Expression and significance of MMP2 and HIF‑1α in hepatocellular carcinoma

Wang,Bin; Ding,You‑Ming; Fan,Ping; Wang,Bing; Xu,Jun‑Hui; Wang,Wei‑Xing

doi:10.3892/ol.2014.2189

Expression and significance of MMP2 and HIF‑1α in hepatocellular carcinoma

Authors:
- Bin Wang
- You‑Ming Ding
- Ping Fan
- Bing Wang
- Jun‑Hui Xu
- Wei‑Xing Wang
View Affiliations

Affiliations: Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: May 28, 2014 https://doi.org/10.3892/ol.2014.2189
Pages: 539-546

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

Hepatocellular carcinoma (HCC) is a serious threat to human health. HCC is a malignant tumor and its invasion and metastasis are the result of multigene interactions. Matrix metalloproteinase‑2 (MMP-2) is capable of degrading the majority of components of the extracellular matrix and is regarded to closely correlate with tumor invasion and metastasis. Furthermore, the hypoxia‑inducible factor 1α (HIF‑1α) is an important transcription factor, which is closely associated with the process of tumor growth. The aim of the present study was to investigate the expression of MMP2 and HIF‑1α) in HCC, and the relationship between MMP2/HIF‑1α protein expression and the clinical/pathological characteristics of HCC. The mRNA levels of MMP2 and HIF‑1α were detected in 32 cases of HCC and the corresponding normal adjacent tissues with fluorescence‑based quantitative polymerase chain reaction (qPCR). The protein expression of MMP2 and HIF‑1α was assessed in 45 HCC cases and 33 cases of corresponding normal adjacent tissue, using immunohistochemical methods. The association between MMP2/HIF‑1α and pathological features of HCC, and the correlation between MMP2 and HIF‑1α were analyzed. The Kaplan‑Meier method was used to assess the impact of MMP2 and HIF‑1α expression on survival. The fluorescence‑based qPCR demonstrated that MMP2 and HIF‑1α mRNA expression levels in the HCC tissues were 0.84±0.17 and 0.87±0.11, respectively, which were significantly higher than those in the adjacent normal tissues (0.70±0.13 and 0.68±0.13, respectively; P<0.05). Immunohistochemical analysis revealed that MMP2 and HIF‑1α protein expression in the HCC tissues was 63.1 and 70.8%, respectively, which was also higher than that in the adjacent normal tissues (34.2 and 36.8%, respectively). There was no significant correlation between the expression of MMP2 or HIF‑1α protein and the age or gender of patients with HCC (P>0.05). However, there was significant correlation between MMP2 or HIF‑1α protein expression and tumor size, metastasis, presence of a capsule and clinical TNM staging of HCC. Their expression also had a significant effect on patient survival time. In conclusion, MMP2 and HIF‑1α are overexpressed in HCC, and the MMP2 signaling pathway may promote the development of HCC together with HIF‑1α.

View Figures

View References

1	Marín-Hernández A, Gallardo-Pérez JC, Ralph SJ, Rodríguez-Enríquez S and Moreno-Sánchez R: HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem. 9:1084–1101. 2009.
2	Littlepage LE, Sternlicht MD, Rougier N, Phillips J, Gallo E, Yu Y, Williams K, Brenot A, Gordon JI and Werb Z: Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res. 6:2224–2234. 2010.
3	Hajitou A, Sounni NE, Devy L, Grignet-Debrus C, Lewalle JM, Li H, Deroanne CF, Lu H, Colige A, Nusgens BV, Frankenne F, Maron A, Yeh P, Perricaudet M, Chang Y, Soria C, Calberg-Bacq CM, Foidart JM and Noël A: Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis. Cancer Res. 8:3450–3457. 2001.
4	Yamasaki M, Nagatomo T, Matsuyama T, Ikeho Y, Kato E and Nishiyama K, Sakakibara Y, Suiko M and Nishiyama K: Conjugated linoleic acids inhibit hypoxia inducible factor-1α stabilization under hypoxic condition in human hepatocellular carcinoma cells. J Oleo Sci. 9:491–496. 2012.
5	Birner P, Schindl M, Obermair A, Plank C, Breitenecker G and Oberhuber G: Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 17:4693–4696. 2000.
6	Karahan N, Güney M, Baspinar S, Oral B, Kapucuoglu N and Mungan T: Expression of gelatinase (MMP-2 and MMP-9) and cyclooxygenase-2 (COX-2) in endometrial carcinoma. Eur J Gynaecol Oncol. 28:184–188. 2007.
7	Sakata H, Fujimura M, Watanabe M and Tominaga T: Association of cavernous malformation within vestibular schwannoma: immunohistochemical analysis of matrix metalloproteinase-2 and -9. Neurol Med Chir. 47:509–512. 2007.
8	Du R, Petritsch C, Lu K, Liu P, Haller A, Ganss R, Song H, Vandenberg S and Bergers G: Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM. Neuro Oncol. 3:254–264. 2008.
9	Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY and Gao DM: Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1α, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. Clin Cancer Res. 16:5463–5472. 2011.
10	Varotti G, Ramacciato G, Ercolani G, Grazi GL, Vetrone G, Cescon M, Del Gaudio M, Ravaioli M, Ziparo V, Lauro A and Pinna A: Comparison between the fifth and sixth editions of the AJCC/UICC TNM staging systems for hepatocellular carcinoma: multicentric study on 393 cirrhotic resected patients. Eur J Surg Oncol. 31:760–767. 2005.
11	Nishida Y, Miyamori H, Thompson EW, Takino T, Endo Y and Sato H: Activation of matrix metalloproteinase-2 (MMP-2) by membrane type 1 matrix metalloproteinase through an artificial receptor for proMMP-2 generates active MMP-2. Cancer Res. 21:9096–9104. 2008.
12	Schoedel KE, Tyner VZ, Kim TH, Michalopoulos GK and Mars WM: HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver. Mod Pathol. 1:14–21. 2003.
13	Kato T, Kure T, Chang JH, Gabison EE, Itoh T, Itohara S and Azar DT: Diminished corneal angiogenesis in gelatinase A-deficient mice. FEBS Lett. 2:187–190. 2001.
14	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 10:721–732. 2003.
15	Hao J, Song X, Song B, Liu Y, Wei L, Wang X and Yu J: Effects of lentivirus-mediated HIF-1alpha knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells. Cancer Gene Ther. 7:449–455. 2008.
16	Burrows N, Resch J, Cowen RL, von Wasielewski R, Hoang-Vu C, West CM, Williams KJ and Brabant G: Expression of hypoxia-inducible factor 1 alpha in thyroid carcinomas. Endocr Relat Cancer. 1:61–72. 2010.
17	Seeber LM, Horrée N, van der Groep P, van der Wall E, Verheijen RH and van Diest PJ: Necrosis related HIF-1alpha expression predicts prognosis in patients with endometrioid endometrial carcinoma. BMC Cancer. 10:3072010.
18	Samulitis BK, Landowski TH and Dorr RT: Inhibition of protein synthesis by imexon reduces HIF-1alpha expression in normoxic and hypoxic pancreatic cancer cells. Invest New Drugs. 1:89–98. 2009.
19	Milosevic M, Fyles A, Hedley D and Hill R: The human tumor microenvironment: invasive (needle) measurement of oxygen and interstitial fluid pressure. Semin Radiat Oncol. 3:249–258. 2004.
20	Vumbaca F, Phoenix KN, Rodriguez-Pinto D, Han DK and Claffey KP: Double-stranded RNA-binding protein regulates vascular endothelial growth factor mRNA stability, translation, and breast cancer angiogenesis. Mol Cell Biol. 2:772–783. 2008.
21	Jing SW, Wang YD, Kuroda M, Su JW, Sun GG, Liu Q, Cheng YJ and Yang CR: HIF-1α contributes to hypoxia-induced invasion and metastasis of esophageal carcinoma via inhibiting E-cadherin and promoting MMP-2 expression. Acta Med Okayama. 5:399–407. 2012.
22	Mimeault M and Batra SK: Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med. 1:30–54. 2013.
23	Nurwidya F, Takahashi F, Minakata K, Murakami A and Takahashi K: From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers. Anat Cell Biol. 2:73–78. 2012.
24	Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P and Semenza GL: Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63:1138–1143. 2003.
25	Xie T, Yuan XL, Yu SY, Yang B and Dong LL: Interference of HIF-1alpha by RNA reduces the expression of matrix metalloproteinase-2 in human cervical carcinoma HeLa cells. Ai Zheng. 6:600–605. 2008.(In Chinese).
26	Giannelli G, Bergamini C, Fransvea E, Marinosci F, Quaranta V and Antonaci S: Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion. Lab Invest. 4:613–627. 2001.
27	Choi SH, Shin HW, Park JY, Yoo JY, Kim do Y, Ro WS, Yun CO and Han KH: Effects of the knockdown of hypoxia inducible factor-1alpha expression by adenovirus-mediated shRNA on angiogenesis and tumor growth in hepatocellular carcinoma cell lines. Korean J Hepatol. 3:280–287. 2010.