Downregulation of vasohibin-2, a novel angiogenesis regulator, suppresses tumor growth by inhibiting angiogenesis in endometrial cancer cells

Koyanagi,Takahiro; Saga,Yasushi; Takahashi,Yoshifumi; Suzuki,Yasuhiro; Suzuki,Mitsuaki; Sato,Yasufumi

doi:10.3892/ol.2013.1119

Downregulation of vasohibin-2, a novel angiogenesis regulator, suppresses tumor growth by inhibiting angiogenesis in endometrial cancer cells

Authors:
- Takahiro Koyanagi
- Yasushi Saga
- Yoshifumi Takahashi
- Yasuhiro Suzuki
- Mitsuaki Suzuki
- Yasufumi Sato
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Shimotsuke‑shi, Tochigi 329-0498, Japan, Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ward, Sendai 980-8575, Japan
Published online on: January 8, 2013 https://doi.org/10.3892/ol.2013.1119
Pages: 1058-1062

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

The vasohibin-2 (VASH2) gene was originally found to be expressed in infiltrating mononuclear cells of a mouse model of hypoxia-induced subcutaneous angiogenesis. These cells are mobilized from bone marrow to promote angiogenesis. Recently, VASH2 has been demonstrated to be expressed in several types of cancer in which it promotes tumor development through angiogenesis. However, its role in endometrial cancer remains unknown. Using quantitative reverse transcription-polymerase chain reaction (RT-PCR), we found that VASH2 was overexpressed in several human endometrial cancer cell lines, including the HEC50B cell line, which we used to further examine the role of VASH2. Although knockdown of VASH2 with stable transfection of shRNA had little effect on the proliferation of HEC50B cells in vitro, knockdown in an in vivo murine xenograft model inhibited tumor growth by decreasing tumor angiogenesis. In addition, the supernatant from HEC50B cells that expressed VASH2 significantly promoted the proliferation of human umbilical vein endothelial cells. By contrast, knockdown of VASH2 significantly attenuated the proliferative effect. These results indicate that VASH2 contributes to the development of endometrial cancer by promoting angiogenesis through a paracrine mode of action. Consequently, VASH2 may be considered to be a novel molecular target for endometrial cancer therapy.

View Figures

View References

1	Jemal A, Siegel R, Xu J and Ward E: Cancer Statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
2	Wolfson AH, Sightler SE and Markoe AM: The prognostic significance of surgical staging for carcinoma of the endometrium. Gynecol Oncol. 45:142–146. 1992. View Article : Google Scholar : PubMed/NCBI
3	Kamat AA, Merritt WM, Coffey D, et al: Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res. 13:7487–7495. 2007. View Article : Google Scholar : PubMed/NCBI
4	Kowanetz M and Ferrara N: Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res. 12:5018–5022. 2006. View Article : Google Scholar : PubMed/NCBI
5	Ortega J, Vigil CE and Chodkiewicz C: Current progress in targeted therapy for colorectal cancer. Cancer Control. 17:7–15. 2010.PubMed/NCBI
6	Koutras AK, Fountzilas G, Makatsoris T, Peroukides S and Kalofonos HP: Bevacizumab in the treatment of breast cancer. Cancer Treat Rev. 36:75–82. 2010. View Article : Google Scholar : PubMed/NCBI
7	Tamaskar I and Pili R: Update on novel agents in renal cell carcinoma. Expert Rev Anticancer Ther. 9:1817–1827. 2009. View Article : Google Scholar : PubMed/NCBI
8	Norden AD, Drappatz J and Wen PY: Antiangiogenic therapies for high-grade glioma. Nat Rev Neurol. 5:610–620. 2009. View Article : Google Scholar : PubMed/NCBI
9	Watanabe K, Hasegawa Y, Yamashita H, et al: Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J Clin Invest. 114:898–907. 2004. View Article : Google Scholar : PubMed/NCBI
10	Kimura H, Miyashita H, Suzuki Y, et al: Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesis. Blood. 113:4810–4818. 2009. View Article : Google Scholar : PubMed/NCBI
11	Xue X, Gao W, Sun B, et al: Vasohibin 2 is transcriptionally activated and promotes angiogenesis in hepatocellular carcinoma. Oncogene. May 21–2012.(Epub ahead of print).
12	Takahashi Y, Koyanagi T, Suzuki Y, et al: Vasohibin-2 expressed in human serous ovarian adenocarcinoma accelerates tumor growth by promoting angiogenesis. Mol Cancer Res. Jul 23–2012.(Epub ahead of print).
13	Kuramoto H, Tamura S and Notake Y: Establishment of a cell line of human endometrial adenocarcinoma in vitro. Am J Obstet Gynecol. 114:1012–1019. 1972.PubMed/NCBI
14	Suzuki M, Kuramoto H, Hamano M, Shirane H and Watanabe K: Effects of oestradiol and progesterone on the alkaline phosphatase activity of a human endometrial cancer cell-line. Acta Endocrinol (Copenh). 93:108–113. 1980.PubMed/NCBI
15	Nishida M: The Ishikawa cells from birth to the present. Hum Cell. 15:104–117. 2002. View Article : Google Scholar : PubMed/NCBI
16	Miyagishi M and Taira K: Strategies for generation of an siRNA expression library directed against the human genome. Oligonucleotides. 13:325–333. 2003. View Article : Google Scholar : PubMed/NCBI
17	Yamamoto O, Hamada T, Tokui N and Sasaguri Y: Comparison of three in vitro assay systems used for assessing cytotoxic effect of heavy metals on cultured human keratinocytes. J UOEH. 23:35–44. 2001.PubMed/NCBI
18	Suzuki Y, Kobayashi M, Miyashita H, Ohta H, Sonoda H and Sato Y: Isolation of a small vasohibin-binding protein (SVBP) and its role in vasohibin secretion. J Cell Sci. 123:3094–3101. 2010. View Article : Google Scholar : PubMed/NCBI
19	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar
20	Ferrara N: Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 29:789–791. 2009. View Article : Google Scholar
21	McMeekin DS, Sill MW, Benbrook D, et al Gynecologic Oncology Group: A phase II trial of thalidomide in patients with refractory endometrial cancer and correlation with angiogenesis biomarkers: a Gynecologic Oncology Group study. Gynecol Oncol. 105:508–516. 2007. View Article : Google Scholar : PubMed/NCBI
22	Sanseverino F, Santopietro R, Torricelli M, et al: pRb2/p130 and VEGF expression in endometrial carcinoma in relation to angiogenesis and histopathologic tumor grade. Cancer Biol Ther. 5:84–88. 2006. View Article : Google Scholar : PubMed/NCBI
23	Hirai M, Nakagawara A, Oosaki T, Hayashi Y, Hirono M and Yoshihara T: Expression of vascular endothelial growth factors (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma. Gynecol Oncol. 80:181–188. 2001. View Article : Google Scholar : PubMed/NCBI
24	Cerezo L, Cardenes H and Michael H: Molecular alterations in the pathogenesis of endometrial adenocarcinoma. Therapeutic implications. Clin Transl Oncol. 8:231–241. 2006. View Article : Google Scholar : PubMed/NCBI
25	Saranadasa M and Wang ES: Vascular endothelial growth factor inhibition: conflicting roles in tumor growth. Cytokine. 53:115–129. 2011. View Article : Google Scholar : PubMed/NCBI
26	Korpal M and Kang Y: The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol. 5:115–119. 2008. View Article : Google Scholar : PubMed/NCBI