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

Journal of Experimental & Clinical Cancer Research

Yajie Zhang¹  Zhen Liu¹  Shuhua Li¹  Tonghui Cai¹  Jie Long¹  Hongyan Wang¹  Xiaobin Xie¹  Huiyu Zhang¹  Xiaoying Guan¹  Xianliang Chen¹ 

[1] Department of Pathology, School of Basic Medical Science, Guangzhou Medical University, 195# Dongfeng West Road, Guangzhou 510180, Guangdong, People’s Republic of China

关键词: HSPA5;    E-cadherin;    Lung cancer;    Epithelial-mesenchymal transition;    Differentially expressed in adenocarcinoma of the lung-1;   

Others  :  1133648
DOI  :  10.1186/s13046-014-0117-2

 received in 2014-10-12, accepted in 2014-12-22,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Chen et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Subramaniam S, Thakur RK, Yadav VK, Nanda R, Chowdhury S, Agrawal A: Lung cancer biomarkers: State of the art. J Carcinog 2013, 12:3.
• [2]Yang J, Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008, 14(6):818-29.
• [3]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.
• [4]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.
• [5]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.
• [6]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.
• [7]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.
• [8]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.
• [9]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.
• [10]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.
• [11]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.
• [12]Garufi A, D’Orazi G: High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity. J Exp Clin Cancer Res 2014, 33:79. BioMed Central Full Text
• [13]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.
• [14]Soda K: The mechanisms by which polyamines accelerate tumor spread. J Exp Clin Cancer Res 2011, 30:95. BioMed Central Full Text
• [15]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.
• [16]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. BioMed Central Full Text
• [17]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.
• [18]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.
• [19]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. BioMed Central Full Text
• [20]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.
• [21]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.
• [22]Bastid J: EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. Cancer Metastasis Rev 2012, 31(1–2):277-83.
• [23]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.
• [24]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.
• [25]Maher ER: Genomics and epigenomics of renal cell carcinoma. Semin Cancer Biol 2013, 23(1):10-7.
• [26]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.
• [27]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.
• [28]Chao YL, Shepard CR, Wells A: Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 2010, 9:179. BioMed Central Full Text
• [29]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.
• [30]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.
• [31]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.
• [32]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.
• [33]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.
• [34]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.
• [35]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.
• [36]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.
• [37]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.
• [38]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.
• [39]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.
• [40]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.
• [41]Lee AS: GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 2007, 67(8):3496-9.
• [42]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.
• [43]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.