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Published in: Journal of Experimental & Clinical Cancer Research 1/2015

Open Access 01-12-2015 | Research

DAL-1 attenuates epithelial-to mesenchymal transition in lung cancer

Authors: Xianliang Chen, Xiaoying Guan, Huiyu Zhang, Xiaobin Xie, Hongyan Wang, Jie Long, Tonghui Cai, Shuhua Li, Zhen Liu, Yajie Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2015

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Abstract

Background

Epithelial-to mesenchymal transition (EMT) involves in metastasis, causing loss of epithelial polarity. Metastasis is the major cause of carcinoma-induced death, but mechanisms are poorly understood. Here we identify differentially expressed in adenocarcinoma of the lung-1 (DAL-1), a protein belongs to the membrane-associated cytoskeleton protein 4.1 family, as an efficient suppressor of EMT in lung cancer.

Methods

The relationship between DAL-1 and EMT markers were analyzed by using immunohistochemistry in the clinical lung cancer tissues. Quantitative real-time PCR and western blot were used to characterize the expression of the EMT indicator mRNAs and proteins in DAL-1 overexpressed or knockdown cells. DAL-1 combined proteins were assessed by co-immunoprecipitation.

Results

DAL-1 levels were strongly reduced even lost in lymph node metastasis and advanced pathological stage of human lung carcinomas. Overexpression of DAL-1 altered the expression of numerous EMT markers, such as E-cadherin, β-catenin Vimentin and N-cadherin expression, meanwhile changed the morphological shape of lung cancer cells, and whereas silencing DAL-1 had an opposite effect. DAL-1 directly combined with E-cadherin promoter and regulated its expression that could be the reason for impairing EMT and decreasing cell migration and invasion. Strikingly, HSPA5 was found as DAL-1 direct binding protein.

Conclusions

These results suggest that tumor suppressor DAL-1 could also attenuate EMT and be important for tumor metastasis in the early transformation process in lung cancer.
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Literature
2.
go back to reference Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.PubMedCrossRef Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.PubMedCrossRef
3.
go back to reference Tran YK, Bogler O, Gorse KM, Wieland I, Green MR, Newsham IF. A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer. Cancer Res. 1999;59(1):35–43.PubMed Tran YK, Bogler O, Gorse KM, Wieland I, Green MR, Newsham IF. A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer. Cancer Res. 1999;59(1):35–43.PubMed
4.
go back to reference Steenbergen RD, Kramer D, Braakhuis BJ, Stern PL, Verheijen RH, Meijer CJ, et al. TSLC1 gene silencing in cervical cancer cell lines and cervical neoplasia. J Natl Cancer Inst. 2004;96(4):294–305.PubMedCrossRef Steenbergen RD, Kramer D, Braakhuis BJ, Stern PL, Verheijen RH, Meijer CJ, et al. TSLC1 gene silencing in cervical cancer cell lines and cervical neoplasia. J Natl Cancer Inst. 2004;96(4):294–305.PubMedCrossRef
5.
go back to reference Lu B, Di W, Wang H, Ma H, Li J, Zhang Q. Tumor suppressor TSLC1 is implicated in cell proliferation, invasion and apoptosis in laryngeal squamous cell carcinoma by regulating Akt signaling pathway. Tumour Biol. 2012;33(6):2007–17.PubMedCrossRef Lu B, Di W, Wang H, Ma H, Li J, Zhang Q. Tumor suppressor TSLC1 is implicated in cell proliferation, invasion and apoptosis in laryngeal squamous cell carcinoma by regulating Akt signaling pathway. Tumour Biol. 2012;33(6):2007–17.PubMedCrossRef
6.
go back to reference Heller G, Geradts J, Ziegler B, Newsham I, Filipits M, Markis-Ritzinger EM, et al. Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat. 2007;103(3):283–91.PubMedCrossRef Heller G, Geradts J, Ziegler B, Newsham I, Filipits M, Markis-Ritzinger EM, et al. Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat. 2007;103(3):283–91.PubMedCrossRef
7.
go back to reference Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G, et al. Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res. 2003;63(19):6320–6.PubMed Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G, et al. Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res. 2003;63(19):6320–6.PubMed
8.
go back to reference Kikuchi S, Yamada D, Fukami T, Masuda M, Sakurai-Yageta M, Williams YN, et al. Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer. Clin Cancer Res. 2005;11(8):2954–61.PubMedCrossRef Kikuchi S, Yamada D, Fukami T, Masuda M, Sakurai-Yageta M, Williams YN, et al. Promoter methylation of DAL-1/4.1B predicts poor prognosis in non-small cell lung cancer. Clin Cancer Res. 2005;11(8):2954–61.PubMedCrossRef
9.
go back to reference Goto A, Niki T, Chi-Pin L, Matsubara D, Murakami Y, Funata N, et al. Loss of TSLC1 expression in lung adenocarcinoma: relationships with histological subtypes, sex and prognostic significance. Cancer Sci. 2005;96(8):480–6.PubMedCrossRef Goto A, Niki T, Chi-Pin L, Matsubara D, Murakami Y, Funata N, et al. Loss of TSLC1 expression in lung adenocarcinoma: relationships with histological subtypes, sex and prognostic significance. Cancer Sci. 2005;96(8):480–6.PubMedCrossRef
10.
go back to reference Kuns R, Kissil JL, Newsham IF, Jacks T, Gutmann DH, Sherman LS. Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation. Oncogene. 2005;24(43):6502–15.PubMed Kuns R, Kissil JL, Newsham IF, Jacks T, Gutmann DH, Sherman LS. Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation. Oncogene. 2005;24(43):6502–15.PubMed
11.
go back to reference Busam RD, Thorsell AG, Flores A, Hammarstrom M, Persson C, Obrink B, et al. Structural basis of tumor suppressor in lung cancer 1 (TSLC1) binding to differentially expressed in adenocarcinoma of the lung (DAL-1/4.1B). J Biol Chem. 2011;286(6):4511–6.PubMedCentralPubMedCrossRef Busam RD, Thorsell AG, Flores A, Hammarstrom M, Persson C, Obrink B, et al. Structural basis of tumor suppressor in lung cancer 1 (TSLC1) binding to differentially expressed in adenocarcinoma of the lung (DAL-1/4.1B). J Biol Chem. 2011;286(6):4511–6.PubMedCentralPubMedCrossRef
13.
go back to reference Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43.PubMedCentralPubMedCrossRef Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43.PubMedCentralPubMedCrossRef
15.
go back to reference Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379(9826):1591–601.PubMedCrossRef Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379(9826):1591–601.PubMedCrossRef
16.
go back to reference Bonomi M, Pilotto S, Milella M, Massari F, Cingarlini S, Brunelli M, et al. Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research. J Exp Clin Cancer Res. 2011;30:115.PubMedCentralPubMedCrossRef Bonomi M, Pilotto S, Milella M, Massari F, Cingarlini S, Brunelli M, et al. Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research. J Exp Clin Cancer Res. 2011;30:115.PubMedCentralPubMedCrossRef
17.
go back to reference Spano D, Heck C, De Antonellis P, Christofori G, Zollo M. Molecular networks that regulate cancer metastasis. Semin Cancer Biol. 2012;22(3):234–49.PubMedCrossRef Spano D, Heck C, De Antonellis P, Christofori G, Zollo M. Molecular networks that regulate cancer metastasis. Semin Cancer Biol. 2012;22(3):234–49.PubMedCrossRef
18.
go back to reference Jan YH, Tsai HY, Yang CJ, Huang MS, Yang YF, Lai TC, et al. Adenylate kinase-4 is a marker of poor clinical outcomes that promotes metastasis of lung cancer by downregulating the transcription factor ATF3. Cancer Res. 2012;72(19):5119–29.PubMedCrossRef Jan YH, Tsai HY, Yang CJ, Huang MS, Yang YF, Lai TC, et al. Adenylate kinase-4 is a marker of poor clinical outcomes that promotes metastasis of lung cancer by downregulating the transcription factor ATF3. Cancer Res. 2012;72(19):5119–29.PubMedCrossRef
19.
go back to reference Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res. 2014;33:62.PubMedCentralPubMedCrossRef Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res. 2014;33:62.PubMedCentralPubMedCrossRef
20.
go back to reference Franco-Chuaire ML, Magda Carolina SC, Chuaire-Noack L. Epithelial-mesenchymal transition (EMT): principles and clinical impact in cancer therapy. Invest Clin. 2013;54(2):186–205.PubMed Franco-Chuaire ML, Magda Carolina SC, Chuaire-Noack L. Epithelial-mesenchymal transition (EMT): principles and clinical impact in cancer therapy. Invest Clin. 2013;54(2):186–205.PubMed
21.
go back to reference Richardson F, Young GD, Sennello R, Wolf J, Argast GM, Mercado P, et al. The evaluation of E-Cadherin and vimentin as biomarkers of clinical outcomes among patients with non-small cell lung cancer treated with erlotinib as second- or third-line therapy. Anticancer Res. 2012;32(2):537–52.PubMed Richardson F, Young GD, Sennello R, Wolf J, Argast GM, Mercado P, et al. The evaluation of E-Cadherin and vimentin as biomarkers of clinical outcomes among patients with non-small cell lung cancer treated with erlotinib as second- or third-line therapy. Anticancer Res. 2012;32(2):537–52.PubMed
22.
go back to reference Bastid J. EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. Cancer Metastasis Rev. 2012;31(1–2):277–83.PubMedCrossRef Bastid J. EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. Cancer Metastasis Rev. 2012;31(1–2):277–83.PubMedCrossRef
23.
go back to reference Selamat SA, Chung BS, Girard L, Zhang W, Zhang Y, Campan M, et al. Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res. 2012;22(7):1197–211.PubMedCentralPubMedCrossRef Selamat SA, Chung BS, Girard L, Zhang W, Zhang Y, Campan M, et al. Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res. 2012;22(7):1197–211.PubMedCentralPubMedCrossRef
24.
go back to reference Takahashi Y, Iwai M, Kawai T, Arakawa A, Ito T, Sakurai-Yageta M, et al. Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. Breast Cancer. 2012;19(3):242–52.PubMedCrossRef Takahashi Y, Iwai M, Kawai T, Arakawa A, Ito T, Sakurai-Yageta M, et al. Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. Breast Cancer. 2012;19(3):242–52.PubMedCrossRef
25.
26.
go back to reference Nunomura W, Denker SP, Barber DL, Takakuwa Y, Gascard P. Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na(+)/H(+) exchanger isoform 1). Biochem J. 2012;446(3):427–35.PubMedCrossRef Nunomura W, Denker SP, Barber DL, Takakuwa Y, Gascard P. Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na(+)/H(+) exchanger isoform 1). Biochem J. 2012;446(3):427–35.PubMedCrossRef
27.
go back to reference Ohno N, Terada N, Komada M, Saitoh S, Costantini F, Pace V, et al. Dispensable role of protein 4.1B/DAL-1 in rodent adrenal medulla regarding generation of pheochromocytoma and plasmalemmal localization of TSLC1. Biochim Biophys Acta. 2009;1793(3):506–15.PubMedCrossRef Ohno N, Terada N, Komada M, Saitoh S, Costantini F, Pace V, et al. Dispensable role of protein 4.1B/DAL-1 in rodent adrenal medulla regarding generation of pheochromocytoma and plasmalemmal localization of TSLC1. Biochim Biophys Acta. 2009;1793(3):506–15.PubMedCrossRef
28.
go back to reference Chao YL, Shepard CR, Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer. 2010;9:179.PubMedCentralPubMedCrossRef Chao YL, Shepard CR, Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer. 2010;9:179.PubMedCentralPubMedCrossRef
29.
go back to reference Kittiniyom K, Mastronardi M, Roemer M, Wells WA, Greenberg ER, Titus-Ernstoff L, et al. Allele-specific loss of heterozygosity at the DAL-1/4.1B (EPB41L3) tumor-suppressor gene locus in the absence of mutation. Genes Chromosomes Cancer. 2004;40(3):190–203.PubMedCrossRef Kittiniyom K, Mastronardi M, Roemer M, Wells WA, Greenberg ER, Titus-Ernstoff L, et al. Allele-specific loss of heterozygosity at the DAL-1/4.1B (EPB41L3) tumor-suppressor gene locus in the absence of mutation. Genes Chromosomes Cancer. 2004;40(3):190–203.PubMedCrossRef
30.
go back to reference Gascard P, Parra MK, Zhao Z, Calinisan VR, Nunomura W, Rivkees SA, et al. Putative tumor suppressor protein 4.1B is differentially expressed in kidney and brain via alternative promoters and 5′ alternative splicing. Biochim Biophys Acta. 2004;1680(2):71–82.PubMedCrossRef Gascard P, Parra MK, Zhao Z, Calinisan VR, Nunomura W, Rivkees SA, et al. Putative tumor suppressor protein 4.1B is differentially expressed in kidney and brain via alternative promoters and 5′ alternative splicing. Biochim Biophys Acta. 2004;1680(2):71–82.PubMedCrossRef
31.
go back to reference Kang Q, Wang T, Zhang H, Mohandas N, An X. A Golgi-associated protein 4.1B variant is required for assimilation of proteins in the membrane. J Cell Sci. 2009;122(Pt 8):1091–9.PubMedCentralPubMedCrossRef Kang Q, Wang T, Zhang H, Mohandas N, An X. A Golgi-associated protein 4.1B variant is required for assimilation of proteins in the membrane. J Cell Sci. 2009;122(Pt 8):1091–9.PubMedCentralPubMedCrossRef
32.
go back to reference Wang H, Liu C, Debnath G, Baines AJ, Conboy JG, Mohandas N, et al. Comprehensive characterization of expression patterns of protein 4.1 family members in mouse adrenal gland: implications for functions. Histochem Cell Biol. 2010;134(4):411–20.PubMedCrossRef Wang H, Liu C, Debnath G, Baines AJ, Conboy JG, Mohandas N, et al. Comprehensive characterization of expression patterns of protein 4.1 family members in mouse adrenal gland: implications for functions. Histochem Cell Biol. 2010;134(4):411–20.PubMedCrossRef
33.
go back to reference Horresh I, Bar V, Kissil JL, Peles E. Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. J Neurosci. 2010;30(7):2480–9.PubMedCentralPubMedCrossRef Horresh I, Bar V, Kissil JL, Peles E. Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. J Neurosci. 2010;30(7):2480–9.PubMedCentralPubMedCrossRef
34.
go back to reference Buttermore ED, Dupree JL, Cheng J, An X, Tessarollo L, Bhat MA. The cytoskeletal adaptor protein band 4.1B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons. J Neurosci. 2011;31(22):8013–24.PubMedCentralPubMedCrossRef Buttermore ED, Dupree JL, Cheng J, An X, Tessarollo L, Bhat MA. The cytoskeletal adaptor protein band 4.1B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons. J Neurosci. 2011;31(22):8013–24.PubMedCentralPubMedCrossRef
35.
go back to reference Einheber S, Meng X, Rubin M, Lam I, Mohandas N, An X, et al. The 4.1B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons. Glia. 2013;61(2):240–53.PubMedCentralPubMedCrossRef Einheber S, Meng X, Rubin M, Lam I, Mohandas N, An X, et al. The 4.1B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons. Glia. 2013;61(2):240–53.PubMedCentralPubMedCrossRef
36.
go back to reference Cifuentes-Diaz C, Chareyre F, Garcia M, Devaux J, Carnaud M, Levasseur G, et al. Protein 4.1B contributes to the organization of peripheral myelinated axons. PLoS One. 2011;6(9):e25043.PubMedCentralPubMedCrossRef Cifuentes-Diaz C, Chareyre F, Garcia M, Devaux J, Carnaud M, Levasseur G, et al. Protein 4.1B contributes to the organization of peripheral myelinated axons. PLoS One. 2011;6(9):e25043.PubMedCentralPubMedCrossRef
37.
go back to reference Ko BS, Chang TC, Hsu C, Chen YC, Shen TL, Chen SC, et al. Overexpression of 14-3-3epsilon predicts tumour metastasis and poor survival in hepatocellular carcinoma. Histopathology. 2011;58(5):705–11.PubMedCrossRef Ko BS, Chang TC, Hsu C, Chen YC, Shen TL, Chen SC, et al. Overexpression of 14-3-3epsilon predicts tumour metastasis and poor survival in hepatocellular carcinoma. Histopathology. 2011;58(5):705–11.PubMedCrossRef
38.
go back to reference Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR, et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J. 2010;430(3):405–13.PubMedCentralPubMedCrossRef Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR, et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J. 2010;430(3):405–13.PubMedCentralPubMedCrossRef
39.
go back to reference Cheng JC, Klausen C, Leung PC. Hypoxia-inducible factor 1 alpha mediates epidermal growth factor-induced down-regulation of E-cadherin expression and cell invasion in human ovarian cancer cells. Cancer Lett. 2013;329(2):197–206.PubMedCrossRef Cheng JC, Klausen C, Leung PC. Hypoxia-inducible factor 1 alpha mediates epidermal growth factor-induced down-regulation of E-cadherin expression and cell invasion in human ovarian cancer cells. Cancer Lett. 2013;329(2):197–206.PubMedCrossRef
40.
go back to reference Kim HJ, Park JW, Cho YS, Cho CH, Kim JS, Shin HW, et al. Pathogenic role of HIF-1alpha in prostate hyperplasia in the presence of chronic inflammation. Biochim Biophys Acta. 2013;1832(1):183–94.PubMedCrossRef Kim HJ, Park JW, Cho YS, Cho CH, Kim JS, Shin HW, et al. Pathogenic role of HIF-1alpha in prostate hyperplasia in the presence of chronic inflammation. Biochim Biophys Acta. 2013;1832(1):183–94.PubMedCrossRef
41.
go back to reference Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007;67(8):3496–9.PubMedCrossRef Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007;67(8):3496–9.PubMedCrossRef
42.
go back to reference Zhang J, Jiang Y, Jia Z, Li Q, Gong W, Wang L, et al. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006;23(7–8):401–10.PubMed Zhang J, Jiang Y, Jia Z, Li Q, Gong W, Wang L, et al. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006;23(7–8):401–10.PubMed
43.
go back to reference Wu HM, Jiang ZF, Fan XY, Wang T, Ke X, Yan XB, et al. Reversed expression of GRIM-1 and GRP78 in human non-small cell lung cancer. Hum Pathol. 2014;45(9):1936–43.PubMedCrossRef Wu HM, Jiang ZF, Fan XY, Wang T, Ke X, Yan XB, et al. Reversed expression of GRIM-1 and GRP78 in human non-small cell lung cancer. Hum Pathol. 2014;45(9):1936–43.PubMedCrossRef
Metadata
Title
DAL-1 attenuates epithelial-to mesenchymal transition in lung cancer
Authors
Xianliang Chen
Xiaoying Guan
Huiyu Zhang
Xiaobin Xie
Hongyan Wang
Jie Long
Tonghui Cai
Shuhua Li
Zhen Liu
Yajie Zhang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2015
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-014-0117-2

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