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Overexpression of MUC1 Enhances Proangiogenic Activity of Non-Small-Cell Lung Cancer Cells Through Activation of Akt and Extracellular Signal-regulated Kinase Pathways

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Abstract

Background

Angiogenesis is an important process required for tumor progression. Mucin 1 (MUC1) is a transmembrane glycoprotein that is aberrantly upregulated in many types of cancer, including non-small-cell lung cancer (NSCLC). However, the biological significance of MUC1 overexpression in lung cancer angiogenesis is not completely understood.

Methods

We showed that enforced expression of MUC1 in two NSCLC cell lines, A549 and NCI-H460, which have a low level of endogenous MUC1, promoted their ability to induce vascular endothelial growth factor (VEGF)-dependent endothelial cell migration and tube formation.

Results

There was a significant increase in VEGF expression in MUC1-overexpressing NSCLC cells. Moreover, MUC1 overexpression resulted in a marked elevation in phosphorylated Akt and extracellular signal-regulated kinase (ERK)1/2, indicative of activation of both signaling pathways. Most importantly, inhibition of Akt or ERK signaling using specific chemical inhibitors restrained the proangiogenic activity of MUC1-overexpressing NSCLC cells.

Conclusions

Taken together, our present data demonstrate that the aberrant upregulation of MUC1 favors tumor angiogenesis in NSCLC, likely through the activation of both Akt and ERK pathways and elevation of VEGF production. MUC1 may thus be a potential antiangiogenic target in NSCLC.

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References

  1. Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomark Prev 19:1893–1907

    Article  Google Scholar 

  2. Yang P, Allen MS, Aubry MC, Wampfler JA, Marks RS, Edell ES, Thibodeau S, Adjei AA, Jett J, Deschamps C (2005) Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest 128:452–462

    Article  PubMed  Google Scholar 

  3. Bunn PA Jr (2002) Chemotherapy for advanced non-small-cell lung cancer: Who, what, when, why? J Clin Oncol 20:23S–33S

    PubMed  CAS  Google Scholar 

  4. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH, Eastern Cooperative Oncology Group (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98

    Article  PubMed  CAS  Google Scholar 

  5. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  PubMed  CAS  Google Scholar 

  6. Gendler SJ, Spicer AP (1995) Epithelial mucin genes. Annu Rev Physiol 57:607–634

    Article  PubMed  CAS  Google Scholar 

  7. Ligtenberg MJ, Kruijshaar L, Buijs F, van Meijer M, Litvinov SV, Hilkens J (1992) Cell-associated episialin is a complex containing two proteins derived from a common precursor. J Biol Chem 267:6171–6177

    PubMed  CAS  Google Scholar 

  8. Kufe DW (2009) Functional targeting of the MUC1 oncogene in human cancers. Cancer Biol Ther 8:1197–1203

    PubMed  CAS  Google Scholar 

  9. Jonckheere N, Van Seuningen I (2010) The membrane-bound mucins: from cell signalling to transcriptional regulation and expression in epithelial cancers. Biochimie 92:1–11

    Article  PubMed  CAS  Google Scholar 

  10. Kim YS, Gum, Brockhausen I (1996) Mucin glycoproteins in neoplasia. Glycoconj J 13:693–707

    Article  PubMed  CAS  Google Scholar 

  11. Aloysius MM, Zaitoun AM, Awad S, Ilyas M, Rowlands BJ, Lobo DN (2010) Mucins and CD56 as markers of tumour invasion and prognosis in periampullary cancer. Br J Surg 97:1269–1278

    Article  PubMed  CAS  Google Scholar 

  12. Aubert S, Fauquette V, Hémon B, Lepoivre R, Briez N, Bernard D, Van Seuningen I, Leroy X, Perrais M (2009) MUC1, a new hypoxia inducible factor target gene, is an actor in clear renal cell carcinoma tumor progression. Cancer Res 69:5707–5715

    Article  PubMed  CAS  Google Scholar 

  13. Creaney J, Segal A, Sterrett G, Platten MA, Baker E, Murch AR, Nowak AK, Robinson BW, Millward MJ (2008) Overexpression and altered glycosylation of MUC1 in malignant mesothelioma. Br J Cancer 98:1562–1569

    Article  PubMed  CAS  Google Scholar 

  14. Retterspitz MF, Mönig SP, Schreckenberg S, Schneider PM, Hölscher AH, Dienes HP, Baldus SE (2010) Expression of {beta}-catenin, MUC1 and c-met in diffuse-type gastric carcinomas: correlations with tumour progression and prognosis. Anticancer Res 30:4635–4641

    PubMed  Google Scholar 

  15. Situ D, Wang J, Ma Y, Zhu Z, Hu Y, Long H, Rong T (2010) Expression and prognostic relevance of MUC1 in stage IB non-small cell lung cancer. Med Oncol. doi: 10.1007/s12032-010-9752-4

  16. Gao J, McConnell MJ, Yu B, Li J, Balko JM, Black EP, Johnson JO, Lloyd MC, Altiok S, Haura EB (2009) MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion. Int J Oncol 35:337–345

    PubMed  CAS  Google Scholar 

  17. Di Domenico M, Ricciardi C, Fusco A, Pierantoni GM (2011) Anti-VEGF therapy in breast and lung mouse models of cancers. J Biomed Biotechnol 2011:947928

    PubMed  Google Scholar 

  18. Giatromanolaki A, Koukourakis MI, Sivridis E, O’Byrne K, Cox G, Thorpe PE, Gatter KC, Harris AL (2000) Coexpression of MUC1 glycoprotein with multiple angiogenic factors in non-small cell lung cancer suggests coactivation of angiogenic and migration pathways. Clin Cancer Res 6:1917–1921

    PubMed  CAS  Google Scholar 

  19. Li X, Wang L, Nunes DP, Troxler RF, Offner GD (2003) Pro-inflammatory cytokines up-regulate MUC1 gene expression in oral epithelial cells. J Dent Res 82:883–887

    Article  PubMed  CAS  Google Scholar 

  20. Su H, Joho S, Huang Y, Barcena A, Arakawa-Hoyt J, Grossman W, Kan YW (2004) Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts. Proc Natl Acad Sci USA 101:16280–16285

    Article  PubMed  CAS  Google Scholar 

  21. Shao ES, Lin L, Yao Y, Boström KI (2009) Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood 114:2197–2206

    Article  PubMed  CAS  Google Scholar 

  22. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    Article  PubMed  CAS  Google Scholar 

  23. Cook KM, Figg WD (2010) Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 60:222–243

    Article  PubMed  Google Scholar 

  24. Arsham AM, Plas DR, Thompson CB, Simon MC (2004) Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Res 64:3500–3507

    Article  PubMed  CAS  Google Scholar 

  25. Zhang Y, Jiang X, Qin X, Ye D, Yi Z, Liu M, Bai O, Liu W, Xie X, Wang Z, Fang J, Chen Y (2010) RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma. Oncogene 29:5404–5415

    Article  PubMed  CAS  Google Scholar 

  26. Khodarev N, Ahmad R, Rajabi H, Pitroda S, Kufe T, McClary C, Joshi MD, MacDermed D, Weichselbaum R, Kufe D (2010) Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer. Oncogene 29:920–929

    Article  PubMed  CAS  Google Scholar 

  27. Woenckhaus M, Merk J, Stoehr R, Schaeper F, Gaumann A, Wiebe K, Hartmann A, Hofstaedter F, Dietmaier W (2008) Prognostic value of FHIT, CTNNB1, and MUC1 expression in non-small cell lung cancer. Hum Pathol 39:126–136

    Article  PubMed  CAS  Google Scholar 

  28. Kaira K, Murakami H, Serizawa M, Koh Y, Abe M, Ohde Y, Takahashi T, Kondo H, Nakajima T, Yamamoto N (2011) MUC1 expression in thymic epithelial tumors: MUC1 may be useful marker as differential diagnosis between type B3 thymoma and thymic carcinoma. Virchows Arch 458(5):615–620

    Article  PubMed  CAS  Google Scholar 

  29. Guddo F, Giatromanolaki A, Patriarca C, Hilkens J, Reina C, Alfano RM, Vignola AM, Koukourakis MI, Gambacorta M, Pruneri G, Coggi G, Bonsignore G (1998) Depolarized expression of episialin (EMA, MUC1) in lung adenocarcinoma is associated with tumor progression. Anticancer Res 18:1915–1920

    PubMed  CAS  Google Scholar 

  30. Ohgami A, Tsuda T, Osaki T, Mitsudomi T, Morimoto Y, Higashi T, Yasumoto K (1999) MUC1 mucin mRNA expression in stage I lung adenocarcinoma and its association with early recurrence. Ann Thorac Surg 67:810–814

    Article  PubMed  CAS  Google Scholar 

  31. Ren J, Agata N, Chen D, Li Y, Yu WH, Huang L, Raina D, Chen W, Kharbanda S, Kufe D (2004) Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents. Cancer Cell 5:163–175

    Article  PubMed  CAS  Google Scholar 

  32. Papadopoulos I, Sivridis E, Giatromanolaki A, Koukourakis MI (2001) Tumor angiogenesis is associated with MUC1 overexpression and loss of prostate-specific antigen expression in prostate cancer. Clin Cancer Res 7:1533–1538

    PubMed  CAS  Google Scholar 

  33. Khodarev NN, Pitroda SP, Beckett MA, MacDermed DM, Huang L, Kufe DW, Weichselbaum RR (2009) MUC1-induced transcriptional programs associated with tumorigenesis predict outcome in breast and lung cancer. Cancer Res 69:2833–2837

    Article  PubMed  CAS  Google Scholar 

  34. Kawano T, Ahmad R, Nogi H, Agata N, Anderson K, Kufe D (2008) MUC1 oncoprotein promotes growth and survival of human multiple myeloma cells. Int J Oncol 33:153–159

    PubMed  CAS  Google Scholar 

  35. Udhayakumar G, Jayanthi V, Devaraj N, Devaraj H (2007) Interaction of MUC1 with beta-catenin modulates the Wnt target gene cyclinD1 in H. pylori-induced gastric cancer. Mol Carcinog 46:807–817

    Article  PubMed  CAS  Google Scholar 

  36. Raina D, Kosugi M, Ahmad R, Panchamoorthy G, Rajabi H, Alam M, Shimamura T, Shapiro GI, Supko JG, Kharbanda S, Kufe DW (2011) Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther 10(5):806–816

    Article  PubMed  CAS  Google Scholar 

  37. Wang H, Lillehoj EP, Kim KC (2004) MUC1 tyrosine phosphorylation activates the extracellular signal-regulated kinase. Biochem Biophys Res Commun 321:448–454

    Article  PubMed  CAS  Google Scholar 

  38. Dai R, Chen R, Li H (2009) Cross-talk between PI3K/Akt and MEK/ERK pathways mediates endoplasmic reticulum stress-induced cell cycle progression and cell death in human hepatocellular carcinoma cells. Int J Oncol 34:1749–1757

    PubMed  CAS  Google Scholar 

  39. Gervais M, Dugourd C, Muller L, Ardidie C, Canton B, Loviconi L, Corvol P, Chneiweiss H, Monnot C (2006) Akt down-regulates ERK1/2 nuclear localization and angiotensin II-induced cell proliferation through PEA-15. Mol Biol Cell 17:3940–3951

    Article  PubMed  CAS  Google Scholar 

  40. Wang CC, Cirit M, Haugh JM (2009) PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk. Mol Syst Biol 5:246

    Article  PubMed  Google Scholar 

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Acknowledgment

This study was supported by Key Medical Research and Technology Program of Educational Commission of Henan of China (No. 2009A320041).

Conflict of interest

All authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Department of Severe Respiratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Mengying Yao, Qingxian Zhang, Lihua Xing, Aiguo Xu & Qiuhong Liu

  2. Department of Anatomy, Nursing College of Zhengzhou University, Zhengzhou, China

    Weihong Zhang

  3. Center of Kidney Diseases, First Affiliated Hospital, Henan College of Traditional Chinese Medicine, Zhengzhou, China

    Bing Cui

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  1. Mengying Yao
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  2. Weihong Zhang
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  3. Qingxian Zhang
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  6. Qiuhong Liu
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Correspondence to Bing Cui.

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Yao, M., Zhang, W., Zhang, Q. et al. Overexpression of MUC1 Enhances Proangiogenic Activity of Non-Small-Cell Lung Cancer Cells Through Activation of Akt and Extracellular Signal-regulated Kinase Pathways. Lung 189, 453–460 (2011). https://doi.org/10.1007/s00408-011-9327-y

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  • DOI: https://doi.org/10.1007/s00408-011-9327-y

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