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01-09-2016 | Original Article

DUSP28 links regulation of Mucin 5B and Mucin 16 to migration and survival of AsPC-1 human pancreatic cancer cells

Authors: Jungwhoi Lee, Jungsul Lee, Jeong-Hun Yun, Dae Gwin Jeong, Jae Hoon Kim

Published in: Tumor Biology | Issue 9/2016

Abstract

The prognosis of pancreatic cancer has not improved despite considerable and continuous effort. Dual-specificity phosphatase 28 (DUSP28) is highly expressed in human pancreatic cancers and exerts critical effects. However, knowledge of its function in pancreatic cancers is extremely limited. Here, we demonstrate the peculiar role of DUSP28 in pancreatic cancers. Analysis using the Gene Expression Omnibus public microarray database indicated higher DUSP28, MUC1, MUC4, MUC5B, MUC16 and MUC20 messenger RNA (mRNA) levels in pancreatic cancers compared with normal pancreas tissues. DUSP28 expression in human pancreatic cancer correlated positively with those of MUC1, MUC4, MUC5B, MUC16 and MUC20. In contrast, there were no significant correlations between DUSP28 and mucins in normal pancreas tissues. Decreased DUSP28 expression resulted in down-regulation of MUC5B and MUC16 at both the mRNA and protein levels; furthermore, transfection with small interfering RNA (siRNA) for MUC5B and MUC16 inhibited the migration and survival of AsPC-1 cells. In addition, transfection of siRNA for MUC5B and MUC16 resulted in a significant decrease in phosphorylation of FAK and ERK1/2 compared with transfection with scrambled-siRNA. These results collectively indicate unique links between DUSP28 and MUC5B/MUC16 and their roles in pancreatic cancer; moreover, they strongly support a rationale for targeting DUSP28 to inhibit development of malignant pancreatic cancer.

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Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMed

Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.CrossRefPubMed

Cano CE, Motoo Y, Iovanna JL. Epithelial-to-mesenchymal transition in pancreatic adenocarcinoma. Scientific WorldJournal. 2010;10:1947–57.CrossRef

Inoue S, Tezel E, Nakao A. Molecular diagnosis of pancreatic cancer. Hepato-Gastroenterology. 2001;48:933–8.PubMed

Singh D, Upadhyay G, Srivastava RK, Shankar S. Recent advances in pancreatic cancer: biology, treatment, and prevention. Biochim Biophys Acta. 1856;2015:13–27.

Masters JR. False cell lines: the problem and a solution. Cytotechnology. 2002;39:69–74.CrossRefPubMedPubMedCentral

Masters JR. Cell-line authentication: end the scandal of false cell lines. Nature. 2012;492:186.CrossRefPubMed

Chen WH, Horoszewicz JS, Leong SS, Shimano T, Penetrante R, Sanders WH, et al. Human pancreatic adenocarcinoma: in vitro and in vivo morphology of a new tumor line established from ascites. In vitro. 1982;18:24–34.CrossRefPubMed

Jonckheere N, Van Seuningen I. The membrane-bound mucins: how large o-glycoproteins play key roles in epithelial cancers and hold promise as biological tools for gene-based and immunotherapies. Crit Rev Oncog. 2008;14:177–96.CrossRefPubMed

10.

Jonckheere N, Skrypek N, Van Seuningen I. Mucins and pancreatic cancer. Cancers. 2010;2:1794–812.CrossRefPubMedPubMedCentral

11.

Kufe DW. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009;9:874–85.CrossRefPubMedPubMedCentral

12.

Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4:45–60.CrossRefPubMed

13.

Kaur S, Kumar S, Momi N, Sasson AR, Batra SK. Mucins in pancreatic cancer and its microenvironment. Nat Rev Gastroenterol Hepatol. 2013;10:607–20.CrossRefPubMedPubMedCentral

14.

Dhillon AS, Hagan S, Rath O, Kolch W. Map kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90.CrossRefPubMed

15.

Kim EK, Choi EJ. Pathological roles of mapk signaling pathways in human diseases. Biochim Biophys Acta. 1802;2010:396–405.

16.

Wang D, Han S, Peng R, Jiao C, Wang X, Han Z, et al. Dusp28 contributes to human hepatocellular carcinoma via regulation of the p38 mapk signaling. Int J Oncol. 2014;45:2596–604.PubMed

17.

Prabhakar S, Asuthkar S, Lee W, Chigurupati S, Zakharian E, Tsung AJ, et al. Targeting dusps in glioblastomas—wielding a double-edged sword? Cell Biol Int. 2014;38:145–53.CrossRefPubMed

18.

Rios P, Nunes-Xavier CE, Tabernero L, Kohn M, Pulido R. Dual-specificity phosphatases as molecular targets for inhibition in human disease. Antioxid Redox Signal. 2014;20:2251–73.CrossRefPubMed

19.

Lee J, Hun Yun J, Lee J, Choi C, Hoon Kim J. Blockade of dual-specificity phosphatase 28 decreases chemo-resistance and migration in human pancreatic cancer cells. Sci Rep. 2015;5:12296.CrossRefPubMedPubMedCentral

20.

Piccolo SR, Withers MR, Francis OE, Bild AH, Johnson WE. Multiplatform single-sample estimates of transcriptional activation. Proc Natl Acad Sci U S A. 2013;110:17778–83.CrossRefPubMedPubMedCentral

21.

Lee J, Lee J, Kim SJ, Kim JH. Quercetin-3-o-glucoside suppresses pancreatic cancer cell migration induced by tumor-deteriorated growth factors in vitro. Oncol Rep. 2016;35:2473–9

22.

Lee J, Han SI, Yun JH, Kim JH. Quercetin 3-o-glucoside suppresses epidermal growth factor-induced migration by inhibiting egfr signaling in pancreatic cancer cells. Tumour Biol. 2015;36:9385–93.CrossRefPubMed

23.

Chaika NV, Gebregiworgis T, Lewallen ME, Purohit V, Radhakrishnan P, Liu X, et al. Muc1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proc Natl Acad Sci U S A. 2012;109:13787–92.CrossRefPubMedPubMedCentral

24.

Skrypek N, Duchene B, Hebbar M, Leteurtre E, van Seuningen I, Jonckheere N. The muc4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the concentrative nucleoside transporter family. Oncogene. 2013;32:1714–23.CrossRefPubMed

25.

Nagata K, Horinouchi M, Saitou M, Higashi M, Nomoto M, Goto M, et al. Mucin expression profile in pancreatic cancer and the precursor lesions. J Hepato-Biliary-Pancreat Surg. 2007;14:243–54.CrossRef

26.

Shukla SK, Gunda V, Abrego J, Haridas D, Mishra A, Souchek J, et al. Muc16-mediated activation of mtor and c-myc reprograms pancreatic cancer metabolism. Oncotarget. 2015;6:19118–31.CrossRefPubMedPubMedCentral

27.

Hirono S, Yamaue H, Hoshikawa Y, Ina S, Tani M, Kawai M, et al. Molecular markers associated with lymph node metastasis in pancreatic ductal adenocarcinoma by genome-wide expression profiling. Cancer Sci. 2010;101:259–66.CrossRefPubMed

28.

Kato S, Hokari R, Crawley S, Gum J, Ahn DH, Kim JW, et al. Muc5ac mucin gene regulation in pancreatic cancer cells. Int J Oncol. 2006;29:33–40.PubMed

29.

Hoshi H, Sawada T, Uchida M, Saito H, Iijima H, Toda-Agetsuma M, et al. Tumor-associated muc5ac stimulates in vivo tumorigenicity of human pancreatic cancer. Int J Oncol. 2011;38:619–27.PubMed

30.

Chen SH, Hung WC, Wang P, Paul C, Konstantopoulos K. Mesothelin binding to ca125/muc16 promotes pancreatic cancer cell motility and invasion via mmp-7 activation. Sci Rep. 2013;3:1870.PubMedPubMedCentral

31.

Ru P, Williams TM, Chakravarti A, Guo D. Tumor metabolism of malignant gliomas. Cancers. 2013;5:1469–84.CrossRefPubMedPubMedCentral

32.

Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, et al. Roles of the raf/mek/erk and pi3k/pten/akt/mtor pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging. 2011;3:192–222.CrossRefPubMedPubMedCentral

Title: DUSP28 links regulation of Mucin 5B and Mucin 16 to migration and survival of AsPC-1 human pancreatic cancer cells
Authors: Jungwhoi Lee
Jungsul Lee
Jeong-Hun Yun
Dae Gwin Jeong
Jae Hoon Kim
Publication date: 01-09-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 9/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-016-5079-x

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