Abstract
Purpose
Altered expression of serine protease inhibitor peptidase inhibitor clade E member 2 (SERPINE2) associates with human cancer development and progression; thus, this study investigated SERPINE2 expression in gastric cancer tissues for association with clinicopathological and survival data from the patients and then investigated the role of SERPINE2 in gastric cancer cells in vitro.
Methods
The levels of SERPINE2 mRNA in 243 gastric cancer tissues and paired non-cancerous mucosa were determined using quantitative PCR. Inhibition of SERPINE2 expression by small interfering RNA (siRNA) was detected by Western blotting. tetrazolium, soft agar, and transwell assays were performed to evaluate the proliferation, anchorage-independent growth, and motility of gastric cancer SGC7901 cells transfected with SERPINE2 siRNA.
Results
Compared with the normal mucosa, SERPINE2 mRNA was increased in gastric cancer tissues and cells. Analysis of the 243 matched specimens showed that high SERPINE2 levels were associated with lymph node metastasis, distant metastasis, and clinical stage. Patients with high SERPINE2 mRNA levels had poorer survival compared with patients with low SERPINE2 mRNA levels. In vitro, SERPINE2 inhibited anchorage-independent growth, migration, and invasion of SGC7901 cells, but not proliferation.
Conclusions
Our findings indicate that upregulated SERPINE2 may contribute to the aggressive phenotype of gastric cancer and suggest that SERPINE2 can be used as a novel prognostic factor and anticancer target in patients with gastric cancer.
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References
Bergeron S, Lemieux E, Durand V, Cagnol S, Carrier JC, Lussier JG, Boucher MJ, Rivard N (2010) The serine protease inhibitor serpinE2 is a novel target of ERK signaling involved in human colorectal tumorigenesis. Mol Cancer 9:271
Buchholz M, Biebl A, Neesse A, Wagner M, Iwamura T, Leder G, Adler G, Gress TM (2003) SERPINE2 (protease nexin I) promotes extracellular matrix production and local invasion of pancreatic tumors in vivo. Cancer Res 63:4945–4951
Candia BJ, Hines WC, Heaphy CM, Griffith JK, Orlando RA (2006) Protease nexin-1 expression is altered in human breast cancer. Cancer Cell Int 6:16
DeMeo D, Mariani T, Lange C, Lake S, Litonjua A, Celedon J, Reilly J, Chapman HA, Sparrow D, Spira A et al (2006) The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Proc Am Thorac Soc 3:502
Dorn J, Beaufort N, Schmitt M, Diamandis EP, Goettig P, Magdolen V (2014) Function and clinical relevance of kallikrein-related peptidases and other serine proteases in gynecological cancers. Crit Rev Clin Lab Sci 51:63–84
Fayard B, Bianchi F, Dey J, Moreno E, Djaffer S, Hynes NE, Monard D (2009) The serine protease inhibitor protease nexin-1 controls mammary cancer metastasis through LRP-1-mediated MMP-9 expression. Cancer Res 69:5690–5698
Gao S, Krogdahl A, Sorensen JA, Kousted TM, Dabelsteen E, Andreasen PA (2008) Overexpression of protease nexin-1 mRNA and protein in oral squamous cell carcinomas. Oral Oncol 44:309–313
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Kukkonen MK, Tiili E, Hämäläinen S, Vehmas T, Oksa P, Piirilä P, Hirvonen A (2011) SERPINE2 haplotype as a risk factor for panlobular type of emphysema. BMC Med Genet 12:157
Li G, Hu Y, Huo Y, Liu M, Freeman D, Gao J, Liu X, Wu DC, Wu H (2006) PTEN deletion leads to up-regulation of a secreted growth factor pleiotrophin. J Biol Chem 281:10663–10668
McKee CM, Xu D, Cao Y, Kabraji S, Allen D, Kersemans V, Beech J, Smart S, Hamdy F, Ishkanian A et al (2012) Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma. J Clin Investig 122:4025–4036
McKee CM, Xu D, Muschel RJ (2013) Protease nexin 1: a novel regulator of prostate cancer cell growth and neo-angiogenesis. Oncotarget 4:1–2
Nagahara A, Nakayama M, Oka D, Tsuchiya M, Kawashima A, Mukai M, Nakai Y, Takayama H, Nishimura K, Jo Y et al (2010) SERPINE2 is a possible candidate promotor for lymph node metastasis in testicular cancer. Biochem Biophys Res Commun 391:1641–1646
Neesse A, Wagner M, Ellenrieder V, Bachem M, Gress TM, Buchholz M (2007) Pancreatic stellate cells potentiate proinvasive effects of SERPINE2 expression in pancreatic cancer xenograft tumors. Pancreatology 7:380–385
Selzer-Plon J, Bornholdt J, Friis S, Bisgaard HC, Lothe IM, Tveit KM, Kure EH, Vogel U, Vogel LK (2009) Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis. BMC Cancer 9:201
Wieczorek E, Wasowicz W, Gromadzinska J, Reszka E (2014) Functional polymorphisms in the matrix metalloproteinase genes and their association with bladder cancer risk and recurrence: A mini-review. Int J Urol. doi:10.1111/iju.12431
Xu D, McKee CM, Cao Y, Ding Y, Kessler BM, Muschel RJ (2010) Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. Cancer Res 70:6988–6998
Acknowledgments
This study is supported by Shandong Province Health Science and Technology Development Program (2009HZ067).
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Kun Wang and Bin Wang have contributed equally to this article.
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Wang, K., Wang, B., Xing, A.Y. et al. Prognostic significance of SERPINE2 in gastric cancer and its biological function in SGC7901 cells. J Cancer Res Clin Oncol 141, 805–812 (2015). https://doi.org/10.1007/s00432-014-1858-1
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DOI: https://doi.org/10.1007/s00432-014-1858-1