Vasohibin-1 inhibits angiogenesis and suppresses tumor growth in renal cell carcinoma

Zhao,Guangning; Na,Ren; Li,Liming; Xiao,Huiyuan; Ding,Na; Sun,Yan; Han,Ruifa

doi:10.3892/or.2017.5746

Vasohibin-1 inhibits angiogenesis and suppresses tumor growth in renal cell carcinoma

Authors:
- Guangning Zhao
- Ren Na
- Liming Li
- Huiyuan Xiao
- Na Ding
- Yan Sun
- Ruifa Han
View Affiliations

Affiliations: Department of Urology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China, Department of Clinical Laboratory, Tianjin Children's Hospital, Tianjin 300074, P.R. China, Department of Urology, Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, P.R. China
Published online on: June 22, 2017 https://doi.org/10.3892/or.2017.5746
Pages: 1021-1028

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

Vasohibin-1 (VASH1) has recently been isolated as a novel inhibitor of angiogenesis. Several studies have demonstrated that VASH1 plays important roles in tumor angiogenesis but the role of this angiogenic inhibitor in renal cell carcinoma (RCC) has not been elucidated. We previously reported that VASH1 expression is reduced and is associated with clinicopathological features in RCC. In the present study, we investigated the biological effects of VASH1 in RCC by evaluating the effects of VASH1 on cell proliferation, cell cycle distribution, cell apoptosis and cell invasion in human umbilical vein endothelial cells (HUVECs) and 786-0 cells, and evaluating the effect of VASH1 on the growth of 786-0 cells in nude mice. A pReceiver-M61-VASH1 was transfected into HUVECs and 786-0 cells, and the expression level of VASH1 protein was examined by western blotting. Cell proliferation was detected by MTT assay, and cell cycle and apoptosis of HUVECs and 786-0 cells were analyzed by flow cytometry. The invasive ability of 786-0 cells was tested by Transwell assay. Finally, nude mouse models were established to evaluate the therapeutic effect of VASH1. The pReceiver-M61-VASH1 effectively induced the expression of VASH1 in HUVECs and 786-0 cells. VASH1 overexpression effectively inhibited cell proliferation, arrested the cell cycle in the G0/G1 phase and promoted cell apoptosis of HUVECs and 786-0 cells. VASH1 overexpression effectively inhibited the subcutaneous growth of 786-0 tumors in vivo. Therefore, VASH1 is a potential molecular-targeted therapy for patients with RCC.

View Figures

View References

1	Rini BI, Campbell SC and Escudier B: Renal cell carcinoma. Lancet. 73:1119–1132. 2009. View Article : Google Scholar
2	Motzer RJ, Bander NH and Nanus DM: Renal-cell carcinoma. N Engl J Med. 335:865–875. 1996. View Article : Google Scholar : PubMed/NCBI
3	Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
4	Qian CN, Huang D, Wondergem B and Teh BT: Complexity of tumor vasculature in clear cell renal cell carcinoma. Cancer. 115:(Suppl 10). S2282–S2289. 2009. View Article : Google Scholar
5	Xu L, Tong R, Cochran DM and Jain RK: Blocking platelet-derived growth factor-D/platelet-derived growth factor receptor beta signaling inhibits human renal cell carcinoma progression in an orthotopic mouse model. Cancer Res. 65:5711–5719. 2005. View Article : Google Scholar : PubMed/NCBI
6	Sulzbacher I, Birner P, Träxler M, Marberger M and Haitel A: Expression of platelet-derived growth factor-alpha alpha receptor is associated with tumor progression in clear cell renal cell carcinoma. Am J Clin Pathol. 120:107–112. 2003. View Article : Google Scholar : PubMed/NCBI
7	Dorević G, Matusan-Ilijas K, Babarović E, Hadzisejdić I, Grahovac M, Grahovac B and Jonjić N: Hypoxia inducible factor-1α correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma. J Exp Clin Cancer Res. 28:402009. View Article : Google Scholar : PubMed/NCBI
8	Watanabe K, Hasegawa Y, Yamashita H, Shimizu K, Ding Y, Abe M, Ohta H, Imagawa K, Hojo K, Maki 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
9	Sonoda H, Ohta H, Watanabe K, Yamashita H, Kimura H and Sato Y: Multiple processing forms and their biological activities of a novel angiogenesis inhibitor vasohibin. Biochem Biophys Res Commun. 342:640–646. 2006. View Article : Google Scholar : PubMed/NCBI
10	Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y and Makino H: Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy. Diabetes. 58:2365–2375. 2009. View Article : Google Scholar : PubMed/NCBI
11	Shen J, Yang X, Xiao WH, Hackett SF, Sato Y and Campochiaro PA: Vasohibin is up-regulated by VEGF in the retina and suppresses VEGF receptor 2 and retinal neovascularization. FASEB J. 20:723–725. 2006.PubMed/NCBI
12	Tamaki K, Moriya T, Sato Y, Ishida T, Maruo Y, Yoshinaga K, Ohuchi N and Sasano H: Vasohibin-1 in human breast carcinoma: A potential negative feedback regulator of angiogenesis. Cancer Sci. 100:88–94. 2009. View Article : Google Scholar : PubMed/NCBI
13	Yoshinaga K, Ito K, Moriya T, Nagase S, Takano T, Niikura H, Yaegashi N and Sato Y: Expression of vasohibin as a novel endothelium-derived angiogenesis inhibitor in endometrial cancer. Cancer Sci. 99:914–919. 2008. View Article : Google Scholar : PubMed/NCBI
14	Yoshinaga K, Ito K, Moriya T, Nagase S, Takano T, Niikura H, Sasano H, Yaegashi N and Sato Y: Roles of intrinsic angiogenesis inhibitor, vasohibin, in cervical carcinomas. Cancer Sci. 102:446–451. 2011. View Article : Google Scholar : PubMed/NCBI
15	Hosaka T, Kimura H, Heishi T, Suzuki Y, Miyashita H, Ohta H, Sonoda H, Moriya T, Suzuki S, Kondo T, et al: Vasohibin-1 expression in endothelium of tumor blood vessels regulates angiogenesis. Am J Pathol. 175:430–439. 2009. View Article : Google Scholar : PubMed/NCBI
16	Wang Q, Tian X, Zhang C and Wang Q: Upregulation of vasohibin-1 expression with angiogenesis and poor prognosis of hepatocellular carcinoma after curative surgery. Med Oncol. 29:2727–2736. 2012. View Article : Google Scholar : PubMed/NCBI
17	Shen Z, Kauttu T, Seppänen H, Vainionpää S, Ye Y, Wang S, Mustonen H and Puolakkainen P: Vasohibin-1 and vasohibin-2 expression in gastric cancer cells and TAMs. Med Oncol. 29:2718–2726. 2012. View Article : Google Scholar : PubMed/NCBI
18	Zhang T, Yu TT, Zhang DM, Hou XM, Liu XJ, Zhao D and Shan L: Vasohibin-1 expression detected by immunohistochemistry correlates with prognosis in non-small cell lung cancer. Med Oncol. 31:9632014. View Article : Google Scholar : PubMed/NCBI
19	Liu S, Han B, Zhang Q, Dou J, Wang F, Lin W, Sun Y and Peng G: Vasohibin-1 suppresses colon cancer. Oncotarget. 6:7880–7898. 2015. View Article : Google Scholar : PubMed/NCBI
20	Takahashi Y, Saga Y, Koyanagi T, Takei Y, Machida S, Taneichi A, Mizukami H, Sato Y, Matsubara S and Fujiwara H: The angiogenesis regulator vasohibin-1 inhibits ovarian cancer growth and peritoneal dissemination and prolongs host survival. Int J Oncol. 47:2057–2063. 2015.PubMed/NCBI
21	Takahashi Y, Saga Y, Koyanagi T, Takei Y, Machida S, Taneichi A, Mizukami H, Sato Y, Matsubara S and Fujiwara H: Vasohibin-1 expression inhibits advancement of ovarian cancer producing various angiogenic factors. Cancer Sci. 107:629–637. 2016. View Article : Google Scholar : PubMed/NCBI
22	Shen Z, Yan Y, Ye C, Wang B, Jiang K, Ye Y, Mustonen H, Puolakkainen P and Wang S: The effect of Vasohibin-1 expression and tumor-associated macrophages on the angiogenesis in vitro and in vivo. Tumour Biol. 37:7267–7276. 2016. View Article : Google Scholar : PubMed/NCBI
23	Zhao G, Yang Y, Tang Y, Han R and Sun Y: Reduced expression of vasohibin-1 is associated with clinicopathological features in renal cell carcinoma. Med Oncol. 29:3325–3334. 2012. View Article : Google Scholar : PubMed/NCBI
24	Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
25	Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29:(Suppl 16). S15–S18. 2002. View Article : Google Scholar
26	Mancilla-Jimenez R, Stanley RJ and Blath RA: Papillary renal cell carcinoma: A clinical, radiologic, and pathologic study of 34 cases. Cancer. 38:2469–2480. 1976. View Article : Google Scholar : PubMed/NCBI
27	Nimmagadda S, Geetha-Loganathan P, Pröls F, Scaal M, Christ B and Huang R: Expression pattern of Vasohibin during chick development. Dev Dyn. 236:1358–1362. 2007. View Article : Google Scholar : PubMed/NCBI
28	Naito H, Kidoya H, Sato Y and Takakura N: Induction and expression of anti-angiogenic vasohibins in the hematopoietic stem/progenitor cell population. J Biochem. 145:653–659. 2009. View Article : Google Scholar : PubMed/NCBI
29	Vitale MG and Cartenì G: Clinical management of metastatic kidney cancer: The role of new molecular drugs. Future Oncol. 12:83–93. 2016. View Article : Google Scholar : PubMed/NCBI
30	Miyashita H, Suzuki H, Ohkuchi A and Sato Y: Mutual balance between vasohibin-1 and soluble VEGFR-1 in endothelial cells. Pharmaceuticals. 4:782–793. 2011. View Article : Google Scholar :
31	Heishi T, Hosaka T, Suzuki Y, Miyashita H, Oike Y, Takahashi T, Nakamura T, Arioka S, Mitsuda Y, Takakura T, et al: Endogenous angiogenesis inhibitor vasohibin1 exhibits broad-spectrum antilymphangiogenic activity and suppresses lymph node metastasis. Am J Pathol. 176:1950–1958. 2010. View Article : Google Scholar : PubMed/NCBI
32	Li D, Zhou K, Wang S, Shi Z and Yang Z: Recombinant adenovirus encoding vasohibin prevents tumor angiogenesis and inhibits tumor growth. Cancer Sci. 101:448–452. 2010. View Article : Google Scholar : PubMed/NCBI