Effects of CoCl2‑simulated hypoxia on the expression levels of matrix metalloproteinases in renal adenocarcinoma cells and renal tubular epithelial cells

Zhang,Xiaoyi; Chen,Ling

doi:10.3892/etm.2018.6337

Effects of CoCl2‑simulated hypoxia on the expression levels of matrix metalloproteinases in renal adenocarcinoma cells and renal tubular epithelial cells

Authors:
- Xiaoyi Zhang
- Ling Chen
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Affiliations: Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
Published online on: June 21, 2018 https://doi.org/10.3892/etm.2018.6337
Pages: 1454-1460

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Abstract

Renal cell carcinoma (RCC) and chronic kidney disease (CKD) are associated with hypoxia, but the effects of hypoxia on the process of angiogenesis in the two diseases are dramatically different. Some of matrix metalloproteinases (MMPs), such as MMP2 and MMP9, may have a role because they represent the most prominent family of proteinases associated with angiogenesis. In the present study, the differential response of human renal cell cancer cells (786‑0), human renal tubular epithelial cells (HK‑2) and human microvascular endothelial cells (HMEC‑1) to hypoxia with regards to the expression of MMP2, MMP9, MMP14, TIMP2, RECK was investigated. Cobalt chloride (CoCl2) treatment was used to simulate the hypoxia environment in RCC and CKD. The expression levels of HIF‑1α, RECK, MMP2, MMP9, MMP14 and TIMP2 in HK2, 786‑0 and HMEC‑1 cells were determined by western blot analysis after incubation with varying concentrations of CoCl2 for 24 h. It was indicated that the effects of hypoxia on the endogenous expression of RECK and MMP2 differed depending on the considered cell type. Notably, the RECK expression was significantly decreased in 786‑0 cells under hypoxia, whereas this expression was slightly increased in HK2 and HMEC‑1 cells. Furthermore, the MMP2 expression was significantly increased in HMEC‑1 cells under hypoxia, whereas the expression was slightly decreased in HK2 and 786‑0 cells. These results demonstrate that 786‑0, HK2 and HMEC‑1 cells respond differently under hypoxic conditions. Furthermore, MMP2 and RECK may serve divergent roles in HK2 and HMEC‑1 cells under hypoxic conditions.

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1	Muz B, de la Puente P, Azab F and Azab AK: The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 3:83–92. 2015. View Article : Google Scholar : PubMed/NCBI
2	Farris AB, Adams CD, Brousaides N, Della Pelle PA, Collins AB, Moradi E, Smith RN, Grimm PC and Colvin RB: Morphometric and visual evaluation of fibrosis in renal biopsies. J Am Soc Nephrol. 22:176–186. 2011. View Article : Google Scholar : PubMed/NCBI
3	Baeriswyl V and Christofori G: The angiogenic switch in carcinogenesis. Semin Cancer Biol. 19:329–337. 2009. View Article : Google Scholar : PubMed/NCBI
4	Chen Q, Jin M, Yang F, Zhu J, Xiao Q and Zhang L: Matrix metalloproteinases: Inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm. 2013:9283152013. View Article : Google Scholar : PubMed/NCBI
5	Loayza-Puch F, Yoshida Y, Matsuzaki T, Takahashi C, Kitayama H and Noda M: Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs. Oncogene. 29:2638–2648. 2010. View Article : Google Scholar : PubMed/NCBI
6	Basilico N, Magnetto C, D'Alessandro S, Panariti A, Rivolta I, Genova T, Khadjavi A, Gulino GR, Argenziano M, Soster M, et al: Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium. Toxicol Appl Pharmacol. 288:330–338. 2015. View Article : Google Scholar : PubMed/NCBI
7	Ben-Yosef Y, Lahat N, Shapiro S, Bitterman H and Miller A: Regulation of endothelial matrix metalloproteinase-2 by hypoxia/reoxygenation. Circ Res. 90:784–791. 2002. View Article : Google Scholar : PubMed/NCBI
8	Galm O, Suzuki H, Akiyama Y, Esteller M, Brock MV, Osieka R, Baylin SB and Herman JG: Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies. Oncogene. 24:4799–4805. 2005. View Article : Google Scholar : PubMed/NCBI
9	Lahat N, Bitterman H, Engelmayer-Goren M, Rosenzweig D, Weiss-Cerem L and Rahat MA: Reduced TIMP-2 in hypoxia enhances angiogenesis. Am J Physiol Cell Physiol. 300:C557–C566. 2011. View Article : Google Scholar : PubMed/NCBI
10	Lin H, Pan JC, Zhang FM, Huang B, Chen X, Zhuang JT, Wang H, Mo CQ, Wang DH and Qiu SP: Matrix metalloproteinase-9 is required for vasculogenic mimicry by clear cell renal carcinoma cells. Urol Oncol. 33(168): e9–e16. 2015.
11	Hamano Y, Zeisberg M, Sugimoto H, Lively JC, Maeshima Y, Yang C, Hynes RO, Werb Z, Sudhakar A and Kalluri R: Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell. 3:589–601. 2003. View Article : Google Scholar : PubMed/NCBI
12	Lee SY, Hörbelt M, Mang HE, Knipe NL, Bacallao RL, Sado Y and Sutton TA: MMP-9 gene deletion mitigates microvascular loss in a model of ischemic acute kidney injury. Am J Physiol Renal Physiol. 301:F101–F109. 2011. View Article : Google Scholar : PubMed/NCBI
13	Galvez BG, Matías-Román S, Albar JP, Sánchez-Madrid F and Arroyo AG: Membrane type 1-matrix metalloproteinase is activated during migration of human endothelial cells and modulates endothelial motility and matrix remodeling. J Biol Chem. 276:37491–37500. 2001. View Article : Google Scholar : PubMed/NCBI
14	Kachgal S, Carrion B, Janson IA and Putnam AJ: Bone marrow stromal cells stimulate an angiogenic program that requires endothelial MT1-MMP. J Cell Physiol. 227:3546–3555. 2012. View Article : Google Scholar : PubMed/NCBI
15	Ando K, Ishibashi T, Ohkawara H, Inoue N, Sugimoto K, Uekita H, Hu C, Okamoto Y, Takuwa Y and Takeishi Y: Crucial role of membrane type 1 matrix metalloproteinase (MT1-MMP) in RhoA/Rac1-dependent signaling pathways in thrombin-stimulated endothelial cells. J Atheroscler Thromb. 18:762–773. 2011. View Article : Google Scholar : PubMed/NCBI
16	Noda K, Ishida S, Shinoda H, Koto T, Aoki T, Tsubota K, Oguchi Y, Okada Y and Ikeda E: Hypoxia induces the expression of membrane-type 1 matrix metalloproteinase in retinal glial cells. Invest Ophthalmol Vis Sci. 46:3817–3824. 2005. View Article : Google Scholar : PubMed/NCBI
17	Miyoshi A, Kitajima Y, Ide T, Ohtaka K, Nagasawa H, Uto Y, Hori H and Miyazaki K: Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-1alpha-independent manner. Int J Oncol. 29:1533–1539. 2006.PubMed/NCBI
18	Li J, Zucker S, Pulkoski-Gross A, Kuscu C, Karaayvaz M, Ju J, Yao H, Song E and Cao J: Conversion of stationary to invasive tumor initiating cells (TICs): Role of hypoxia in membrane type 1-matrix metalloproteinase (MT1-MMP) trafficking. PLoS One. 7:e384032012. View Article : Google Scholar : PubMed/NCBI
19	Hu J, Ni S, Cao Y, Zhang T, Wu T, Yin X, Lang Y and Lu H: The Angiogenic Effect of microRNA-21 Targeting TIMP3 through the Regulation of MMP2 and MMP9. PLoS One. 11:e01495372016. View Article : Google Scholar : PubMed/NCBI
20	Zhang X, Liu L, Liu J, Cheng Z, Wang Z, Shi C, Ding F, Chen S and Chen P: Endothelial cells co-cultured with renal carcinoma cells significantly reduce RECK expression under chemical hypoxia. Cell Biol Int. 41:922–927. 2017. View Article : Google Scholar : PubMed/NCBI