CEACAM6 induces epithelial-mesenchymal transition and mediates invasion and metastasis in pancreatic cancer

Chen,Jianmin; Li,Qiang; An,Yong; Lv,Nan; Xue,Xiaofeng; Wei,Jishu; Jiang,Kuirong; Wu,Junli; Gao,Wentao; Qian,Zhuyin; Dai,Cuncai; Xu,Zekuan; Miao,Yi

doi:10.3892/ijo.2013.2015

CEACAM6 induces epithelial-mesenchymal transition and mediates invasion and metastasis in pancreatic cancer

Authors:
- Jianmin Chen
- Qiang Li
- Yong An
- Nan Lv
- Xiaofeng Xue
- Jishu Wei
- Kuirong Jiang
- Junli Wu
- Wentao Gao
- Zhuyin Qian
- Cuncai Dai
- Zekuan Xu
- Yi Miao
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Affiliations: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China, Laboratory of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China, Department of General Surgery, The First Affiliated Hospital of Suzhou University, Suzhou, P.R. China
Published online on: July 12, 2013 https://doi.org/10.3892/ijo.2013.2015
Pages: 877-885

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Abstract

Pancreatic cancer is a disease with an extremely poor prognosis. The acquisition of invasion properties in pancreatic cancer is accompanied by the process of epithelial-mesenchymal transition (EMT). Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is emerging as an important determinant of the malignant phenotype in a range of cancers, including pancreatic cancer. Therefore, the aim of this study was to evaluate the potential involvement of CEACAM6 in the invasion and metastasis of pancreatic cancer cells via EMT regulation. The results of our study showed a positive association between CEACAM6 expression and poor prognosis of pancreatic cancer, differentiation and lymph node metastasis. Elevated levels of CEACAM6 in pancreatic cancer cells promoted EMT, migration and invasion in vitro and metastasis in animal models, whereas shRNA-mediated CEACAM6 knockdown had the opposite effect. Furthermore, we demonstrated that miR-29a/b/c specific for CEACAM6 could regulate its expression at the post-transcriptional level. Collectively, our findings identified CEACAM6, which is regulated by miR-29a/b/c, as an important positive regulator of EMT in pancreatic cancer offering an explanation for how elevated levels of CEACAM6 are likely to contribute to the highly metastatic phenotype of pancreatic cancer.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar
3	Hidalgo M: Pancreatic cancer. N Engl J Med. 362:1605–1617. 2010. View Article : Google Scholar
4	Savagner P: The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol. 21(Suppl 7): vii89–92. 2010.
5	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
6	Iwatsuki M, Mimori K, Yokobori T, et al: Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 101:293–299. 2010. View Article : Google Scholar : PubMed/NCBI
7	Zeisberg M and Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 119:1429–1437. 2009. View Article : Google Scholar : PubMed/NCBI
8	Rhim AD, Mirek ET, Aiello NM, et al: EMT and dissemination precede pancreatic tumor formation. Cell. 148:349–361. 2012. View Article : Google Scholar : PubMed/NCBI
9	Cano CE, Motoo Y and Iovanna JL: Epithelial-to-mesenchymal transition in pancreatic adenocarcinoma. ScientificWorldJournal. 10:1947–1957. 2010. View Article : Google Scholar : PubMed/NCBI
10	Krantz SB, Shields MA, Dangi-Garimella S, Munshi HG and Bentrem DJ: Contribution of epithelial-to-mesenchymal transition and cancer stem cells to pancreatic cancer progression. J Surg Res. 173:105–112. 2012. View Article : Google Scholar : PubMed/NCBI
11	Kim T, Veronese A, Pichiorri F, et al: p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exp Med. 208:875–883. 2011. View Article : Google Scholar : PubMed/NCBI
12	Park SM, Gaur AB, Lengyel E and Peter ME: The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22:894–907. 2008. View Article : Google Scholar : PubMed/NCBI
13	Tellez CS, Juri DE, Do K, et al: EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res. 71:3087–3097. 2011. View Article : Google Scholar
14	Li Y, Van den Boom TG II, Kong D, Wang Z, Ali S, Philip PA and Sarkar FH: Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 69:6704–6712. 2009. View Article : Google Scholar : PubMed/NCBI
15	Jantscheff P, Terracciano L, Lowy A, et al: Expression of CEACAM6 in resectable colorectal cancer: a factor of independent prognostic significance. J Clin Oncol. 21:3638–3646. 2003. View Article : Google Scholar : PubMed/NCBI
16	Maraqa L, Cummings M, Peter MB, et al: Carcinoembryonic antigen cell adhesion molecule 6 predicts breast cancer recurrence following adjuvant tamoxifen. Clin Cancer Res. 14:405–411. 2008. View Article : Google Scholar : PubMed/NCBI
17	Poola I, Shokrani B, Bhatnagar R, DeWitty RL, Yue Q and Bonney G: Expression of carcinoembryonic antigen cell adhesion molecule 6 oncoprotein in atypical ductal hyperplastic tissues is associated with the development of invasive breast cancer. Clin Cancer Res. 12:4773–4783. 2006. View Article : Google Scholar : PubMed/NCBI
18	Singer BB, Scheffrahn I, Kammerer R, Suttorp N, Ergun S and Slevogt H: Deregulation of the CEACAM expression pattern causes undifferentiated cell growth in human lung adenocarcinoma cells. PLoS One. 5:e87472010. View Article : Google Scholar : PubMed/NCBI
19	Ieta K, Tanaka F, Utsunomiya T, Kuwano H and Mori M: CEACAM6 gene expression in intrahepatic cholangiocarcinoma. Br J Cancer. 95:532–540. 2006. View Article : Google Scholar : PubMed/NCBI
20	Strickland LA, Ross J, Williams S, et al: Preclinical evaluation of carcinoembryonic cell adhesion molecule (CEACAM) 6 as potential therapy target for pancreatic adenocarcinoma. J Pathol. 218:380–390. 2009. View Article : Google Scholar : PubMed/NCBI
21	Duxbury MS, Ito H, Zinner MJ, Ashley SW and Whang EE: CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene. 23:465–473. 2004. View Article : Google Scholar : PubMed/NCBI
22	Iacobuzio-Donahue CA, Maitra A, Olsen M, et al: Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol. 162:1151–1162. 2003. View Article : Google Scholar : PubMed/NCBI
23	Duxbury MS, Ito H, Benoit E, Waseem T, Ashley SW and Whang EE: A novel role for carcinoembryonic antigen-related cell adhesion molecule 6 as a determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells. Cancer Res. 64:3987–3993. 2004. View Article : Google Scholar
24	Fu X, Tao L, Li M, Fisher WE and Zhang X: Effective treatment of pancreatic cancer xenografts with a conditionally replicating virus derived from type 2 herpes simplex virus. Clin Cancer Res. 12:3152–3157. 2006. View Article : Google Scholar : PubMed/NCBI
25	Duxbury MS, Matros E, Clancy T, et al: CEACAM6 is a novel biomarker in pancreatic adenocarcinoma and PanIN lesions. Ann Surg. 241:491–496. 2005. View Article : Google Scholar : PubMed/NCBI
26	Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW and Whang EE: Overexpression of CEACAM6 promotes insulin-like growth factor I-induced pancreatic adenocarcinoma cellular invasiveness. Oncogene. 23:5834–5842. 2004. View Article : Google Scholar
27	Duxbury MS, Ito H, Benoit E, Ashley SW and Whang EE: CEACAM6 is a determinant of pancreatic adenocarcinoma cellular invasiveness. Br J Cancer. 91:1384–1390. 2004. View Article : Google Scholar : PubMed/NCBI
28	Lewis-Wambi JS, Cunliffe HE, Kim HR, Willis AL and Jordan VC: Overexpression of CEACAM6 promotes migration and invasion of oestrogen-deprived breast cancer cells. Eur J Cancer. 44:1770–1779. 2008. View Article : Google Scholar : PubMed/NCBI
29	Acloque H, Adams MS, Fishwick K, Bronner-Fraser M and Nieto MA: Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 119:1438–1449. 2009. View Article : Google Scholar : PubMed/NCBI
30	Eastham AM, Spencer H, Soncin F, Ritson S, Merry CL, Stern PL and Ward CM: Epithelial-mesenchymal transition events during human embryonic stem cell differentiation. Cancer Res. 67:11254–11262. 2007. View Article : Google Scholar : PubMed/NCBI
31	Leshem O, Madar S, Kogan-Sakin I, et al: TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model. PLoS One. 6:e216502011. View Article : Google Scholar : PubMed/NCBI
32	Cummins JM, He Y, Leary RJ, et al: The colorectal microRNAome. Proc Natl Acad Sci USA. 103:3687–3692. 2006. View Article : Google Scholar : PubMed/NCBI
33	Yanaihara N, Caplen N, Bowman E, et al: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 9:189–198. 2006. View Article : Google Scholar : PubMed/NCBI
34	Mott JL, Kobayashi S, Bronk SF and Gores GJ: mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene. 26:6133–6140. 2007. View Article : Google Scholar : PubMed/NCBI
35	Braconi C, Kogure T, Valeri N, et al: microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene. 30:4750–4756. 2011. View Article : Google Scholar : PubMed/NCBI
36	Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH and Zhuang SM: Effects of microRNA-29 on apoptosis, tumorigenicity and prognosis of hepatocellular carcinoma. Hepatology. 51:836–845. 2010.PubMed/NCBI