Full-length soluble CD147 promotes MMP-2 expression and is a potential serological marker in detection of hepatocellular carcinoma

Journal of Translational Medicine

Huijie Bian¹  Zhi-Nan Chen¹  Gang Nan¹  Bin Wang¹  Xiu-Xuan Sun¹  Fei Song¹  Xin Zhang¹  Hao Tang¹  Xiang-Min Yang¹  You-Xu Zhao¹  Zhi-Wei Hao¹  Jiao Wu¹ 

[1] Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an 710032, China

关键词: Serological marker;    Alpha-fetoprotein;    Matrix metalloproteinases;    Soluble CD147;    Hepatocellular carcinoma;   

Others  :  1148781
DOI  :  10.1186/1479-5876-12-190

 received in 2014-02-08, accepted in 2014-06-30,  发布年份 2014

【 摘 要 】

Background

As a surface glycoprotein, CD147 is capable of stimulating the production of matrix metalloproteinases (MMPs) from neighboring fibroblasts. The aim of the present study is to explore the role of soluble CD147 on MMPs secretion from hepatocellular carcinoma (HCC) cells, and to investigate the diagnostic value of serum soluble CD147 in the HCC detection.

Methods

We identified the form of soluble CD147 in cell culture supernate of HCC cells and serum of patients with HCC, and explored the role of soluble CD147 on MMPs secretion. Serum CD147 levels were detected by the enzyme-linked immunosorbent assay, and the value of soluble CD147 as a marker in HCC detection was analyzed.

Results

Full length soluble CD147 was presented in the culture medium of HCC cells and serum of patients with HCC. The extracellular domain of soluble CD147 promoted the expression of CD147 and MMP-2 from HCC cells. Knockdown of CD147 markedly diminished the up-regulation of CD147 and MMP-2 which induced by soluble CD147. Soluble CD147 activated ERK, FAK, and PI3K/Akt pathways, leading to the up-regulation of MMP-2. The level of soluble CD147 in serum of patients with HCC was significantly elevated compared with healthy individuals (P < 0.001). Soluble CD147 levels were found to be associated with HCC tumor size (P = 0.007) and Child-Pugh grade (P = 0.007). Moreover, soluble CD147 showed a better performance in distinguishing HCC compared with alpha-fetoprotein.

Conclusions

The extracellular domain of soluble CD147 enhances the secretion of MMP-2 from HCC cells, requiring the cooperation of membrane CD147 and activation of ERK, FAK, and PI3K/Akt signaling. The measurement of soluble CD147 may offer a useful approach in diagnosis of HCC.

【 授权许可】

   
2014 Wu et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Forner A, Llovet JM, Bruix J: Hepatocellular carcinoma. Lancet 2012, 379:1245-1255.
• [2]Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM: Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 2013, 144:512-527.
• [3]Kessenbrock K, Plaks V, Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010, 141:52-67.
• [4]Weidle UH, Scheuer W, Eggle D, Klostermann S, Stockinger H: Cancer-related issues of CD147. Cancer Genomics Proteomics 2010, 7:157-169.
• [5]Kanekura T, Chen X: CD147/basigin promotes progression of malignant melanoma and other cancers. J Dermatol Sci 2010, 57:149-154.
• [6]Xu J, Xu HY, Zhang Q, Song F, Jiang JL, Yang XM, Mi L, Wen N, Tian R, Wang L, Yao H, Feng Q, Zhang Y, Xing JL, Zhu P, Chen ZN: HAb18G/CD147 functions in invasion and metastasis of hepatocellular carcinoma. Mol Cancer Res 2007, 5:605-614.
• [7]Zhang Q, Zhou J, Ku XM, Chen XG, Zhang L, Xu J, Chen GS, Li Q, Qian F, Tian R, Wen N, Chen ZN: Expression of CD147 as a significantly unfavorable prognostic factor in hepatocellular carcinoma. Eur J Cancer Prev 2007, 16:196-202.
• [8]Li Y, Wu J, Song F, Tang J, Wang SJ, Yu XL, Chen ZN, Jiang JL: Extracellular membrane-proximal domain of HAb18G/CD147 binds to metal ion-dependent adhesion site (MIDAS) motif of integrin β1 to modulate malignant properties of hepatoma cells. J Biol Chem 2012, 287:4759-4772.
• [9]Dai JY, Dou KF, Wang CH, Zhao P, Lau WB, Tao L, Wu YM, Tang J, Jiang JL, Chen ZN: The interaction of HAb18G/CD147 with integrin alpha6beta1 and its implications for the invasion potential of human hepatoma cells. BMC Cancer 2009, 9:337.
• [10]Tang J, Wu YM, Zhao P, Yang XM, Jiang JL, Chen ZN: Overexpression of HAb18G/CD147 promotes invasion and metastasis via alpha3beta1 integrin mediated FAK-paxillin and FAK-PI3K-Ca2+ pathways. Cell Mol Life Sci 2008, 65:2933-2942.
• [11]Gallagher SM, Castorino JJ, Wang D, Philp NJ: Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res 2007, 67:4182-4189.
• [12]Sidhu SS, Mengistab AT, Tauscher AN, LaVail J, Basbaum C: The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions. Oncogene 2004, 23:956-963.
• [13]Taylor PM, Woodfield RJ, Hodgkin MN, Pettitt TR, Martin A, Kerr DJ, Wakelam MJ: Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A (2) and 5-lipoxygenase catalyzed pathway. Oncogene 2002, 21:5765-5772.
• [14]Haug C, Lenz C, Díaz F, Bachem MG: Oxidized low-density lipoproteins stimulate extracellular matrix metalloproteinase Inducer (EMMPRIN) release by coronary smooth muscle cells. Arterioscler Thromb Vasc Biol 2004, 24:1823-1829.
• [15]Egawa N, Koshikawa N, Tomari T, Nabeshima K, Isobe T, Seiki M: Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells. J Biol Chem 2006, 281:37576-37585.
• [16]Belton RJ Jr, Chen L, Mesquita FS, Nowak RA: Basigin-2 is a cell surface receptor for soluble basigin ligand. J Biol Chem 2008, 283:17805-17814.
• [17]Tang Y, Kesavan P, Nakada MT, Yan L: Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN. Mol Cancer Res 2004, 2:73-80.
• [18]Hanata K, Yamaguchi N, Yoshikawa K, Mezaki Y, Miura M, Suzuki S, Senoo H, Ishikawa K: Soluble EMMPRIN (extra-cellular matrix metalloproteinase inducer) stimulates the migration of HEp-2 human laryngeal carcinoma cells, accompanied by increased MMP-2 production in fibroblasts. Arch Histol Cytol 2007, 70:267-277.
• [19]Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY, 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 2011, 17:5463-5472.
• [20]Chen R, Cui J, Xu C, Xue T, Guo K, Gao D, Liu Y, Ye S, Ren Z: The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection. Ann Surg Oncol 2012, 19(Suppl 3):S375-S384.
• [21]Ku XM, Liao CG, Li Y, Yang XM, Yang B, Yao XY, Wang L, Kong LM, Zhao P, Chen ZN: Epitope mapping of series of monoclonal antibodies against the hepatocellular carcinoma-associated antigen HAb18G/CD147. Scand J Immunol 2007, 65:435-443.
• [22]Zhang Z, Yang X, Yang H, Yu X, Li Y, Xing J, Chen Z: New strategy for large-scale preparation of the extracellular domain of tumor-associated antigen HAb18G/CD147 (HAb18GED). J Biosci Bioeng 2011, 111:1-6.
• [23]Wu J, Ru NY, Zhang Y, Li Y, Wei D, Ren Z, Huang XF, Chen ZN, Bian H: HAb18G/CD147 promotes epithelial-mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug. Oncogene 2011, 30:4410-4427.
• [24]Grass GD, Bratoeva M, Toole BP: Regulation of invadopodia formation and activity by CD147. J Cell Sci 2012, 125:777-788.
• [25]Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Hamaguchi Y, Sato S: Increased serum soluble CD147 levels in patients with systemic sclerosis: association with scleroderma renal crisis. Clin Rheumatol 2012, 31:835-839.
• [26]Moonsom S, Tayapiwatana C, Wongkham S, Kongtawelert P, Kasinrerk W: A Competitive ELISA for quantifying serum CD147: reduction of soluble CD147 levels in cancer patient sera. Hybridoma (Larchmt) 2010, 29:45-52.
• [27]Onodera J, Onodera S, Kondo E, Betsuyaku T, Yasuda K: A soluble factor (EMMPRIN) in exudate influences knee motion after total arthroplasty. Knee Surg Sports Traumatol Arthrosc 2009, 17:298-304.
• [28]Määttä M, Tervahartiala T, Kaarniranta K, Tang Y, Yan L, Tuukkanen J, Sorsa T: Immunolocalization of EMMPRIN (CD147) in the human eye and detection of soluble form of EMMPRIN in ocular fluids. Curr Eye Res 2006, 31:917-924.
• [29]Odajima N, Betsuyaku T, Nasuhara Y, Itoh T, Fukuda Y, Senior RM, Nishimura M: Extracellular matrix metalloproteinase inducer in interstitial pneumonias. Hum Pathol 2006, 37:1058-1065.
• [30]Venkatesan B, Valente AJ, Prabhu SD, Shanmugam P, Delafontaine P, Chandrasekar B: EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB and MKK7/JNK/AP-1 signaling. J Mol Cell Cardiol 2010, 49:655-663.
• [31]Cui HY, Guo T, Wang SJ, Zhao P, Dong ZS, Zhang Y, Jiang JL, Chen ZN, Yu XL: Dimerization is essential for HAb18G/CD147 promoting tumor invasion via MAPK pathway. Biochem Biophys Res Commun 2012, 419:517-522.
• [32]Kuyvenhoven JP, van Hoek B, Blom E, van Duijn W, Hanemaaijer R, Verheijen JH, Lamers CB, Verspaget HW: Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma. Thromb Haemost 2003, 89:718-725.
• [33]Bei R, Mizejewski GJ: Alpha fetoprotein is more than a hepatocellular cancer biomarker: from spontaneous immue response in cancer patients to the development of an AFP-based cancer vaccine. Curr Mol Med 2011, 11:564-581.
• [34]Malaguarnera G, Giordano M, Paladina I, Berretta M, Cappellani A, Malaguarnera M: Serum markers of hepatocellular carcinoma. Dig Dis Sci 2010, 55:2744-2755.