Latexin exhibits tumor-suppressor potential in pancreatic ductal adenocarcinoma

Xue,Zhanxiong; Zhou,Yuhui; Wang,Cheng; Zheng,Jihang; Zhang,Pu; Zhou,Lingling; Wu,Liang; Shan,Yunfeng; Ye,Mengsi; He,Yun; Cai,Zhenzhai

doi:10.3892/or.2015.4353

Latexin exhibits tumor-suppressor potential in pancreatic ductal adenocarcinoma

Authors:
- Zhanxiong Xue
- Yuhui Zhou
- Cheng Wang
- Jihang Zheng
- Pu Zhang
- Lingling Zhou
- Liang Wu
- Yunfeng Shan
- Mengsi Ye
- Yun He
- Zhenzhai Cai
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Affiliations: Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: October 27, 2015 https://doi.org/10.3892/or.2015.4353
Pages: 50-58
Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Recent studies suggest that latexin (Lxn) expression is involved in stem cell regulation and that it plays significant roles in tumor cell migration and invasion. The clinicopathological significance of Lxn expression and its possible correlation with CD133 expression in pancreatic ductal adenocarcinoma (PDAC) is currently unknown. In the present study, immunohistochemical analysis was performed to determine Lxn and CD133 expression in 43 PDAC patient samples and in 32 corresponding adjacent non-cancerous samples. The results were analyzed and compared with patient age, gender, tumor site and size, histological grade, clinical stage and overall mean survival time. Lxn expression was clearly decreased in the PDAC tissues compared with that in the adjacent non-cancerous tissues, while CD133 expression was increased. Low Lxn expression in the PDAC tissues was significantly correlated with tumor size (P=0.002), histological grade (P=0.000), metastasis (P=0.007) and clinical stage (P=0.018), but not with age (P=0.451), gender (P=0.395) or tumor site (P=0.697). Kaplan-Meier survival analysis revealed that low Lxn expression was significantly correlated with reduced overall survival time (P=0.000). Furthermore, Lxn expression was found to be inversely correlated with CD133 expression (r=-0.485, P=0.001). Furthermore, CD133-positive MIA PaCa-2 pancreatic tumor cells were sorted by magnetic-activated cell sorting (MACS), and those that overexpressed Lxn exhibited a significantly higher rate of apoptosis and lower proliferative activity. Our findings suggest that Lxn may function as a tumor suppressor that targets CD133-positive pancreatic cancer cells.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008.
2	Sultana A, Smith CT, Cunningham D, Starling N, Neoptolemos JP and Ghaneh P: Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol. 25:2607–2615. 2007.
3	Tan BT, Park CY, Ailles LE and Weissman IL: The cancer stem cell hypothesis: A work in progress. Lab Invest. 86:1203–1207. 2006.
4	Hruban RH, Maitra A and Goggins M: Update on pancreatic intraepithelial neoplasia. Int J Clin Exp Pathol. 1:306–316. 2008.
5	Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF and Simeone DM: Identification of pancreatic cancer stem cells. Cancer Res. 67:1030–1037. 2007.
6	Huang P, Wang CY, Gou SM, Wu HS, Liu T and Xiong JX: Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J Gastroenterol. 14:3903–3907. 2008.
7	Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Kayashima T, Hayashi A, Nakata K and Tanaka M: Characterization of CD24 expression in intraductal papillary mucinous neoplasms and ductal carcinoma of the pancreas. Hum Pathol. 41:1466–1474. 2010.
8	Hong SP, Wen J, Bang S, Park S and Song SY: CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Int J Cancer. 125:2323–2331. 2009.
9	Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH, Pasca di Magliano M and Simeone DM: c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 141:2218–2227.e5. 2011.
10	Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ and Heeschen C: Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 1:313–323. 2007.
11	Olempska M, Eisenach PA, Ammerpohl O, Ungefroren H, Fandrich F and Kalthoff H: Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary Pancreat Dis Int. 6:92–97. 2007.
12	Kim MP, Fleming JB, Wang H, Abbruzzese JL, Choi W, Kopetz S, McConkey DJ, Evans DB and Gallick GE: ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS One. 6:e206362011.
13	Maeda S, Shinchi H, Kurahara H, Mataki Y, Maemura K, Sato M, Natsugoe S, Aikou T and Takao S: CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br J Cancer. 98:1389–1397. 2008.
14	Maréchal R, Demetter P, Nagy N, Berton A, Decaestecker C, Polus M, Closset J, Devière J, Salmon I and Van Laethem JL: High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer. 100:1444–1451. 2009.
15	Kawamoto M, Ishiwata T, Cho K, Uchida E, Korc M, Naito Z and Tajiri T: Nestin expression correlates with nerve and retro-peritoneal tissue invasion in pancreatic cancer. Hum Pathol. 40:189–198. 2009.
16	Youssef EM, Chen XQ, Higuchi E, Kondo Y, Garcia-Manero G, Lotan R and Issa JP: Hypermethylation and silencing of the putative tumor suppressor Tazarotene-induced gene 1 in human cancers. Cancer Res. 64:2411–2417. 2004.
17	Liang Y, Jansen M, Aronow B, Geiger H and Van Zant G: The quantitative trait gene latexin influences the size of the hematopoietic stem cell population in mice. Nat Genet. 39:178–188. 2007.
18	Mitsunaga K, Kikuchi J, Wada T and Furukawa Y: Latexin regulates the abundance of multiple cellular proteins in hematopoietic stem cells. J Cell Physiol. 227:1138–1147. 2012.
19	Muthusamy V, Premi S, Soper C, Platt J and Bosenberg M: The hematopoietic stem cell regulatory gene latexin has tumor-suppressive properties in malignant melanoma. J Invest Dermatol. 133:1827–1833. 2013.
20	Xue ZX, Zheng JH, Zheng ZQ, Cai JL, Ye XH, Wang C, Sun WJ, Zhou X, Lu MD, Li PH, et al: Latexin inhibits the proliferation of CD133⁺ miapaca-2 pancreatic cancer stem-like cells. World J Surg Oncol. 12:4042014.
21	Shmelkov SV, St Clair R, Lyden D and Rafii S: AC133/CD133/Prominin-1. Int J Biochem Cell Biol. 37:715–719. 2005.
22	Banerjee S, Nomura A, Sangwan V, Chugh R, Dudeja V, Vickers SM and Saluja A: CD133⁺ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide. Clin Cancer Res. 20:2388–2399. 2014.
23	Nomura A, Banerjee S, Chugh R, Dudeja V, Yamamoto M, Vickers SM and Saluja AK: CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer. Oncotarget. 6:8313–8322. 2015.
24	Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007.
25	Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821–5828. 2003.
26	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004.
27	Kim HS, Yoo SY, Kim KT, Park JT, Kim HJ and Kim JC: Expression of the stem cell markers CD133 and nestin in pancreatic ductal adenocarcinoma and clinical relevance. Int J Clin Exp Pathol. 5:754–761. 2012.
28	Chen K, Li Z, Jiang P, Zhang X, Zhang Y, Jiang Y, He Y and Li X: Co-expression of CD133, CD44v6 and human tissue factor is associated with metastasis and poor prognosis in pancreatic carcinoma. Oncol Rep. 32:755–763. 2014.
29	Hou YC, Chao YJ, Tung HL, Wang HC and Shan YS: Coexpression of CD44-positive/CD133-positive cancer stem cells and CD204-positive tumor-associated macrophages is a predictor of survival in pancreatic ductal adenocarcinoma. Cancer. 120:2766–2777. 2014.
30	Chu X, Zhao P, Lv Y and Liu L: Decreased expression of TFPI-2 correlated with increased expression of CD133 in cholangiocarcinoma. Int J Clin Exp Pathol. 8:328–336. 2015.
31	Hao XP, Willis JE, Pretlow TG, Rao JS, MacLennan GT, Talbot IC and Pretlow TP: Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions. Cancer Res. 60:18–21. 2000.
32	Arimatsu Y: Latexin: A molecular marker for regional specification in the neocortex. Neurosci Res. 20:131–135. 1994.
33	Jin M, Ishida M, Katoh-Fukui Y, Tsuchiya R, Higashinakagawa T, Ikegami S and Arimatsu Y: Reduced pain sensitivity in mice lacking latexin, an inhibitor of metallocarboxypeptidases. Brain Res. 1075:117–121. 2006.
34	Aagaard A, Listwan P, Cowieson N, Huber T, Ravasi T, Wells CA, Flanagan JU, Kellie S, Hume DA, Kobe B, et al: An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: Relationship to cystatins and the tumor suppressor TIG1. Structure. 13:309–317. 2005.
35	Jing C, El-Ghany MA, Beesley C, Foster CS, Rudland PS, Smith P and Ke Y: Tazarotene-induced gene 1 (TIG1) expression in prostate carcinomas and its relationship to tumorigenicity. J Natl Cancer Inst. 94:482–490. 2002.
36	Kwong J, Lo KW, Chow LS, Chan FL, To KF and Huang DP: Silencing of the retinoid response gene TIG1 by promoter hyper-methylation in nasopharyngeal carcinoma. Int J Cancer. 113:386–392. 2005.
37	Zhang J, Liu L and Pfeifer GP: Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene. Oncogene. 23:2241–2249. 2004.
38	Li Y, Basang Z, Ding H, Lu Z, Ning T, Wei H, Cai H and Ke Y: Latexin expression is downregulated in human gastric carcinomas and exhibits tumor suppressor potential. BMC Cancer. 11:1212011.
39	Ni QF, Tian Y, Kong LL, Lu YT, Ding WZ and Kong LB: Latexin exhibits tumor suppressor potential in hepatocellular carcinoma. Oncol Rep. 31:1364–1372. 2014.
40	Liu Y, Howard D, Rector K, Swiderski C, Brandon J, Schook L, Mehta J, Bryson JS, Bondada S and Liang Y: Latexin is downregulated in hematopoietic malignancies and restoration of expression inhibits lymphoma growth. PLoS One. 7:e449792012.
41	Oldridge EE, Walker HF, Stower MJ, Simms MS, Mann VM, Collins AT, Pellacani D and Maitland NJ: Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN. Oncogenesis. 2:e452013.
42	Zhang H, Ren Y, Pang D and Liu C: Clinical implications of AGbL2 expression and its inhibitor latexin in breast cancer. World J Surg Oncol. 12:1422014.
43	Immervoll H, Hoem D, Sakariassen PØ, Steffensen OJ and Molven A: Expression of the 'stem cell marker' CD133 in pancreas and pancreatic ductal adenocarcinomas. BMC Cancer. 8:482008.
44	Kure S, Matsuda Y, Hagio M, Ueda J, Naito Z and Ishiwata T: Expression of cancer stem cell markers in pancreatic intraepithelial neoplasias and pancreatic ductal adenocarcinomas. Int J Oncol. 41:1314–1324. 2012.
45	Vizio B, Mauri FA, Prati A, Trivedi P, Giacobino A, Novarino A, Satolli MA, Ciuffreda L, Camandona M, Gasparri G, et al: Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma. Oncol Rep. 27:69–76. 2012.