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Cancer Cell International
Published in: Cancer Cell International 1/2017

Open Access 01-12-2017 | Primary Research

HNRNPA2B1 regulates the epithelial–mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway

Authors: Shengjie Dai, Jie Zhang, Shihao Huang, Bin Lou, Binbo Fang, Tingting Ye, Xince Huang, Bicheng Chen, Mengtao Zhou

Published in: Cancer Cell International | Issue 1/2017

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Abstract

Background

Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is closely related to tumour occurrence and development, oncogene expression, apoptosis inhibition and invasion and metastasis capacities. However, its function in the epithelial–mesenchymal transition (EMT) of pancreatic cancer is not fully understood.

Methods

By comparing various wild-type pancreatic cancer cell lines, we determined which have a higher expression level of HNRNPA2B1 accompanied by the higher expression of N-cadherin and vimentin and lower expression of E-cadherin. Therefore, to elucidate the role of HNRNPA2B1 in EMT, we generated models of HNRNPA2B1 knockdown and overexpression in different types of pancreatic cancer cell lines (MIA Paca-2, PANC-1 and Patu-8988) and examined changes in expression of EMT-related factors, including CDH1, CDH2, vimentin and snail.

Results

The results show that HNRNPA2B1 promotes EMT development by down-regulating E-cadherin and up-regulating N-cadherin and vimentin, and also stimulates the invasion capacity and inhibits viability in human pancreatic cancer cell lines, the similar results in vivo experiments. Moreover, we found that HNRNPA2B1 likely regulates EMT progression in pancreatic carcinoma via the ERK/snail signalling pathway.

Conclusions

The results of this work suggest that HNRNPA2B1 inhibition has potential antitumour effects, which warrants in-depth investigation.
Literature
1.
2.
Diener MK, Combs SE, Büchler MW. Chemoradiotherapy for locally advanced pancreatic cancer. Lancet Oncol. 2013;14(4):269–70.CrossRefPubMed
3.
Ko AH. Progress in the treatment of metastatic pancreatic cancer and the search for next opportunities. J Clin Oncol. 2015;33(16):1779–86.CrossRefPubMed
4.
Hartwig W, Werner J, Jäger D, Debus J, Büchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 2013;14(11):e476–85.CrossRefPubMed
5.
Ferrone CR, Brennan MF, Gonen M, Coit DG, Fong Y, Chung S, Tang L, Klimstra D, Allen PJ. Pancreatic adenocarcinoma: the actual 5-year survivors. J Gastrointest Surg. 2008;12(4):701–6.CrossRefPubMed
6.
Dreyfuss G, Matunis MJ, Pinol-Roma S, Burd CG. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321.CrossRefPubMed
7.
Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, D’Alessio AC, Young RA, Weinberg RA. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013;154(1):61–74.CrossRefPubMedPubMedCentral
8.
Gos M, Miloszewska J, Przybyszewska M. Epithelial–mesenchymal transition in cancer progression. Postepy Biochem. 2009;55(2):121–8.PubMed
9.
Huang RY, Guilford P, Thiery JP. Early events in cell adhesion and polarity during epithelial–mesenchymal transition. J Cell Sci. 2012;125(Pt 19):4417–22.CrossRefPubMed
10.
Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148(1–2):349–61.CrossRefPubMedPubMedCentral
11.
Andreolas C, Kalogeropoulou M, Voulgari A, Pintzas A. Fra-1 regulates vimentin during Ha-RAS-induced epithelial mesenchymal transition in human colon carcinoma cells. Int J Cancer. 2008;122(8):1745–56.CrossRefPubMed
12.
Briegel KJ. Embryonic transcription factors in human breast cancer. IUBMB Life. 2006;58(3):123–32.CrossRefPubMed
13.
14.
Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16(6):488–94.CrossRefPubMed
15.
Shaul YD, Freinkman E, Comb WC, Cantor JR, Tam WL, Thiru P, Kim D, Kanarek N, Pacold ME, Chen WW, et al. Dihydropyrimidine accumulation is required for the epithelial–mesenchymal transition. Cell. 2014;158(5):1094–109.CrossRefPubMedPubMedCentral
16.
Zhou ZJ, Dai Z, Zhou SL, Hu ZQ, Chen Q, Zhao YM, Shi YH, Gao Q, Wu WZ, Qiu SJ, et al. HNRNPAB induces epithelial–mesenchymal transition and promotes metastasis of hepatocellular carcinoma by transcriptionally activating SNAIL. Cancer Res. 2014;74(10):2750–62.CrossRefPubMed
17.
Barcelo C, Etchin J, Mansour MR, Sanda T, Ginesta MM, Sanchez-Arevalo Lobo VJ, Real FX, Capella G, Estanyol JM, Jaumot M, et al. Ribonucleoprotein HNRNPA2B1 interacts with and regulates oncogenic KRAS in pancreatic ductal adenocarcinoma cells. Gastroenterology. 2014;147(4):882–92.CrossRefPubMed
18.
Shilo A, Ben Hur V, Denichenko P, Stein I, Pikarsky E, Rauch J, Kolch W, Zender L, Karni R. Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development. RNA. 2014;20(4):505–15.CrossRefPubMedPubMedCentral
19.
Barbera MJ, Puig I, Dominguez D, Julien-Grille S, Guaita-Esteruelas S, Peiro S, Baulida J, Franci C, Dedhar S, Larue L, et al. Regulation of snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene. 2004;23(44):7345–54.CrossRefPubMed
20.
Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, De Herreros AG. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2(2):84–9.CrossRefPubMed
21.
Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, Berx G, Cano A, Beug H, Foisner R. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005;24(14):2375–85.CrossRefPubMed
22.
Hsu YL, Hou MF, Kuo PL, Huang YF, Tsai EM. Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/snail signaling pathway. Oncogene. 2013;32(37):4436–47.CrossRefPubMed
23.
Kong C, Wang C, Wang L, Ma M, Niu C, Sun X, Du J, Dong Z, Zhu S, Lu J, et al. NEDD9 is a positive regulator of epithelial–mesenchymal transition and promotes invasion in aggressive breast cancer. PLoS ONE. 2011;6(7):e22666.CrossRefPubMedPubMedCentral
24.
Makrodouli E, Oikonomou E, Koc M, Andera L, Sasazuki T, Shirasawa S, Pintzas A. BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study. Mol Cancer. 2011;10:118.CrossRefPubMedPubMedCentral
25.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.CrossRefPubMed
26.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRefPubMed
27.
Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg. 2003;237(1):74–85.CrossRefPubMedPubMedCentral
28.
Wang J, Xin B, Wang H, He X, Wei W, Zhang T, Shen X. Gastrin regulates ABCG2 to promote the migration, invasion and side populations in pancreatic cancer cells via activation of NF-kappaB signaling. Exp Cell Res. 2016;346(1):74–84.CrossRefPubMed
29.
He X, Wang J, Wei W, Shi M, Xin B, Zhang T, Shen X. Hypoxia regulates ABCG2 activity through the activivation of ERK1/2/HIF-1alpha and contributes to chemoresistance in pancreatic cancer cells. Cancer Biol Ther. 2016;17(2):188–98.CrossRefPubMed
30.
Roberts JK, Birg AV, Lin T, Daryani VM, Panetta JC, Broniscer A, Robinson GW, Gajjar AJ, Stewart CF. Population pharmacokinetics of oral topotecan in infants and very young children with brain tumors demonstrates a role of ABCG2 rs4148157 on the absorption rate constant. Drug Metab Dispos. 2016;44(7):1116–22.CrossRefPubMed
31.
Kraege S, Stefan K, Juvale K, Ross T, Willmes T, Wiese M. The combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2). Eur J Med Chem. 2016;117:212–29.CrossRefPubMed
32.
Chen H, Tu H, Meng ZQ, Chen Z, Wang P, Liu LM. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur J Surg Oncol. 2010;36(7):657–62.CrossRefPubMed
33.
Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15(14):4674–9.CrossRefPubMedPubMedCentral
34.
Steele CW, Karim SA, Leach JD, Bailey P, Upstill-Goddard R, Rishi L, Foth M, Bryson S, McDaid K, Wilson Z, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016;29(6):832–45.CrossRefPubMedPubMedCentral
35.
Tauler J, Zudaire E, Liu H, Shih J, Mulshine JL. hnRNP A2/B1 modulates epithelial–mesenchymal transition in lung cancer cell lines. Cancer Res. 2010;70(18):7137–47.CrossRefPubMed
36.
Dowling P, Pollard D, Larkin A, Henry M, Meleady P, Gately K, O’Byrne K, Barr MP, Lynch V, Ballot J, et al. Abnormal levels of heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) in tumour tissue and blood samples from patients diagnosed with lung cancer. Mol BioSyst. 2015;11(3):743–52.CrossRefPubMed
37.
Deng J, Chen S, Wang F, Zhao H, Xie Z, Xu Z, Zhang Q, Liang P, Zhai X, Cheng Y. Effects of hnRNP A2/B1 knockdown on inhibition of glioblastoma cell invasion growth and survival. Mol Neurobiol. 2016;53(2):1132–44.CrossRefPubMed
38.
Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28(1–2):15–33.CrossRefPubMed
39.
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.CrossRefPubMed
40.
Sleeman JP, Thiery JP. SnapShot: the epithelial–mesenchymal transition. Cell. 2011;145(1):162.e161.CrossRef
41.
Radisky DC, LaBarge MA. Epithelial–mesenchymal transition and the stem cell phenotype. Cell Stem Cell. 2008;2(6):511–2.CrossRefPubMed
42.
Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G. Tumor invasion in the absence of epithelial–mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell. 2006;9(4):261–72.CrossRefPubMed
43.
Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Basecke J, Stivala F, Donia M, Fagone P, Nicoletti F, et al. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia. 2011;25(7):1080–94.CrossRefPubMed
44.
Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 2008;22(4):686–707.CrossRefPubMed
45.
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18(2):189–218.CrossRefPubMed
46.
Lee JT Jr, McCubrey JA. The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia. Leukemia. 2002;16(4):486–507.CrossRefPubMed
Metadata
Title
HNRNPA2B1 regulates the epithelial–mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway
Authors
Shengjie Dai
Jie Zhang
Shihao Huang
Bin Lou
Binbo Fang
Tingting Ye
Xince Huang
Bicheng Chen
Mengtao Zhou
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2017
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0368-4

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