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Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer

Oncogene volume 37, pages 744–755 (2018)Cite this article

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Abstract

Extracellular matrix protein 1 (ECM1) is related to strong invasiveness and poor prognosis in major malignancies, but the underlying mechanism remains unknown. Here we aimed to elucidate the function of ECM1 on cell metastasis and glucose metabolism in gastric cancer (GC). The level of ECM1 in sera and tissues of patient with GC were positively correlated with tumor invasion and recurrence. Genetic manipulation of ECM1 expression affected cell metastasis and glucose metabolism in GC cell lines. Enhanced ECM1 expression facilitated gene expression levels associated with epithelial–mesenchymal transition (EMT) and glucose metabolism. Interestingly, our results indicated that ECM1 directly interacted with integrin β4 (ITGB4) and activated ITGB4/focal adhesion kinase (FAK)/glycogen synthase kinase 3β signaling pathway, which further induced the expression of transcription factor SOX2. Aberrant expression of SOX2 altered gene expression of EMT factors and glucose metabolism enzymes. Furthermore, SOX2 enhanced hypoxia-inducible factor α (HIF-1α) promoter activity to regulate glucose metabolism. The micro-positron emission tomography/computed tomography imaging of xenograft model showed that ECM1 substantially increased 18F-fluorodeoxyglucose uptake in xenograft tumors. Using in vivo mouse tail vein injection experiments, ECM1 was also found to increase in lung surface metastasis. These findings provide evidence that ECM1 regulates GC cell metastasis and glucose metabolism by inducing ITGB4/FAK/SOX2/HIF-1α signal pathway and have important implications for the development of therapeutic target to prevent tumor metastasis and recurrence.

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References

  1. Gomez-Contreras P, Ramiro-Diaz JM, Sierra A, Stipp C, Domann FE, Weigel RJ et al. Extracellular matrix 1 (ECM1) regulates the actin cytoskeletal architecture of aggressive breast cancer cells in part via S100A4 and Rho-family GTPases. Clin Exp Metastasis 2016.

  2. Mathieu E, Meheus L, Raymackers J, Merregaert J . Characterization of the osteogenic stromal cell line MN7: identification of secreted MN7 proteins using two-dimensional polyacrylamide gel electrophoresis, western blotting, and microsequencing. J Bone Miner Res 1994; 9: 903–913.

    Article  CAS  Google Scholar 

  3. Chen H, Jia W, Li J . ECM1 promotes migration and invasion of hepatocellular carcinoma by inducing epithelial-mesenchymal transition. World J Surg Oncol 2016; 14: 195.

    Article  Google Scholar 

  4. Fujimoto N, Terlizzi J, Aho S, Brittingham R, Fertala A, Oyama N et al. Extracellular matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein interactions. Exp Dermatol 2006; 15: 300–307.

    Article  CAS  Google Scholar 

  5. Han Z, Ni J, Smits P, Underhill CB, Xie B, Chen Y et al. Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells. FASEB J 2001; 15: 988–994.

    Article  CAS  Google Scholar 

  6. Lee KM, Nam K, Oh S, Lim J, Kim RK, Shim D et al. ECM1 regulates tumor metastasis and CSC-like property through stabilization of beta-catenin. Oncogene 2015; 34: 6055–6065.

    Article  CAS  Google Scholar 

  7. Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown AM, Iozzo RV . Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J Biol Chem 2003; 278: 17491–17499.

    Article  CAS  Google Scholar 

  8. Xiong GP, Zhang JX, Gu SP, Wu YB, Liu JF . Overexpression of ECM1 contributes to migration and invasion in cholangiocarcinoma cell. Neoplasma 2012; 59: 409–415.

    Article  CAS  Google Scholar 

  9. Ye H, Yu X, Xia J, Tang X, Tang L, Chen F . MiR-486-3p targeting ECM1 represses cell proliferation and metastasis in cervical cancer. Biomed Pharmacother 2016; 80: 109–114.

    Article  CAS  Google Scholar 

  10. Gao F, Xia Y, Wang J, Lin Z, Ou Y, Liu X et al. Integrated analyses of DNA methylation and hydroxymethylation reveal tumor suppressive roles of ECM1, ATF5, and EOMES in human hepatocellular carcinoma. Genome Biol 2014; 15: 533.

    Article  Google Scholar 

  11. Wang L, Yu J, Ni J, Xu XM, Wang J, Ning H et al. Extracellular matrix protein 1 (ECM1) is over-expressed in malignant epithelial tumors. Cancer Lett 2003; 200: 57–67.

    Article  CAS  Google Scholar 

  12. Chen H, Jia WD, Li JS, Wang W, Xu GL, Ma JL et al. Extracellular matrix protein 1, a novel prognostic factor, is associated with metastatic potential of hepatocellular carcinoma. Med Oncol 2011; 28 (Suppl 1): S318–S325.

    Article  Google Scholar 

  13. Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK et al. Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol 2010; 28: 4316–4323.

    Article  Google Scholar 

  14. Lal G, Hashimi S, Smith BJ, Lynch CF, Zhang L, Robinson RA et al. Extracellular matrix 1 (ECM1) expression is a novel prognostic marker for poor long-term survival in breast cancer: a Hospital-based Cohort Study in Iowa. Ann Surg Oncol 2009; 16: 2280–2287.

    Article  Google Scholar 

  15. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76–83.

    Article  CAS  Google Scholar 

  16. Roszkowski M, Spreat S . A comparison of the psychometric and clinical methods of determining level of mental retardation. Appl Res Ment Retard 1981; 2: 359–366.

    Article  CAS  Google Scholar 

  17. Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 2015; 525: 256–260.

    Article  CAS  Google Scholar 

  18. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015; 527: 525–530.

    Article  CAS  Google Scholar 

  19. Harper KL, Sosa MS, Entenberg D, Hosseini H, Cheung JF, Nobre R et al. Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature 2016; 540: 588–592.

    Article  CAS  Google Scholar 

  20. Huang PH, Lu PJ, Ding LY, Chu PC, Hsu WY, Chen CS et al. TGFbeta promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1. Oncogene 2017; 36: 2202–2214.

    Article  CAS  Google Scholar 

  21. Basan M, Hui S, Okano H, Zhang Z, Shen Y, Williamson JR et al. Overflow metabolism in Escherichia coli results from efficient proteome allocation. Nature 2015; 528: 99–104.

    Article  CAS  Google Scholar 

  22. Beger RD . A review of applications of metabolomics in cancer. Metabolites 2013; 3: 552–574.

    Article  CAS  Google Scholar 

  23. Semenza GL, Artemov D, Bedi A, Bhujwalla Z, Chiles K, Feldser D et al. 'The metabolism of tumours': 70 years later. Novartis Found Symp 2001; 240: 251–260 discussion 260–264.

    CAS  PubMed  Google Scholar 

  24. Ci Y, Qiao J, Han M . Molecular mechanisms and metabolomics of natural polyphenols interfering with breast cancer metastasis. Molecules 2016; 21: pii: E1634 doi:10.3390/molecules21121634.

    Article  Google Scholar 

  25. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  26. Cantor JR, Sabatini DM . Cancer cell metabolism: one hallmark, many faces. Cancer Discov 2012; 2: 881–898.

    Article  CAS  Google Scholar 

  27. Li B, Simon MC . Molecular pathways: targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer. Clin Cancer Res 2013; 19: 5835–5841.

    Article  CAS  Google Scholar 

  28. Semenza GL . Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 2009; 19: 12–16.

    Article  CAS  Google Scholar 

  29. Lee KM, Nam K, Oh S, Lim J, Lee T, Shin I . ECM1 promotes the Warburg effect through EGF-mediated activation of PKM2. Cell Signal 2015; 27: 228–235.

    Article  CAS  Google Scholar 

  30. Lee KM, Nam K, Oh S, Lim J, Kim YP, Lee JW et al. Extracellular matrix protein 1 regulates cell proliferation and trastuzumab resistance through activation of epidermal growth factor signaling. Breast Cancer Res 2014; 16: 479.

    Article  Google Scholar 

  31. Bergamaschi A, Tagliabue E, Sorlie T, Naume B, Triulzi T, Orlandi R et al. Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J Pathol 2008; 214: 357–367.

    Article  CAS  Google Scholar 

  32. Chamoto K, Gibney BC, Lee GS, Ackermann M, Konerding MA, Tsuda A et al. Migration of CD11b+ accessory cells during murine lung regeneration. Stem Cell Res 2013; 10: 267–277.

    Article  CAS  Google Scholar 

  33. Leask A . Integrin beta1: a mechanosignaling sensor essential for connective tissue deposition by fibroblasts. Adv Wound Care 2013; 2: 160–166.

    Article  Google Scholar 

  34. Bugaj LJ, Spelke DP, Mesuda CK, Varedi M, Kane RS, Schaffer DV . Regulation of endogenous transmembrane receptors through optogenetic Cry2 clustering. Nat Commun 2015; 6: 6898.

    Article  CAS  Google Scholar 

  35. Desrochers LM, Bordeleau F, Reinhart-King CA, Cerione RA, Antonyak MA . Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation. Nat Commun 2016; 7: 11958.

    Article  CAS  Google Scholar 

  36. Khurana S, Schouteden S, Manesia JK, Santamaria-Martinez A, Huelsken J, Lacy-Hulbert A et al. Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis. Nat Commun 2016; 7: 13500.

    Article  CAS  Google Scholar 

  37. Massari F, Ciccarese C, Santoni M, Iacovelli R, Mazzucchelli R, Piva F et al. Metabolic phenotype of bladder cancer. Cancer Treat Rev 2016; 45: 46–57.

    Article  CAS  Google Scholar 

  38. Lauwers GY CF, Graham DY, Curado MP Tumours of the stomach. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds). WHO Classification of Tumours of the Digestive System 2010, pp 48–59.

  39. Du X, Xu MD, Wang Y, Weng WW, Wei P, Qi P et al. A positive feedback loop of lncRNA-PVT1 and FOXM1 facilitates gastric cancer growth and invasion. Clin Cancer Res 2017; 23: 2071–2080.

    Article  Google Scholar 

  40. Qi P, Xu MD, Shen XH, Ni SJ, Huang D, Tan C et al. Reciprocal repression between TUSC7 and miR-23b in gastric cancer. Int J Cancer 2015; 137: 1269–1278.

    Article  CAS  Google Scholar 

  41. Wang Z, Liu Y, Lu L, Yang L, Yin S, Wang Y et al. Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis. Oncotarget 2015; 6: 6670–6683.

    PubMed  PubMed Central  Google Scholar 

  42. Zhang W, Tong D, Liu F, Li D, Li J, Cheng X et al. RPS7 inhibits colorectal cancer growth via decreasing HIF-1alpha-mediated glycolysis. Oncotarget 2016; 7: 5800–5814.

    PubMed  Google Scholar 

  43. Yang G, Chang B, Yang F, Guo X, Cai KQ, Xiao XS et al. Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2. Clin Cancer Res 2010; 16: 3171–3181.

    Article  CAS  Google Scholar 

  44. Duan J, Ba Q, Wang Z, Hao M, Li X, Hu P et al. Knockdown of ribosomal protein S7 causes developmental abnormalities via p53 dependent and independent pathways in zebrafish. Int J Biochem Cell Biol 2011; 43: 1218–1227.

    Article  CAS  Google Scholar 

  45. Wang Z, Hou J, Lu L, Qi Z, Sun J, Gao W et al. Small ribosomal protein subunit S7 suppresses ovarian tumorigenesis through regulation of the PI3K/AKT and MAPK pathways. PLoS One 2013; 8: e79117.

    Article  CAS  Google Scholar 

  46. Nie W, Xu MD, Gan L, Huang H, Xiu Q, Li B . Overexpression of stathmin 1 is a poor prognostic biomarker in non-small cell lung cancer. Lab Invest 2015; 95: 56–64.

    Article  CAS  Google Scholar 

  47. Ji S, Qin Y, Liang C, Huang R, Shi S, Liu J et al. FBW7 (F-box and WD repeat domain-containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin-binding protein) axis in pancreatic cancer. Clin Cancer Res 2016; 22: 3950–3960.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Nature Science Young Foundation of China (81502235, 81302096 and 81602078), Shanghai Natural Science Foundation (17ZR1406500), Hospital Foundation of Fudan University Shanghai Cancer Center (YJ201504) and by the project of Shanghai Municipal Health Bureau (20114009).

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Author notes

  1. L Gan, J Meng, M Xu, W Weng and W Sheng: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China

    L Gan, J Meng, M Liu, P Zhang & Z Wang

  2. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

    L Gan, J Meng, Y Qi & M Huang

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    L Gan, M Xu, Y Qi, C Tan, W Weng, W Sheng, M Huang & Z Wang

  4. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China

    L Gan

  5. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

    M Xu, C Tan, W Weng & W Sheng

  6. Nanchang Medical College, Nanchang University, Nanchang, China

    Y Wang

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Gan, L., Meng, J., Xu, M. et al. Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer. Oncogene 37, 744–755 (2018). https://doi.org/10.1038/onc.2017.363

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