science. 298:1959–1964. 2002. View Article : Google Scholar : PubMed/NCBI
11	Bielenberg DR, Hida Y, Shimizu A, et al: Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 114:1260–1271. 2004. View Article : Google Scholar : PubMed/NCBI
12	Christensen C, Ambartsumian N, Gilestro G, et al: Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 65:6167–6177. 2005. View Article : Google Scholar : PubMed/NCBI
13	Neufeld G and Kessler O: The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer. 8:632–645. 2008. View Article : Google Scholar : PubMed/NCBI
14	Kigel B, Varshavsky A, Kessler O and Neufeld G: Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells. PLoS One. 3:e32872008. View Article : Google Scholar : PubMed/NCBI
15	Kessler O, Shraga-Heled N, Lange T, et al: Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res. 64:1008–1015. 2004. View Article : Google Scholar : PubMed/NCBI
16	Casazza A, Fu X, Johansson I, et al: Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models. Arterioscler Thromb Vasc Biol. 31:741–749. 2011. View Article : Google Scholar : PubMed/NCBI
17	Maione F, Molla F, Meda C, et al: Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest. 119:3356–3372. 2009.PubMed/NCBI
18	Sakurai A, Gavard J, Annas-Linhares Y, et al: Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras. Mol Cell Biol. 30:3086–3098. 2010. View Article : Google Scholar : PubMed/NCBI
19	Varshavsky A, Kessler O, Abramovitch S, et al: Semaphorin-3B is an angiogenesis inhibitor that is inactivated by furin-like pro-protein convertases. Cancer Res. 68:6922–6931. 2008. View Article : Google Scholar : PubMed/NCBI
20	Rolny C, Capparuccia L, Casazza A, et al: The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment. J Exp Med. 205:1155–1171. 2008. View Article : Google Scholar : PubMed/NCBI
21	Zheng C, Zhou Q, Wu F, et al: Semaphorin3F down-regulates the expression of integrin alpha(v)beta3 and sensitizes multicellular tumor spheroids to chemotherapy via the neuropilin-2 receptor in vitro. Chemotherapy. 55:344–352. 2009. View Article : Google Scholar : PubMed/NCBI
22	Bagci T, Wu JK, Pfannl R, Ilag LL and Jay DG: Autocrine semaphorin 3A signaling promotes glioblastoma dispersal. Oncogene. 28:3537–3550. 2009. View Article : Google Scholar : PubMed/NCBI
23	Li K, Chen MK, Li LY, et al: The predictive value of sema-phorins 3 expression in biopsies for biochemical recurrence of patients with low- and intermediate-risk prostate cancer. Neoplasma. 60:683–689. 2013. View Article : Google Scholar
24	Staton CA, Shaw LA, Valluru M, et al: Expression of class 3 semaphorins and their receptors in human breast neoplasia. Histopathology. 59:274–282. 2011.PubMed/NCBI
25	Neufeld G, Shraga-Heled N, Lange T, Guttmann-Raviv N, Herzog Y and Kessler O: Semaphorins in cancer. Front Biosci. 10:751–760. 2005. View Article : Google Scholar
26	Goshima Y, Ito T, Sasaki Y and Nakamura F: Semaphorins as signals for cell repulsion and invasion. J Clin Invest. 109:993–998. 2002. View Article : Google Scholar : PubMed/NCBI
27	Tomizawa Y, Sekido Y, Kondo M, et al: Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci USA. 98:13954–13959. 2001. View Article : Google Scholar : PubMed/NCBI
28	Xiang R, Davalos AR, Hensel CH, Zhou XJ, Tse C and Naylor SL: Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice. Cancer Res. 62:2637–2643. 2002.PubMed/NCBI
29	Vacca A, Scavelli C, Serini G, et al: Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood. 108:1661–1667. 2006. View Article : Google Scholar : PubMed/NCBI
30	Moriya J, Minamino T, Tateno K, et al: Inhibition of semaphorin as a novel strategy for therapeutic angiogenesis. Circ Res. 106:391–398. 2010. View Article : Google Scholar
31	Pan H, Wanami LS, Dissanayake TR and Bachelder RE: Autocrine semaphorin3A stimulates alpha2 beta1 integrin expression/function in breast tumor cells. Breast Cancer Res Treat. 118:197–205. 2009. View Article : Google Scholar
32	Herman JG and Meadows GG: Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol. 30:1231–1238. 2007.PubMed/NCBI
33	Catalano A, Caprari P, Rodilossi S, et al: Cross-talk between vascular endothelial growth factor and semaphorin-3A pathway in the regulation of normal and malignant mesothelial cell proliferation. FASEB J. 18:358–360. 2004.
34	Oinuma I, Ishikawa Y, Katoh H and Negishi M: The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science. 305:862–865. 2004. View Article : Google Scholar : PubMed/NCBI
35	Toyofuku T, Yoshida J, Sugimoto T, et al: FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci. 8:1712–1719. 2005. View Article : Google Scholar : PubMed/NCBI
36	Gaziel-Sovran A, Segura MF, Di Micco R, et al: miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell. 20:104–118. 2011. View Article : Google Scholar : PubMed/NCBI
37	Dubois L, Andersson K, Asplund A and Bjorkelund H: Evaluating real-time immunohistochemistry on multiple tissue samples, multiple targets and multiple antibody labeling methods. BMC Res Notes. 6:5422013. View Article : Google Scholar : PubMed/NCBI