Overexpression of KiSS-1 reduces colorectal cancer cell invasion by downregulating MMP-9 via blocking PI3K/Akt/NF-κB signal pathway

Chen,Shaoqin; Chen,Wei; Zhang,Xiang; Lin,Suyong; Chen,Zhihua

doi:10.3892/ijo.2016.3368

Overexpression of KiSS-1 reduces colorectal cancer cell invasion by downregulating MMP-9 via blocking PI3K/Akt/NF-κB signal pathway

Authors:
- Shaoqin Chen
- Wei Chen
- Xiang Zhang
- Suyong Lin
- Zhihua Chen
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Affiliations: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
Published online on: February 2, 2016 https://doi.org/10.3892/ijo.2016.3368
Pages: 1391-1398

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Abstract

Metastasis of colorectal cancer (CRC) depends critically on MMP-9. KiSS-1 is a human malignant melanoma metastasis-suppressor gene. Thus, the interaction between MMP-9 and KiSS-1 has drawn considerable attention in recent years. In the present study, it was hypothesized that KiSS-1 gene could repress the metastatic potential of colorectal cancer cells by inhibiting the expression of MMP-9. Stable transfection of KiSS-1 specific siRNA and KiSS-1 expression vector in human CRC cell line HCT-116 was achieved by lentivirus infection. Moreover, the cell proliferation, invasiveness, and apoptosis were evaluated by CCK-8 method, transwell experiment, and fluorescence activated cell sorter, respectively. We also investigated the expression of MMP-9, PI3K, Akt, pAKt, and NF-кB subunit p65 using western blotting. KiSS-1 overexpression significantly decreased the cell proliferation and invasiveness of HCT-119 cells, while apoptosis was enhanced. The result of western blotting showed that synthesis of MMP-9, PI3K, p65, and phosphorylation of Akt were significantly blocked by overexpression of KiSS-1. Concatenated treatment of KiSS-1 overexpression vector with PI3K and Akt agonists attenuated the effect of KiSS-1 on the biological activity of CRC cells and also released the expression of MMP-9, PI3K, p65, and phosphorylation of Akt from the influence of overexpression of KiSS-1. Overexpression of KiSS-1 suppressed the invasiveness of CRC cells, and the gene exerted its function by reducing the expression of MMP-9 via blocking of tge PI3K/Akt/NF-κB pathway.

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1	Meijer G: GLOBOCAN 1: Cancer incidence and mortality worldwide. J Clin Pathol. 53:1642000. View Article : Google Scholar
2	Wang H, Dwyer-Lindgren L, Lofgren KT, Rajaratnam JK, Marcus JR, Levin-Rector A, Levitz CE, Lopez AD and Murray CJ: Age-specific and sex-specific mortality in 187 countries, 1970–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 380:2071–2094. 2012. View Article : Google Scholar : PubMed/NCBI
3	Blanco-Calvo M, Concha Á, Figueroa A, Garrido F and Valladares-Ayerbes M: Colorectal cancer classification and cell heterogeneity: A systems oncology approach. Int J Mol Sci. 16:13610–13632. 2015. View Article : Google Scholar : PubMed/NCBI
4	Langley RR and Fidler IJ: The seed and soil hypothesis revisited - the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer. 128:2527–2535. 2011. View Article : Google Scholar : PubMed/NCBI
5	Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM and Bos JL: Genetic alterations during colorectal-tumor development. N Engl J Med. 319:525–532. 1988. View Article : Google Scholar : PubMed/NCBI
6	Zucker S, Lysik RM, Zarrabi MH and Moll U: M(r) 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res. 53:140–146. 1993.PubMed/NCBI
7	Onisto M, Garbisa S, Caenazzo C, Freda MP, Di F, Nitti D and Stetler-Stevenson WG: Reverse transcription-polymerase chain reaction phenotyping of metalloproteinases and inhibitors involved in tumor matrix invasion. Diagn Mol Pathol. 2:74–80. 1993. View Article : Google Scholar : PubMed/NCBI
8	Tutton MG, George ML, Eccles SA, Burton S, Swift RI and Abulafi AM: Use of plasma MMP-2 and MMP-9 levels as a surrogate for tumour expression in colorectal cancer patients. Int J Cancer. 107:541–550. 2003. View Article : Google Scholar : PubMed/NCBI
9	Liabakk NB, Talbot I, Smith RA, Wilkinson K and Balkwill F: Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res. 56:190–196. 1996.PubMed/NCBI
10	Cheng JC, Chou CH, Kuo ML and Hsieh CY: Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene. 25:7009–7018. 2006. View Article : Google Scholar : PubMed/NCBI
11	Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE and Welch DR: KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 88:1731–1737. 1996. View Article : Google Scholar : PubMed/NCBI
12	Lee J-H and Welch DR: Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. 57:2384–2387. 1997.PubMed/NCBI
13	Hamid T, Gu Y, Ortines RV, Bhattacharya C, Wang G, Xuan YT and Prabhu SD: Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: Role of nuclear factor-kappaB and inflammatory activation. Circulation. 119:1386–1397. 2009. View Article : Google Scholar : PubMed/NCBI
14	Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 61:759–767. 1990. View Article : Google Scholar : PubMed/NCBI
15	Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B and Starling N: Colorectal cancer. Lancet. 375:1030–1047. 2010. View Article : Google Scholar : PubMed/NCBI
16	Shinto E, Baker K, Tsuda H, Mochizuki H, Ueno H, Matsubara O, Foulkes WD and Jass JR: Tumor buds show reduced expression of laminin-5 gamma 2 chain in DNA mismatch repair deficient colorectal cancer. Dis Colon Rectum. 49:1193–1202. 2006. View Article : Google Scholar : PubMed/NCBI
17	García-Solano J, Conesa-Zamora P, Trujillo-Santos J, Torres-Moreno D, Mäkinen MJ and Pérez-Guillermo M: Immunohistochemical expression profile of β-catenin, E-cadherin, P-cadherin, laminin-5γ2 chain, and SMAD4 in colorectal serrated adenocarcinoma. Hum Pathol. 43:1094–1102. 2012. View Article : Google Scholar
18	Matrisian LM: Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet. 6:121–125. 1990. View Article : Google Scholar : PubMed/NCBI
19	Yan C, Wang H and Boyd DD: KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha-induced block of p65/p50 nuclear translocation. J Biol Chem. 276:1164–1172. 2001. View Article : Google Scholar
20	Criswell T, Leskov K, Miyamoto S, Luo G and Boothman DA: Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation. Oncogene. 22:5813–5827. 2003. View Article : Google Scholar : PubMed/NCBI
21	Dent P, Yacoub A, Contessa J, Caron R, Amorino G, Valerie K, Hagan MP, Grant S and Schmidt-Ullrich R: Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat Res. 159:283–300. 2003. View Article : Google Scholar : PubMed/NCBI
22	Ruhul Amin AR, Senga T, Oo ML, Thant AA and Hamaguchi M: Secretion of matrix metalloproteinase-9 by the proinflammatory cytokine, IL-1beta: a role for the dual signalling pathways, Akt and Erk. Genes Cells. 8:515–523. 2003. View Article : Google Scholar : PubMed/NCBI
23	Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
24	Arlt A and Schäfer H: NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther. 40:336–347. 2002. View Article : Google Scholar : PubMed/NCBI
25	Karin M, Cao Y, Greten FR and Li ZW: NF-kappaB in cancer: From innocent bystander to major culprit. Nat Rev Cancer. 2:301–310. 2002. View Article : Google Scholar : PubMed/NCBI
26	Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G and Sizemore N: The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene. 24:1021–1031. 2005. View Article : Google Scholar