Scutellarin inhibits the growth and invasion of human tongue squamous carcinoma through the inhibition of matrix metalloproteinase-2 and -9 and αvβ6 integrin

Li,Haixia; Huang,Dayong; Gao,Zhongxiuzi; Chen,Yan; Zhang,Lina; Zheng,Jinhua

doi:10.3892/ijo.2013.1873

Scutellarin inhibits the growth and invasion of human tongue squamous carcinoma through the inhibition of matrix metalloproteinase-2 and -9 and αvβ6 integrin

Authors:
- Haixia Li
- Dayong Huang
- Zhongxiuzi Gao
- Yan Chen
- Lina Zhang
- Jinhua Zheng
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Affiliations: Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin 150081, P.R. China
Published online on: March 28, 2013 https://doi.org/10.3892/ijo.2013.1873
Pages: 1674-1681

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Abstract

Scutellarin can inhibit the growth and migration of tongue cancer cells in vitro and can regulate cell adhesion; such agents will be the next generation anticancer therapeutics. In this study, we evaluated the antitumor effects of the scutellarin on human tongue squamous carcinoma (SAS) cell line and investigated its molecular mechanism. To explore the possible mechanisms underlying the antitumor effect of scutellarin, we studied its impact on the growth and invasion of SAS cells xenografted into nude mice, on the expression of MMP-2, MMP-9, integrin αvβ6, and c-JUN, and also on changes in collagen fibers. We observed that the growth of xenograft SAS tumors in nude mice was significantly inhibited by the administration of scutellarin without major adverse effects. Results showed that scutellarin mediated inhibition of tumor cell proliferation, induced apoptosis, and regulated expression of matrix metalloproteinase (MMP)-2 and -9, and integrin αvβ6 at the mRNA and protein levels in vivo. Moreover, scutellarin regulated the expression of collagen fibers in the tumor microenvironment (surrounding the tumor), thereby inhibiting cell invasion and metastasis. Our in vitro and in vivo studies have shown that scutellarin reduces the expression of MMP-2 and -9, and integrin αvβ6 in SAS cells, possibly through the regulation of expression of transcription factor AP-1. These results suggest that scutellarin can have an anti-tumor therapeutic effect by inhibition of the ability of SAS cells to invade and metastasize.

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1.	Scully C and Bagan J: Oral squamous cell carcinoma overview. Oral Oncol. 45:301–308. 2009. View Article : Google Scholar : PubMed/NCBI
2.	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
3.	Gustafsson E and Fassler R: Insights into extracellular matrix functions from mutant mouse models. Exp Cell Res. 261:52–68. 2000. View Article : Google Scholar : PubMed/NCBI
4.	Thomas GT, Lewis MP and Speight PM: Matrix metalloproteinases and oral cancer. Oral Oncol. 35:227–233. 1999. View Article : Google Scholar : PubMed/NCBI
5.	Singh RD, Haridas N, Patel JB, et al: Matrix metalloproteinases and their inhibitors: correlation with invasion and metastasis in oral cancer. Indian J Clin Biochem. 25:250–259. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Fan HX, Li HX, Chen D, Gao ZX and Zheng JH: Changes in the expression of MMP2, MMP9, and ColIV in stromal cells in oral squamous tongue cell carcinoma: relationships and prognostic implications. J Exp Clin Cancer Res. 31:902012. View Article : Google Scholar : PubMed/NCBI
7.	De Vicente JC, Fresno MF, Villalain L, Vega JA and Hernandez Vallejo G: Expression and clinical significance of matrix metalloproteinase-2 and matrix metalloproteinase-9 in oral squamous cell carcinoma. Oral Oncol. 41:283–293. 2005.PubMed/NCBI
8.	Hynes RO: Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 69:11–25. 1992. View Article : Google Scholar : PubMed/NCBI
9.	Breuss JM, Gallo J, De Lisser HM, et al: Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci. 108:2241–2251. 1995.PubMed/NCBI
10.	Bandyopadhyay A and Raghavan S: Defining the role of integrin alphavbeta6 in cancer. Curr Drug Targets. 10:645–652. 2009. View Article : Google Scholar : PubMed/NCBI
11.	Thomas GJ, Lewis MP, Whawell SA, et al: Expression of the alphavbeta6 integrin promotes migration and invasion in squamous carcinoma cells. J Invest Dermatol. 117:67–73. 2001. View Article : Google Scholar : PubMed/NCBI
12.	Ramos DM, Dang D and Sadler S: The role of the integrin alpha v beta6 in regulating the epithelial to mesenchymal transition in oral cancer. Anticancer Res. 29:125–130. 2009.PubMed/NCBI
13.	Thomas GJ, Lewis MP, Hart IR, Marshall JF and Speight PM: AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9. Int J Cancer. 92:641–650. 2001. View Article : Google Scholar : PubMed/NCBI
14.	Yang GY, Xu KS, Pan ZQ, et al: Integrin alpha v beta 6 mediates the potential for colon cancer cells to colonize in and metastasize to the liver. Cancer Sci. 99:879–887. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Souza LF, Souza VF, Silva LD, Santos JN and Reis SR: Expression of basement membrane laminin in oral squamous cell carcinomas. Braz J Otorhinolaryngol. 73:768–774. 2007.PubMed/NCBI
16.	Sakamoto S and Kyprianou N: Targeting anoikis resistance in prostate cancer metastasis. Mol Aspects Med. 31:205–214. 2010. View Article : Google Scholar : PubMed/NCBI
17.	Rajalalitha P and Vali S: Molecular pathogenesis of oral submucous fibrosis - a collagen metabolic disorder. J Oral Pathol Med. 34:321–328. 2005. View Article : Google Scholar : PubMed/NCBI
18.	Verde P, Casalino L, Talotta F, Yaniv M and Weitzman JB: Deciphering AP-1 function in tumorigenesis: fraternizing on target promoters. Cell Cycle. 6:2633–2639. 2007. View Article : Google Scholar : PubMed/NCBI
19.	Cowles EA, Brailey LL and Gronowicz GA: Integrin-mediated signaling regulates AP-1 transcription factors and proliferation in osteoblasts. J Biomed Mater Res. 52:725–737. 2000. View Article : Google Scholar : PubMed/NCBI
20.	Jin YJ, Park I, Hong IK, et al: Fibronectin and vitronectin induce AP-1-mediated matrix metalloproteinase-9 expression through integrin alpha(5)beta(1)/alpha(v)beta(3)-dependent Akt, ERK and JNK signaling pathways in human umbilical vein endothelial cells. Cell Signal. 23:125–134. 2011. View Article : Google Scholar
21.	Singh NK, Quyen DV, Kundumani-Sridharan V, Brooks PC and Rao GN: AP-1 (Fra-1/c-Jun)-mediated induction of expression of matrix metalloproteinase-2 is required for 15S-hydroxyeicosate traenoic acid-induced angiogenesis. J Biol Chem. 285:16830–16843. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Li H, Huang D, Gao Z, et al: Scutellarin inhibits cell migration by regulating production of alphavbeta6 integrin and E-cadherin in human tongue cancer cells. Oncol Rep. 24:1153–1160. 2010.PubMed/NCBI
23.	Laitakari J and Stenback F: Collagen matrix in development and progression of experimentally induced respiratory neoplasms in the hamster. Toxicol Pathol. 29:514–527. 2001. View Article : Google Scholar : PubMed/NCBI
24.	Suh SJ, Yoon JW, Lee TK, et al: Chemoprevention of Scutellaria bardata on human cancer cells and tumorigenesis in skin cancer. Phytother Res. 21:135–141. 2007. View Article : Google Scholar : PubMed/NCBI
25.	Goh D, Lee YH and Ong ES: Inhibitory effects of a chemically standardized extract from Scutellaria barbata in human colon cancer cell lines, LoVo. J Agric Food Chem. 53:8197–8204. 2005. View Article : Google Scholar : PubMed/NCBI
26.	Wang CZ, Li XL, Wang QF, Mehendale SR and Yuan CS: Selective fraction of Scutellaria baicalensis and its chemopreventive effects on MCF-7 human breast cancer cells. Phytomedicine. 17:63–68. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Feng Y, Zhang S, Tu J, et al: Novel function of scutellarin in inhibiting cell proliferation and inducing cell apoptosis of human Burkitt lymphoma Namalwa cells. Leuk Lymphoma. 53:2456–2464. 2012. View Article : Google Scholar : PubMed/NCBI
28.	Wang LX, Zeng JP, Wei XB, Wang FW, Liu ZP and Zhang XM: Effects of scutellarin on apoptosis induced by cobalt chloride in PC12 cells. Chin J Physiol. 50:301–307. 2007.PubMed/NCBI
29.	Chan JY, Tan BK and Lee SC: Scutellarin sensitizes drug-evoked colon cancer cell apoptosis through enhanced caspase-6 activation. Anticancer Res. 29:3043–3047. 2009.PubMed/NCBI
30.	Ramos DM, But M, Regezi J, et al: Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma. Matrix Biol. 21:297–307. 2002. View Article : Google Scholar : PubMed/NCBI
31.	Mignatti P and Rifkin DB: Biology and biochemistry of proteinases in tumor invasion. Physiol Rev. 73:161–195. 1993.PubMed/NCBI
32.	Vargova V, Pytliak M and Mechirova V: Matrix metalloproteinases. EXS. 103:1–33. 2012.
33.	Itoh Y and Nagase H: Matrix metalloproteinases in cancer. Essays Biochem. 38:21–36. 2002.PubMed/NCBI
34.	Patel BP, Shah SV, Shukla SN, Shah PM and Patel PS: Clinical significance of MMP-2 and MMP-9 in patients with oral cancer. Head Neck. 29:564–572. 2007. View Article : Google Scholar : PubMed/NCBI
35.	Sullivan BP, Kassel KM, Manley S, Baker AK and Luyendyk JP: Regulation of transforming growth factor-beta1-dependent integrin beta6 expression by p38 mitogen-activated protein kinase in bile duct epithelial cells. J Pharmacol Exp Ther. 337:471–478. 2011. View Article : Google Scholar : PubMed/NCBI
36.	Hong IK, Kim YM, Jeoung DI, Kim KC and Lee H: Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells. Exp Mol Med. 37:230–239. 2005. View Article : Google Scholar : PubMed/NCBI
37.	Chakraborti S, Mandal M, Das S, Mandal A and Chakraborti T: Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem. 253:269–285. 2003. View Article : Google Scholar : PubMed/NCBI
38.	Corbi AL, Jensen UB and Watt FM: The alpha2 and alpha5 integrin genes: identification of transcription factors that regulate promoter activity in epidermal keratinocytes. FEBS Lett. 474:201–207. 2000. View Article : Google Scholar : PubMed/NCBI
39.	Gao ZX, Huang DY, Li HX, et al: Scutellarin promotes in vitro angiogenesis in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 400:151–156. 2010. View Article : Google Scholar : PubMed/NCBI