Upregulation of the splice variant MUC4/Y in the pancreatic cancer cell line MIA PaCa-2 potentiates proliferation and suppresses apoptosis: New insight into the presence of the transcript variant of MUC4

Xie,Kunling; Zhi,Xiaofei; Tang,Jie; Zhu,Yi; Zhang,Jingjing; Li,Zheng; Tao,Jinqiu; Xu,Zekuan

doi:10.3892/or.2014.3113

Upregulation of the splice variant MUC4/Y in the pancreatic cancer cell line MIA PaCa-2 potentiates proliferation and suppresses apoptosis: New insight into the presence of the transcript variant of MUC4

Authors:
- Kunling Xie
- Xiaofei Zhi
- Jie Tang
- Yi Zhu
- Jingjing Zhang
- Zheng Li
- Jinqiu Tao
- Zekuan Xu
View Affiliations

Affiliations: Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: March 27, 2014 https://doi.org/10.3892/or.2014.3113
Pages: 2187-2194

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

MUC4/Y, the transcript variant 4 of MUC4, lacks exon 2 as compared with the transcript variant 1 of MUC4. To date, direct evidence for the function of MU4/Y remains to be reported. Previous studies based their hypotheses regarding the function of MUC4/Y on the characteristic structure domains of this variant. The aim of the present study was to investigate the specific function of MUC4/Y. The pancreatic cancer cell line MIA PaCa-2 with low MUC4/Y expression was used to establish a stable cell model of MUC4/Y upregulation using a lentivirus vector system. Results showed that MUC4/Y anchored on the cytomembrane and affected cell morphology and cell cycle. Functional analyses indicated that MUC4/Y upregulation slightly potentiated cell proliferation and significantly suppressed apoptosis both in vivo and in vitro. Further studies revealed that the JNK and AKT signalling pathways were activated. Meanwhile, MUC4/Y upregulation elicited minimal effect on the phosphorylation level of HER2, a membrane partner of MUC4. These results suggest that MUC4/Y promotes tumour progression through its anti-apoptotic and weak mitogenic effect on MIA PaCa-2 cells.

View Figures

View References

1	Mall AS: Analysis of mucins: role in laboratory diagnosis. J Clin Pathol. 61:1018–1024. 2008. View Article : Google Scholar : PubMed/NCBI
2	Escande F, Lemaitre L, Moniaux N, Batra SK, Aubert JP and Buisine MP: Genomic organization of MUC4 mucin gene. Towards the characterization of splice variants. Eur J Biochem. 269:3637–3644. 2002. View Article : Google Scholar : PubMed/NCBI
3	Andrianifahanana M, Moniaux N, Schmied BM, et al: Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. Clin Cancer Res. 7:4033–4040. 2001.PubMed/NCBI
4	Chaturvedi P, Singh AP and Batra SK: Structure, evolution, and biology of the MUC4 mucin. FASEB J. 22:966–981. 2008. View Article : Google Scholar : PubMed/NCBI
5	Moniaux N, Escande F, Batra SK, Porchet N, Laine A and Aubert JP: Alternative splicing generates a family of putative secreted and membrane-associated MUC4 mucins. Eur J Biochem. 267:4536–4544. 2000. View Article : Google Scholar : PubMed/NCBI
6	Baruch A, Hartmann M, Zrihan-Licht S, et al: Preferential expression of novel MUC1 tumor antigen isoforms in human epithelial tumors and their tumor-potentiating function. Int J Cancer. 71:741–749. 1997. View Article : Google Scholar
7	Baruch A, Hartmann M, Yoeli M, et al: The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein. Cancer Res. 59:1552–1561. 1999.PubMed/NCBI
8	Zrihan-Licht S, Baruch A, Elroy-Stein O, Keydar I and Wreschner DH: Tyrosine phosphorylation of the MUC1 breast cancer membrane proteins. Cytokine receptor-like molecules. FEBS Lett. 356:130–136. 1994. View Article : Google Scholar : PubMed/NCBI
9	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
10	Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar : PubMed/NCBI
11	Lukas J, Bartkova J and Bartek J: Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Mol Cell Biol. 16:6917–6925. 1996.PubMed/NCBI
12	Komatsu M, Jepson S, Arango ME, Carothers Carraway CA and Carraway KL: Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor. Oncogene. 20:461–470. 2001. View Article : Google Scholar : PubMed/NCBI
13	Croce CM: Oncogenes and cancer. N Engl J Med. 358:502–511. 2008. View Article : Google Scholar
14	Cantley LC: The phosphoinositide 3-kinase pathway. Science. 296:1655–1657. 2002. View Article : Google Scholar : PubMed/NCBI
15	Junttila MR, Li SP and Westermarck J: Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J. 22:954–965. 2008. View Article : Google Scholar : PubMed/NCBI
16	Workman HC, Sweeney C and Carraway KL III: The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. Cancer Res. 69:2845–2852. 2009. View Article : Google Scholar : PubMed/NCBI
17	Cullen PJ, Sabbagh W Jr, Graham E, et al: A signaling mucin at the head of the Cdc42- and MAPK-dependent filamentous growth pathway in yeast. Genes Dev. 18:1695–1708. 2004. View Article : Google Scholar : PubMed/NCBI
18	Komatsu M, Carraway CA, Fregien NL and Carraway KL: Reversible disruption of cell-matrix and cell-cell interactions by overexpression of sialomucin complex. J Biol Chem. 272:33245–33254. 1997. View Article : Google Scholar : PubMed/NCBI
19	Carraway KL, Ramsauer VP and Carraway CA: Glycoprotein contributions to mammary gland and mammary tumor structure and function: roles of adherens junctions, ErbBs and membrane MUCs. J Cell Biochem. 96:914–926. 2005. View Article : Google Scholar : PubMed/NCBI
20	Ramsauer VP, Pino V, Farooq A, Carothers Carraway CA, Salas PJ and Carraway KL: Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Mol Biol Cell. 17:2931–2941. 2006. View Article : Google Scholar : PubMed/NCBI
21	Chaturvedi P, Singh AP, Chakraborty S, et al: MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Res. 68:2065–2070. 2008. View Article : Google Scholar : PubMed/NCBI
22	Jonckheere N, Skrypek N, Merlin J, et al: The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways. PLoS One. 7:e322322012. View Article : Google Scholar
23	Moasser MM: The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 26:6469–6487. 2007. View Article : Google Scholar : PubMed/NCBI
24	Bafna S, Kaur S and Batra SK: Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 29:2893–2904. 2010. View Article : Google Scholar : PubMed/NCBI
25	Jepson S, Komatsu M, Haq B, et al: Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27(kip), but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways. Oncogene. 21:7524–7532. 2002. View Article : Google Scholar
26	Gesbert F, Sellers WR, Signoretti S, Loda M and Griffin JD: BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway. J Biol Chem. 275:39223–39230. 2000. View Article : Google Scholar : PubMed/NCBI
27	Horowitz JC, Lee DY, Waghray M, et al: Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem. 279:1359–1367. 2004. View Article : Google Scholar : PubMed/NCBI
28	Davis RJ: Signal transduction by the JNK group of MAP kinases. Cell. 103:239–252. 2000. View Article : Google Scholar : PubMed/NCBI
29	Fan M, Goodwin M, Vu T, Brantley-Finley C, Gaarde WA and Chambers TC: Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. J Biol Chem. 275:29980–29985. 2000. View Article : Google Scholar : PubMed/NCBI