Emerging Role of LOXL2 in the Promotion of Pancreas Cancer Metastasis

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Jun 11

PMID 27285767

Citations 31

Authors

Joon Seong Park

Ji-Hae Lee

Yun Sun Lee

Jae Keun Kim

Seung Myung Dong

Dong Sup Yoon

Affiliations

Soon will be listed here.

Abstract

Lysyl oxidase-like 2 (LOXL2) is associated with invasiveness and metastasis in cancer. We analyzed the prognostic impact of LOXL2 in pancreatic cancer patients and investigated the role of LOXL2 in pancreatic cancer cell lines. Immunohistochemical analysis was performed in samples from 80 patients and showed LOXL2 expression in 81.2% of patients with pancreatic cancer. Regarding recurrence patterns, LOXL2-positive tumors showed a significantly higher rate of distant recurrence. The 1-year and 3-year disease-free survival rates were 84.6% and 0.0%, respectively, for LOXL2-negative patients, and 27.8 % and 0.0 %, respectively, for LOXL2-positive patients. On univariate analysis, combined resection of major vessels, depth of invasion, tumor stage, and LOXL2- positive status were significant factors for poor prognosis. After identification of LOXL2 expression in pancreatic cancer cell lines, LOXL2-silenced and LOXL2-overexpressed cell lines were used to perform transwell invasion and transendothelial migration assays.In vitro studies indicated that LOXL2 silencing in MIA PaCa-2 and PANC-1 cells induced a mesenchymal-epithelial transition (MET)-like process associated with decreased invasive and migratory properties. LOXL2 overexpression in AsPC-1 and BxPC-3 cells enhanced the epithelial-mesenchymal transition (EMT)-like process and increased migratory and invasive activity. These clinical and preclinical data confirm that higher LOXL2 expression is associated with the invasiveness of pancreatic cancer cells and the low survival rate of pancreatic cancer patients. Our results suggest the clinical value of LOXL2 as a therapeutic target in pancreatic cancer.

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References

Cuevas E, Moreno-Bueno G, Canesin G, Santos V, Portillo F, Cano A . LOXL2 catalytically inactive mutants mediate epithelial-to-mesenchymal transition. Biol Open. 2014; 3(2):129-37. PMC: 3925316. DOI: 10.1242/bio.20146841. View

Hollosi P, Yakushiji J, Fong K, Csiszar K, Fong S . Lysyl oxidase-like 2 promotes migration in noninvasive breast cancer cells but not in normal breast epithelial cells. Int J Cancer. 2009; 125(2):318-27. DOI: 10.1002/ijc.24308. View

Zhang H, Wong C, Wei H, Gilkes D, Korangath P, Chaturvedi P . HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene. 2011; 31(14):1757-70. PMC: 3223555. DOI: 10.1038/onc.2011.365. View

Lucero H, Kagan H . Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci. 2006; 63(19-20):2304-16. PMC: 11136443. DOI: 10.1007/s00018-006-6149-9. View

Ruckert F, Joensson P, Saeger H, Grutzmann R, Pilarsky C . Functional analysis of LOXL2 in pancreatic carcinoma. Int J Colorectal Dis. 2009; 25(3):303-11. DOI: 10.1007/s00384-009-0853-5. View

Ben Q, An W, Fei J, Xu M, Li G, Li Z . Downregulation of L1CAM inhibits proliferation, invasion and arrests cell cycle progression in pancreatic cancer cells . Exp Ther Med. 2014; 7(4):785-790. PMC: 3961134. DOI: 10.3892/etm.2014.1519. View

Akiri G, Sabo E, Dafni H, Vadasz Z, Kartvelishvily Y, Gan N . Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res. 2003; 63(7):1657-66. View

Wiel C, Augert A, Vincent D, Gitenay D, Vindrieux D, Le Calve B . Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis. Cell Death Dis. 2013; 4:e855. PMC: 3824691. DOI: 10.1038/cddis.2013.382. View

Semenza G . Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med. 2012; 18(9):534-43. PMC: 3449282. DOI: 10.1016/j.molmed.2012.08.001. View

10.

Ahn S, Dong S, Oshima A, Kim W, Lee H, Ah Lee S . LOXL2 expression is associated with invasiveness and negatively influences survival in breast cancer patients. Breast Cancer Res Treat. 2013; 141(1):89-99. PMC: 6944271. DOI: 10.1007/s10549-013-2662-3. View

11.

Peinado H, Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong K, Vega S . A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 2005; 24(19):3446-58. PMC: 1276164. DOI: 10.1038/sj.emboj.7600781. View

12.

Galvan J, Zlobec I, Wartenberg M, Lugli A, Gloor B, Perren A . Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer. Br J Cancer. 2015; 112(12):1944-50. PMC: 4580384. DOI: 10.1038/bjc.2015.177. View

13.

Lu P, Weaver V, Werb Z . The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012; 196(4):395-406. PMC: 3283993. DOI: 10.1083/jcb.201102147. View

14.

Grutzmann R, Foerder M, Alldinger I, Staub E, Brummendorf T, Ropcke S . Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch. 2003; 443(4):508-17. DOI: 10.1007/s00428-003-0884-1. View

15.

Gronborg M, Kristiansen T, Iwahori A, Chang R, Reddy R, Sato N . Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics. 2005; 5(1):157-71. DOI: 10.1074/mcp.M500178-MCP200. View

16.

Cox T, Erler J . Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech. 2011; 4(2):165-78. PMC: 3046088. DOI: 10.1242/dmm.004077. View

17.

Canesin G, Cuevas E, Santos V, Lopez-Menendez C, Moreno-Bueno G, Huang Y . Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization. Oncogene. 2014; 34(8):951-64. DOI: 10.1038/onc.2014.23. View

18.

Hase H, Jingushi K, Ueda Y, Kitae K, Egawa H, Ohshio I . LOXL2 status correlates with tumor stage and regulates integrin levels to promote tumor progression in ccRCC. Mol Cancer Res. 2014; 12(12):1807-17. DOI: 10.1158/1541-7786.MCR-14-0233. View

19.

Barker H, Bird D, Lang G, Erler J . Tumor-secreted LOXL2 activates fibroblasts through FAK signaling. Mol Cancer Res. 2013; 11(11):1425-36. PMC: 3833835. DOI: 10.1158/1541-7786.MCR-13-0033-T. View

20.

Herranz N, Dave N, Millanes-Romero A, Morey L, Diaz V, Lorenz-Fonfria V . Lysyl oxidase-like 2 deaminates lysine 4 in histone H3. Mol Cell. 2012; 46(3):369-76. DOI: 10.1016/j.molcel.2012.03.002. View