Suppression of lung cancer cell invasion by LKB1 is due to the downregulation of tissue factor and vascular endothelial growth factor, partly dependent on SP1

Liang,Xuan; Li,Zhao-Lun; Jiang,Li-Li; Guo,Qian-Qian; Liu,Meng-Jie; Nan,Ke-Jun

doi:10.3892/ijo.2014.2351

Suppression of lung cancer cell invasion by LKB1 is due to the downregulation of tissue factor and vascular endothelial growth factor, partly dependent on SP1

Authors:
- Xuan Liang
- Zhao-Lun Li
- Li-Li Jiang
- Qian-Qian Guo
- Meng-Jie Liu
- Ke-Jun Nan
View Affiliations

Affiliations: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China, Department of Urology, Second Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, P.R. China
Published online on: March 19, 2014 https://doi.org/10.3892/ijo.2014.2351
Pages: 1989-1997

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

LKB1 encodes a serine/threonine kinase generally inactivated in many human cancers, which mediates cancer cell proliferation, migration and differentiation. Recent studies indicated that LKB1 exhibits potent anti-metastatic activity. However, the underlying molecular mechanisms of this activity remain unclear. In this study, we re‑introduced LKB1 into A549 lung cancer cells that lack the LKB1 gene to investigate how LKB1 affects tumor invasiveness and metastasis. We demonstrated that overexpression of the LKB1 protein in lung cancer cells resulted in significant inhibition of invasion. Furthermore, transfected lung cancer cells with LKB1 suppressed tissue factor (TF) and vascular endothelial growth factor (VEGF) expression at both the mRNA and protein levels. Here, we provided evidence showing that downregulation of TF and VEGF by LKB1 is correlated well with the inhibition of cell invasion. Overexpression of the LKB1 protein in human lung cancer is significantly associated with a decrease in activity and expression of the transcription factor SP1. Constitutive activation of the transcription factor Sp1 plays a critical role in TF and VEGF overexpression. We conclude that suppression of lung cancer cell invasion by LKB1 through downregulation of TF and VEGF may partly depend on its inhibitory effect on the transcription factor Sp1. Collectively, our data provide a novel molecular mechanism for the antitumor activity of LKB1 and may help further improve its effectiveness in controlling lung cancer growth and invasion.

View Figures

View References

1.	Bennett A and White J: Improving care and quality of life for patients with lung cancer. Nursing Stand. 28:50–58. 2013. View Article : Google Scholar : PubMed/NCBI
2.	Gutierrez-Fernandez A, Fueyo A, Folgueras AR, et al: Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion. Cancer Res. 68:2755–2763. 2008. View Article : Google Scholar : PubMed/NCBI
3.	Sugahara KN, Hirata T, Tanaka T, et al: Chondroitin sulfate E fragments enhance CD44 cleavage and CD44-dependent motility in tumor cells. Cancer Res. 68:7191–7199. 2008. View Article : Google Scholar : PubMed/NCBI
4.	Ghaffar H, Sahin F, Sanchez-Cepedes M, et al: LKB1 protein expression in the evolution of glandular neoplasia of the lung. Clin Cancer Res. 9:2998–3003. 2003.PubMed/NCBI
5.	Jimenez AI, Fernandez P, Dominguez O, Dopazo A and Sanchez-Cespedes M: Growth and molecular profile of lung cancer cells expressing ectopic LKB1: down-regulation of the phosphatidylinositol 3′-phosphate kinase/PTEN pathway. Cancer Res. 63:1382–1388. 2003.PubMed/NCBI
6.	Marcus AI and Zhou W: LKB1 regulated pathways in lung cancer invasion and metastasis. J Thorac oncol. 5:1883–1886. 2010. View Article : Google Scholar : PubMed/NCBI
7.	Liang X, Nan KJ and Xu QZ: Effect of small interfering RNA-induced LKB1 gene silencing on the biological behavior of lung carcinoma cells. Nan Fang Yi Ke Da Xue Xue Bao. 27:1303–1306. 2007.(In Chinese).
8.	Liang X, Nan KJ, Li CL, Yao Y, Tian T and Wang SH: Effect of transfection of LKB1 on biological behavior of human lung adenocarcinoma cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 24:1140–1142. 2008.(In Chinese).
9.	Liang X, Nan KJ, Li ZL and Xu QZ: Overexpression of the LKB1 gene inhibits lung carcinoma cell proliferation partly through degradation of c-myc protein. Oncol Rep. 21:925–931. 2009.PubMed/NCBI
10.	Ylikorkala A, Rossi DJ, Korsisaari N, et al: Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science. 293:1323–1326. 2001. View Article : Google Scholar : PubMed/NCBI
11.	Brugarolas J and Kaelin WG Jr: Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell. 6:7–10. 2004. View Article : Google Scholar
12.	Nakasaki T, Wada H, Shigemori C, et al: Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer. Am J Hematol. 69:247–254. 2002. View Article : Google Scholar : PubMed/NCBI
13.	Zhang J, Ding J, Zhang X, Shao X and Hao Z: Regulation of vascular endothelial growth factor (VEGF) production and angiogenesis by tissue factor (TF) in SGC-7901 gastric cancer cells. Cancer Biol Ther. 4:769–772. 2005. View Article : Google Scholar : PubMed/NCBI
14.	Koomagi R and Volm M: Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. Int J Cancer. 79:19–22. 1998. View Article : Google Scholar
15.	Li ZL, Xu WJ, Tian PX, et al: Recombinant adenovirus-mediated RNA silencing of tissue factor expression in human islet: an in vitro study. Nan Fang Yi Ke Da Xue Xue Bao. 27:1299–1302. 2007.(In Chinese).
16.	Ji H, Ramsey MR, Hayes DN, et al: LKB1 modulates lung cancer differentiation and metastasis. Nature. 448:807–810. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Xu C, Gui Q, Chen W, et al: Small interference RNA targeting tissue factor inhibits human lung adenocarcinoma growth in vitro and in vivo. J Exp Clin Cancer Res. 30:632011. View Article : Google Scholar : PubMed/NCBI
18.	Minamiya Y, Matsuzaki I, Sageshima M, et al: Expression of tissue factor mRNA and invasion of blood vessels by tumor cells in non-small cell lung cancer. Surg Today. 34:1–5. 2004. View Article : Google Scholar : PubMed/NCBI
19.	Mohammadi B, Haghpanah V and Larijani B: A stochastic model of tumor angiogenesis. Comput Biol Med. 38:1007–1011. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Vokes E, Herbst R and Sandler A: Angiogenesis inhibition in the treatment of lung cancer. Clin Adv Hematol Oncol. 4:1–10. 2006.PubMed/NCBI
21.	Wang S, Liu H, Ren L, Pan Y and Zhang Y: Inhibiting colorectal carcinoma growth and metastasis by blocking the expression of VEGF using RNA interference. Neoplasia. 10:399–407. 2008.PubMed/NCBI
22.	Rickles FR, Shoji M and Abe K: The role of the hemostatic system in tumor growth, metastasis, and angiogenesis: tissue factor is a bifunctional molecule capable of inducing both fibrin deposition and angiogenesis in cancer. Int J Hematol. 73:145–150. 2001. View Article : Google Scholar
23.	Regina S, Rollin J, Blechet C, Iochmann S, Reverdiau P and Gruel Y: Tissue factor expression in non-small cell lung cancer: relationship with vascular endothelial growth factor expression, microvascular density, and K-ras mutation. J Thorac Oncol. 3:689–697. 2008. View Article : Google Scholar : PubMed/NCBI
24.	Poon RT, Lau CP, Ho JW, Yu WC, Fan ST and Wong J: Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma. Clin Cancer Res. 9:5339–5345. 2003.PubMed/NCBI
25.	Regina S, Valentin JB, Lachot S, Lemarie E, Rollin J and Gruel Y: Increased tissue factor expression is associated with reduced survival in non-small cell lung cancer and with mutations of TP53 and PTEN. Clin Chem. 55:1834–1842. 2009. View Article : Google Scholar : PubMed/NCBI
26.	Han S and Roman J: COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sites. Int J Cancer. 116:536–546. 2005. View Article : Google Scholar : PubMed/NCBI
27.	Zhang J, Jia Z, Li Q, et al: Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer. 109:1478–1486. 2007. View Article : Google Scholar
28.	Lutzner N, De-Castro AJ and Rosl F: Gene expression of the tumour suppressor LKB1 is mediated by Sp1, NF-Y and FOXO transcription factors. PLoS One. 7:e325902012. View Article : Google Scholar : PubMed/NCBI
29.	Shi Q, Le X, Abbruzzese JL, et al: Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res. 61:4143–4154. 2001.PubMed/NCBI
30.	Ishibashi H, Nakagawa K, Onimaru M, et al: Sp1 decoy transfected to carcinoma cells suppresses the expression of vascular endothelial growth factor, transforming growth factor beta1, and tissue factor and also cell growth and invasion activities. Cancer Res. 60:6531–6536. 2000.