Advertisement

Mucin glycoproteins block apoptosis; promote invasion, proliferation, and migration; and cause chemoresistance through diverse pathways in epithelial cancers

  • Ian S. Reynolds
  • Michael Fichtner
  • Deborah A. McNamara
  • Elaine W. Kay
  • Jochen H.M. Prehn
  • John P. BurkeEmail author
NON-THEMATIC REVIEW
  • 134 Downloads

Abstract

Overexpression of mucin glycoproteins has been demonstrated in many epithelial-derived cancers. The significance of this overexpression remains uncertain. The aim of this paper was to define the association of mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers by performing a systematic review of all published data. A systematic review of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify all papers that evaluated the association between mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers. PRISMA guidelines were adhered to. Results of individual studies were extracted and pooled together based on the organ in which the cancer was derived from. The initial search revealed 2031 papers, of which 90 were deemed eligible for inclusion in the study. The studies included details on MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16. The majority of studies evaluated MUC1. MUC1 overexpression was consistently associated with resistance to apoptosis and resistance to chemotherapy. There was also evidence that overexpression of MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16 conferred resistance to apoptosis in epithelial-derived cancers. The overexpression of mucin glycoproteins is associated with resistance to apoptosis in numerous epithelial cancers. They cause resistance through diverse signaling pathways. Targeting the expression of mucin glycoproteins represents a potential therapeutic target in the treatment of epithelial-derived cancers.

Keywords

Mucin glycoproteins Epithelial cancer Chemoresistance Apoptosis 

Notes

Author contributions

Study concept and design—JPB; scientific guidance—EWK and JHMP; data collection—ISR; manuscript preparation—ISR and DAM; manuscript review—all authors.

Funding information

Funding for this project was received from the Beaumont Hospital Colorectal Research Trust.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Krysko, O., Aaes, T. L., Kagan, V. E., D’Herde, K., Bachert, C., Leybaert, L., et al. (2017). Necroptotic cell death in anti-cancer therapy. Immunological Reviews, 280(1), 207–219.CrossRefPubMedGoogle Scholar
  2. 2.
    Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.CrossRefPubMedGoogle Scholar
  3. 3.
    Laubenbacher, R., Hower, V., Jarrah, A., Torti, S. V., Shulaev, V., Mendes, P., et al. (2009). A systems biology view of cancer. Biochimica et Biophysica Acta, 1796(2), 129–139.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Eum, K. H., & Lee, M. (2011). Crosstalk between autophagy and apoptosis in the regulation of paclitaxel-induced cell death in v-Ha-ras-transformed fibroblasts. Molecular and Cellular Biochemistry, 348(1–2), 61–68.CrossRefPubMedGoogle Scholar
  5. 5.
    Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. British Journal of Cancer, 26(4), 239–257.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ghobrial, I. M., Witzig, T. E., & Adjei, A. A. (2005). Targeting apoptosis pathways in cancer therapy. CA: a Cancer Journal for Clinicians, 55(3), 178–194.Google Scholar
  7. 7.
    Joshi, S., Kumar, S., Choudhury, A., Ponnusamy, M. P., & Batra, S. K. (2014). Altered mucins (MUC) trafficking in benign and malignant conditions. Oncotarget, 5(17), 7272–7284.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Jonckheere, N., Skrypek, N., Frenois, F., & Van Seuningen, I. (2013). Membrane-bound mucin modular domains: from structure to function. Biochimie, 95(6), 1077–1086.CrossRefPubMedGoogle Scholar
  9. 9.
    Albrecht, H., & Carraway, K. L., 3rd. (2011). MUC1 and MUC4: switching the emphasis from large to small. Cancer Biotherapy & Radiopharmaceuticals., 26(3), 261–271.CrossRefGoogle Scholar
  10. 10.
    Kufe, D. W. (2009). Mucins in cancer: function, prognosis and therapy. Nature Reviews. Cancer, 9(12), 874–885.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Senapati, S., Das, S., & Batra, S. K. (2010). Mucin-interacting proteins: from function to therapeutics. Trends in Biochemical Sciences., 35(4), 236–245.CrossRefPubMedGoogle Scholar
  12. 12.
    Rachagani, S., Torres, M. P., Moniaux, N., & Batra, S. K. (2009). Current status of mucins in the diagnosis and therapy of cancer. BioFactors (Oxford, England)., 35(6), 509–527.CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Kaur, S., Kumar, S., Momi, N., Sasson, A. R., & Batra, S. K. (2013). Mucins in pancreatic cancer and its microenvironment. Nature Reviews Gastroenterology & Hepatology., 10(10), 607–620.CrossRefGoogle Scholar
  14. 14.
    Chaturvedi, P., Singh, A. P., & Batra, S. K. (2008). Structure, evolution, and biology of the MUC4 mucin. FASEB Journal: official publication of the Federation of American Societies for Experimental Biology., 22(4), 966–981.CrossRefGoogle Scholar
  15. 15.
    Tarang, S., Kumar, S., & Batra, S. K. (2012). Mucins and toll-like receptors: kith and kin in infection and cancer. Cancer Letters., 321(2), 110–119.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    van der Sluis, M., Melis, M. H., Jonckheere, N., Ducourouble, M. P., Buller, H. A., Renes, I., et al. (2004). The murine Muc2 mucin gene is transcriptionally regulated by the zinc-finger GATA-4 transcription factor in intestinal cells. Biochemical and Biophysical Research Communications., 325(3), 952–960.CrossRefPubMedGoogle Scholar
  17. 17.
    Niv, Y. (2016). Mucin gene expression in the intestine of ulcerative colitis patients: a systematic review and meta-analysis. European Journal of Gastroenterology & Hepatology, 28(11), 1241–1245.CrossRefGoogle Scholar
  18. 18.
    Jonckheere, N., Skrypek, N., & Van Seuningen, I. (2014). Mucins and tumor resistance to chemotherapeutic drugs. Biochimica et Biophysica Acta, 1846(1), 142–151.PubMedGoogle Scholar
  19. 19.
    Moniaux, N., Andrianifahanana, M., Brand, R. E., & Batra, S. K. (2004). Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy. British Journal of Cancer., 91(9), 1633–1638.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Jonckheere, N., & Van Seuningen, I. (2010). The membrane-bound mucins: from cell signalling to transcriptional regulation and expression in epithelial cancers. Biochimie, 92(1), 1–11.CrossRefPubMedGoogle Scholar
  21. 21.
    Mukhopadhyay, P., Chakraborty, S., Ponnusamy, M. P., Lakshmanan, I., Jain, M., & Batra, S. K. (2011). Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy. Biochimica et Biophysica Acta, 1815(2), 224–240.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Lakshmanan, I., Ponnusamy, M. P., Macha, M. A., Haridas, D., Majhi, P. D., Kaur, S., et al. (2015). Mucins in lung cancer: diagnostic, prognostic, and therapeutic implications. Journal of Thoracic Oncology: official publication of the International Association for the Study of Lung Cancer., 10(1), 19–27.CrossRefGoogle Scholar
  23. 23.
    Krishn, S. R., Kaur, S., Smith, L. M., Johansson, S. L., Jain, M., Patel, A., et al. (2016). Mucins and associated glycan signatures in colon adenoma-carcinoma sequence: prospective pathological implication(s) for early diagnosis of colon cancer. Cancer letters., 374(2), 304–314.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pai, P., Rachagani, S., Dhawan, P., & Batra, S. K. (2016). Mucins and Wnt/beta-catenin signaling in gastrointestinal cancers: an unholy nexus. Carcinogenesis, 37(3), 223–232.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kumar, S., Das, S., Rachagani, S., Kaur, S., Joshi, S., Johansson, S. L., et al. (2015). NCOA3-mediated upregulation of mucin expression via transcriptional and post-translational changes during the development of pancreatic cancer. Oncogene, 34(37), 4879–4889.CrossRefPubMedGoogle Scholar
  26. 26.
    Perrais, M., Rousseaux, C., Ducourouble, M. P., Courcol, R., Vincent, P., Jonckheere, N., et al. (2014). Helicobacter pylori urease and flagellin alter mucin gene expression in human gastric cancer cells. Gastric Cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association., 17(2), 235–246.CrossRefGoogle Scholar
  27. 27.
    Shibahara, H., Higashi, M., Yokoyama, S., Rousseau, K., Kitazono, I., Osako, M., et al. (2014). A comprehensive expression analysis of mucins in appendiceal carcinoma in a multicenter study: MUC3 is a novel prognostic factor. PLoS One, 9(12), e115613.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jonckheere, N., & Van Seuningen, I. (2008). The membrane-bound mucins: how large O-glycoproteins play key roles in epithelial cancers and hold promise as biological tools for gene-based and immunotherapies. Critical Reviews in Oncogenesis., 14(2–3), 177–196.CrossRefPubMedGoogle Scholar
  29. 29.
    Andrianifahanana, M., Moniaux, N., Schmied, B. M., Ringel, J., Friess, H., Hollingsworth, M. A., et al. (2001). Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. Clinical Cancer Research : an official journal of the American Association for Cancer Research, 7(12), 4033–4040.Google Scholar
  30. 30.
    Mukhopadhyay, P., Lakshmanan, I., Ponnusamy, M. P., Chakraborty, S., Jain, M., Pai, P., et al. (2013). MUC4 overexpression augments cell migration and metastasis through EGFR family proteins in triple negative breast cancer cells. PLoS One, 8(2), e54455.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Senapati, S., Chaturvedi, P., Sharma, P., Venkatraman, G., Meza, J. L., El-Rifai, W., et al. (2008). Deregulation of MUC4 in gastric adenocarcinoma: potential pathobiological implication in poorly differentiated non-signet ring cell type gastric cancer. British Journal of Cancer, 99(6), 949–956.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Singh, A. P., Chauhan, S. C., Bafna, S., Johansson, S. L., Smith, L. M., Moniaux, N., et al. (2006). Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas. The Prostate, 66(4), 421–429.CrossRefPubMedGoogle Scholar
  33. 33.
    Kaur, S., Momi, N., Chakraborty, S., Wagner, D. G., Horn, A. J., Lele, S. M., et al. (2014). Altered expression of transmembrane mucins, MUC1 and MUC4, in bladder cancer: pathological implications in diagnosis. PLoS One, 9(3), e92742.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Moher, D., Shamseer, L., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., et al. (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews, 4, 1.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Dilly, A. K., Honick, B. D., Lee, Y. J., Guo, Z. S., Zeh, H. J., Bartlett, D. L., et al. (2017). Targeting G-protein coupled receptor-related signaling pathway in a murine xenograft model of appendiceal pseudomyxoma peritonei. Oncotarget, 8(63), 106888–106900.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Garcia, E. P., Tiscornia, I., Libisch, G., Trajtenberg, F., Bollati-Fogolin, M., Rodriguez, E., et al. (2016). MUC5B silencing reduces chemo-resistance of MCF-7 breast tumor cells and impairs maturation of dendritic cells. International Journal of Oncology, 48(5), 2113–2123.CrossRefPubMedGoogle Scholar
  37. 37.
    Lakshmanan, I., Ponnusamy, M. P., Das, S., Chakraborty, S., Haridas, D., Mukhopadhyay, P., et al. (2012). MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells. Oncogene, 31(7), 805–817.CrossRefPubMedGoogle Scholar
  38. 38.
    Workman, H. C., Sweeney, C., & Carraway, K. L., 3rd. (2009). The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. Cancer Research, 69(7), 2845–2852.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hattrup, C. L., & Gendler, S. J. (2006). MUC1 alters oncogenic events and transcription in human breast cancer cells. Breast Cancer Research, 8(4), R37.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Schroeder, J. A., Masri, A. A., Adriance, M. C., Tessier, J. C., Kotlarczyk, K. L., Thompson, M. C., et al. (2004). MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene, 23(34), 5739–5747.CrossRefPubMedGoogle Scholar
  41. 41.
    Li, Y., Pang, Z., Dong, X., Liao, X., Deng, H., Liao, C., et al. (2018). MUC1 induces M2 type macrophage influx during postpartum mammary gland involution and triggers breast cancer. Oncotarget, 9(3), 3446–3458.PubMedGoogle Scholar
  42. 42.
    Jin, W., Liao, X., Lv, Y., Pang, Z., Wang, Y., Li, Q., et al. (2017). MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner. Cell Death & Disease, 8(8), e2980.CrossRefGoogle Scholar
  43. 43.
    Zhu, X., Long, X., Luo, X., Song, Z., Li, S., & Wang, H. (2016). Abrogation of MUC5AC expression contributes to the apoptosis and cell cycle arrest of colon cancer cells. Cancer Biotherapy & Radiopharmaceuticals, 31(7), 261–267.CrossRefGoogle Scholar
  44. 44.
    Sheng, Y. H., He, Y., Hasnain, S. Z., Wang, R., Tong, H., Clarke, D. T., et al. (2017). MUC13 protects colorectal cancer cells from death by activating the NF-kappaB pathway and is a potential therapeutic target. Oncogene, 36(5), 700–713.CrossRefPubMedGoogle Scholar
  45. 45.
    Chen, Q., Li, D., Ren, J., Li, C., & Xiao, Z. X. (2013). MUC1 activates JNK1 and inhibits apoptosis under genotoxic stress. Biochemical and Biophysical Research Communications, 440(1), 179–183.CrossRefPubMedGoogle Scholar
  46. 46.
    Ren, J., Agata, N., Chen, D., Li, Y., Yu, W. H., Huang, L., et al. (2004). Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents. Cancer Cell, 5(2), 163–175.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Costa, N. R., Paulo, P., Caffrey, T., Hollingsworth, M. A., & Santos-Silva, F. (2011). Impact of MUC1 mucin downregulation in the phenotypic characteristics of MKN45 gastric carcinoma cell line. PLoS One, 6(11), e26970.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Yi, F. T., & Lu, Q. P. (2017). Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2/STAT3 signaling. Oncology Letters, 14(6), 7571–7576.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Yuan, H., Wang, J., Wang, F., Zhang, N., Li, Q., Xie, F., et al. (2015). Mucin 1 gene silencing inhibits the growth of SMMC-7721 human hepatoma cells through Bax-mediated mitochondrial and caspase-8-mediated death receptor apoptotic pathways. Molecular Medicine Reports, 12(5), 6782–6788.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Li, Q., Wang, F., Liu, G., Yuan, H., Chen, T., Wang, J., et al. (2014). Impact of Mucin1 knockdown on the phenotypic characteristics of the human hepatocellular carcinoma cell line SMMC-7721. Oncology Reports, 31(6), 2811–2819.CrossRefPubMedGoogle Scholar
  51. 51.
    Xu, T., Li, D., Wang, H., Zheng, T., Wang, G., & Xin, Y. (2017). MUC1 downregulation inhibits non-small cell lung cancer progression in human cell lines. Experimental and Therapeutic Medicine, 14(5), 4443–4447.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Xu, X., Wells, A., Padilla, M. T., Kato, K., Kim, K. C., & Lin, Y. (2014). A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance. Carcinogenesis, 35(11), 2457–2466.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Gao, J., McConnell, M. J., Yu, B., Li, J., Balko, J. M., Black, E. P., et al. (2009). MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion. International Journal of Oncology, 35(2), 337–345.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Grover, P., Nath, S., Nye, M. D., Zhou, R., Ahmad, M., & Mukherjee, P. (2018). SMAD4-independent activation of TGF-beta signaling by MUC1 in a human pancreatic cancer cell line. Oncotarget, 9(6), 6897–6910.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Zhao, P., Meng, M., Xu, B., Dong, A., Ni, G., & Lu, L. (2017). Decreased expression of MUC1 induces apoptosis and inhibits migration in pancreatic cancer PANC-1 cells via regulation of Slug pathway. Cancer Biomarkers, 20(4), 469–476.CrossRefPubMedGoogle Scholar
  56. 56.
    Trehoux, S., Duchene, B., Jonckheere, N., & Van Seuningen, I. (2015). The MUC1 oncomucin regulates pancreatic cancer cell biological properties and chemoresistance. Implication of p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways. Biochemical and Biophysical Research Communications, 456(3), 757–762.CrossRefPubMedGoogle Scholar
  57. 57.
    Jonckheere, N., Skrypek, N., Merlin, J., Dessein, A. F., Dumont, P., Leteurtre, E., et al. (2012). The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways. PLoS One, 7(2), e32232.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Bafna, S., Kaur, S., Momi, N., & Batra, S. K. (2009). Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin. British Journal of Cancer, 101(7), 1155–1161.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Chaturvedi, P., Singh, A. P., Moniaux, N., Senapati, S., Chakraborty, S., Meza, J. L., et al. (2007). MUC4 mucin potentiates pancreatic tumor cell proliferation, survival, and invasive properties and interferes with its interaction to extracellular matrix proteins. Molecular Cancer Research: MCR, 5(4), 309–320.CrossRefPubMedGoogle Scholar
  60. 60.
    Hoshi, H., Sawada, T., Uchida, M., Iijima, H., Kimura, K., Hirakawa, K., et al. (2013). MUC5AC protects pancreatic cancer cells from TRAIL-induced death pathways. International Journal of Oncology, 42(3), 887–893.CrossRefPubMedGoogle Scholar
  61. 61.
    Sheng, Y., Ng, C. P., Lourie, R., Shah, E. T., He, Y., Wong, K. Y., et al. (2017). MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance. International Journal of Cancer, 140(10), 2351–2363.CrossRefPubMedGoogle Scholar
  62. 62.
    Zhao, Q., Piyush, T., Chen, C., Hollingsworth, M. A., Hilkens, J., Rhodes, J. M., et al. (2014). MUC1 extracellular domain confers resistance of epithelial cancer cells to anoikis. Cell Death & Disease, e1438, 5.Google Scholar
  63. 63.
    Yin, L., Li, Y., Ren, J., Kuwahara, H., & Kufe, D. (2003). Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress. The Journal of Biological Chemistry, 278(37), 35458–35464.CrossRefPubMedGoogle Scholar
  64. 64.
    Raina, D., Ahmad, R., Kumar, S., Ren, J., Yoshida, K., Kharbanda, S., et al. (2006). MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. The EMBO Journal, 25(16), 3774–3783.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Rowson-Hodel, A. R., Wald, J. H., Hatakeyama, J., O’Neal, W. K., Stonebraker, J. R., VanderVorst, K., et al. (2018). Membrane mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. Oncogene, 37(2), 197–207.CrossRefPubMedGoogle Scholar
  66. 66.
    Astashchanka, A., Shroka, T. M., & Jacobsen, B. M. (2018). Mucin 2 (MUC2) modulates the aggressiveness of breast cancer. Breast Cancer Research and Treatment.Google Scholar
  67. 67.
    Reinartz, S., Failer, S., Schuell, T., & Wagner, U. (2012). CA125 (MUC16) gene silencing suppresses growth properties of ovarian and breast cancer cells. European Journal of Cancer (Oxford, England: 1990), 48(10), 1558–1569.CrossRefGoogle Scholar
  68. 68.
    Liu, Q., Cheng, Z., Luo, L., Yang, Y., Zhang, Z., Ma, H., et al. (2016). C-terminus of MUC16 activates Wnt signaling pathway through its interaction with beta-catenin to promote tumorigenesis and metastasis. Oncotarget, 7(24), 36800–36813.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Valque, H., Gouyer, V., Gottrand, F., & Desseyn, J. L. (2012). MUC5B leads to aggressive behavior of breast cancer MCF7 cells. PLoS One, 7(10), e46699.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Fessler, S. P., Wotkowicz, M. T., Mahanta, S. K., & Bamdad, C. (2009). MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. Breast Cancer Research and Treatment, 118(1), 113–124.CrossRefPubMedGoogle Scholar
  71. 71.
    Chen, A. C., Migliaccio, I., Rimawi, M., Lopez-Tarruella, S., Creighton, C. J., Massarweh, S., et al. (2012). Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies. Breast Cancer Research and Treatment, 134(2), 583–593.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Maeda, T., Hiraki, M., Jin, C., Rajabi, H., Tagde, A., Alam, M., et al. (2018). MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. Cancer Research., 78(1), 205–215.CrossRefPubMedGoogle Scholar
  73. 73.
    Alam, M., Rajabi, H., Ahmad, R., Jin, C., & Kufe, D. (2014). Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells. Oncotarget, 5(9), 2622–2634.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Kharbanda, A., Rajabi, H., Jin, C., Raina, D., & Kufe, D. (2013). Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer. Molecular Cancer Research: MCR, 11(7), 714–723.CrossRefPubMedGoogle Scholar
  75. 75.
    Raina, D., Uchida, Y., Kharbanda, A., Rajabi, H., Panchamoorthy, G., Jin, C., et al. (2014). Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene, 33(26), 3422–3431.CrossRefPubMedGoogle Scholar
  76. 76.
    Uchida, Y., Raina, D., Kharbanda, S., & Kufe, D. (2013). Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells. Cancer Biology & Therapy, 14(2), 127–134.CrossRefGoogle Scholar
  77. 77.
    Das, S., Rachagani, S., Sheinin, Y., Smith, L. M., Gurumurthy, C. B., Roy, H. K., et al. (2016). Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer. Oncogene, 35(20), 2645–2654.CrossRefPubMedGoogle Scholar
  78. 78.
    Gupta, B. K., Maher, D. M., Ebeling, M. C., Stephenson, P. D., Puumala, S. E., Koch, M. R., et al. (2014). Functions and regulation of MUC13 mucin in colon cancer cells. Journal of Gastroenterology, 49(10), 1378–1391.CrossRefPubMedGoogle Scholar
  79. 79.
    Bruyere, E., Jonckheere, N., Frenois, F., Mariette, C., & Van Seuningen, I. (2011). The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein. Biochemical and Biophysical Research Communications, 413(2), 325–329.CrossRefPubMedGoogle Scholar
  80. 80.
    Gronnier, C., Bruyere, E., Lahdaoui, F., Jonckheere, N., Perrais, M., Leteurtre, E., et al. (2014). The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells. Biochimica et Biophysica Acta, 1843(11), 2432–2437.CrossRefPubMedGoogle Scholar
  81. 81.
    Lahdaoui, F., Messager, M., Vincent, A., Hec, F., Gandon, A., Warlaumont, M., et al. (2017). Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/beta-catenin pathway. The Biochemical Journal, 474(22), 3733–3746.CrossRefPubMedGoogle Scholar
  82. 82.
    Deng, M., Jing, D. D., & Meng, X. J. (2013). Effect of MUC1 siRNA on drug resistance of gastric cancer cells to trastuzumab. Asian Pacific Journal of Cancer Prevention: APJCP, 14(1), 127–131.CrossRefPubMedGoogle Scholar
  83. 83.
    Shi, M., Yang, Z., Hu, M., Liu, D., Hu, Y., Qian, L., et al. (2013). Catecholamine-induced beta2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression. Journal of Immunology (Baltimore, Md: 1950), 190(11), 5600–5608.CrossRefGoogle Scholar
  84. 84.
    Macha, M. A., Rachagani, S., Pai, P., Gupta, S., Lydiatt, W. M., Smith, R. B., et al. (2015). MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene, 34(13), 1698–1708.CrossRefPubMedGoogle Scholar
  85. 85.
    Lakshmanan, I., Salfity, S., Seshacharyulu, P., Rachagani, S., Thomas, A., Das, S., et al. (2017). MUC16 regulates TSPYL5 for lung cancer cell growth and chemoresistance by suppressing p53. Clinical Cancer Research, 23(14), 3906–3917.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Lakshmanan, I., Rachagani, S., Hauke, R., Krishn, S. R., Paknikar, S., Seshacharyulu, P., et al. (2016). MUC5AC interactions with integrin beta4 enhances the migration of lung cancer cells through FAK signaling. Oncogene, 35(31), 4112–4121.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Majhi, P. D., Lakshmanan, I., Ponnusamy, M. P., Jain, M., Das, S., Kaur, S., et al. (2013). Pathobiological implications of MUC4 in non-small-cell lung cancer. Journal of Thoracic Oncology: official publication of the International Association for the Study of Lung Cancer, 8(4), 398–407.CrossRefGoogle Scholar
  88. 88.
    Kanwal, M., Ding, X. J., Song, X., Zhou, G. B., & Cao, Y. (2018). MUC16 overexpression induced by gene mutations promotes lung cancer cell growth and invasion. Oncotarget, 9(15), 12226–12239.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Raina, D., Kosugi, M., Ahmad, R., Panchamoorthy, G., Rajabi, H., Alam, M., et al. (2011). Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Molecular Cancer Therapeutics, 10(5), 806–816.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Bouillez, A., Gnemmi, V., Gaudelot, K., Hemon, B., Ringot, B., Pottier, N., et al. (2014). MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway. Oncotarget, 5(3), 754–763.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Aubert, S., Fauquette, V., Hemon, B., Lepoivre, R., Briez, N., Bernard, D., et al. (2009). MUC1, a new hypoxia inducible factor target gene, is an actor in clear renal cell carcinoma tumor progression. Cancer Research, 69(14), 5707–5715.CrossRefPubMedGoogle Scholar
  92. 92.
    Alam, M., Ahmad, R., Rajabi, H., Kharbanda, A., & Kufe, D. (2013). MUC1-C oncoprotein activates ERK-->C/EBPbeta signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer cells. The Journal of Biological Chemistry, 288(43), 30892–30903.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Mimeault, M., Johansson, S. L., Senapati, S., Momi, N., Chakraborty, S., & Batra, S. K. (2010). MUC4 down-regulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies. Cancer Letters, 295(1), 69–84.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Huang, W. C., Chan, M. L., Chen, M. J., Tsai, T. H., & Chen, Y. J. (2016). Modulation of macrophage polarization and lung cancer cell stemness by MUC1 and development of a related small-molecule inhibitor pterostilbene. Oncotarget, 7(26), 39363–39375.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Wang, R., Yang, L., Li, S., Ye, D., Yang, L., Liu, Q., et al. (2018). Quercetin inhibits breast cancer stem cells via downregulation of aldehyde dehydrogenase 1A1 (ALDH1A1), chemokine receptor type 4 (CXCR4), mucin 1 (MUC1), and epithelial cell adhesion molecule (EpCAM). Medical Science Monitor: international medical journal of experimental and clinical research, 24, 412–420.CrossRefGoogle Scholar
  96. 96.
    Hiraki, M., Maeda, T., Bouillez, A., Alam, M., Tagde, A., Hinohara, K., et al. (2017). MUC1-C activates BMI1 in human cancer cells. Oncogene, 36(20), 2791–2801.CrossRefPubMedGoogle Scholar
  97. 97.
    Zhou, N., Zhang, Y., Zhang, X., Lei, Z., Hu, R., Li, H., et al. (2015). Exposure of tumor-associated macrophages to apoptotic MCF-7 cells promotes breast cancer growth and metastasis. International Journal of Molecular Sciences, 16(6), 11966–11982.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Engelmann, K., Shen, H., & Finn, O. J. (2008). MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer research, 68(7), 2419–2426.CrossRefPubMedGoogle Scholar
  99. 99.
    Das, S., Rachagani, S., Torres-Gonzalez, M. P., Lakshmanan, I., Majhi, P. D., Smith, L. M., et al. (2015). Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells. Oncotarget, 6(8), 5772–5787.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Skrypek, N., Duchene, B., Hebbar, M., Leteurtre, E., van Seuningen, I., & Jonckheere, N. (2013). The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene, 32(13), 1714–1723.CrossRefPubMedGoogle Scholar
  101. 101.
    Lahdaoui, F., Delpu, Y., Vincent, A., Renaud, F., Messager, M., Duchene, B., et al. (2015). miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer. Oncogene, 34(6), 780–788.CrossRefPubMedGoogle Scholar
  102. 102.
    Trehoux, S., Lahdaoui, F., Delpu, Y., Renaud, F., Leteurtre, E., Torrisani, J., et al. (2015). Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells. Biochimica et Biophysica Acta, 1853(10 Pt A), 2392–2403.CrossRefPubMedGoogle Scholar
  103. 103.
    Jahan, R., Macha, M. A., Rachagani, S., Das, S., Smith, L. M., Kaur, S., et al. (2018). Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-beta1/FAK/ERK pathway. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(8), 2538–2549.CrossRefPubMedGoogle Scholar
  104. 104.
    Muniyan, S., Haridas, D., Chugh, S., Rachagani, S., Lakshmanan, I., Gupta, S., et al. (2016). MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism. Genes & Cancer, 7(3–4), 110–124.Google Scholar
  105. 105.
    Seshacharyulu, P., Ponnusamy, M. P., Rachagani, S., Lakshmanan, I., Haridas, D., Yan, Y., et al. (2015). Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer. Oncotarget, 6(7), 5164–5181.CrossRefPubMedGoogle Scholar
  106. 106.
    Lakshmanan, I., Seshacharyulu, P., Haridas, D., Rachagani, S., Gupta, S., Joshi, S., et al. (2015). Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells. Oncotarget, 6(25), 21085–21099.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Pai, P., Rachagani, S., Lakshmanan, I., Macha, M. A., Sheinin, Y., Smith, L. M., et al. (2016). The canonical Wnt pathway regulates the metastasis-promoting mucin MUC4 in pancreatic ductal adenocarcinoma. Molecular Oncology, 10(2), 224–239.CrossRefPubMedGoogle Scholar
  108. 108.
    Rachagani, S., Macha, M. A., Ponnusamy, M. P., Haridas, D., Kaur, S., Jain, M., et al. (2012). MUC4 potentiates invasion and metastasis of pancreatic cancer cells through stabilization of fibroblast growth factor receptor 1. Carcinogenesis, 33(10), 1953–1964.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Momi, N., Ponnusamy, M. P., Kaur, S., Rachagani, S., Kunigal, S. S., Chellappan, S., et al. (2013). Nicotine/cigarette smoke promotes metastasis of pancreatic cancer through alpha7nAChR-mediated MUC4 upregulation. Oncogene, 32(11), 1384–1395.CrossRefPubMedGoogle Scholar
  110. 110.
    Moniaux, N., Chaturvedi, P., Varshney, G. C., Meza, J. L., Rodriguez-Sierra, J. F., Aubert, J. P., et al. (2007). Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells. British Journal of Cancer, 97(3), 345–357.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Senapati, S., Gnanapragassam, V. S., Moniaux, N., Momi, N., & Batra, S. K. (2012). Role of MUC4-NIDO domain in the MUC4-mediated metastasis of pancreatic cancer cells. Oncogene, 31(28), 3346–3356.CrossRefPubMedGoogle Scholar
  112. 112.
    Shukla, S. K., Gunda, V., Abrego, J., Haridas, D., Mishra, A., Souchek, J., et al. (2015). MUC16-mediated activation of mTOR and c-Myc reprograms pancreatic cancer metabolism. Oncotarget, 6(22), 19118–19131.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Singh, A. P., Moniaux, N., Chauhan, S. C., Meza, J. L., & Batra, S. K. (2004). Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. Cancer Research, 64(2), 622–630.CrossRefPubMedGoogle Scholar
  114. 114.
    Torres, M. P., Ponnusamy, M. P., Chakraborty, S., Smith, L. M., Das, S., Arafat, H. A., et al. (2010). Effects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies. Molecular Cancer Therapeutics, 9(5), 1419–1431.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Shimizu, A., Hirono, S., Tani, M., Kawai, M., Okada, K., Miyazawa, M., et al. (2012). Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma. Cancer Science, 103(4), 739–746.CrossRefPubMedGoogle Scholar
  116. 116.
    Lee, J., Lee, J., Yun, J. H., Jeong, D. G., & Kim, J. H. (2016). DUSP28 links regulation of mucin 5B and mucin 16 to migration and survival of AsPC-1 human pancreatic cancer cells. Tumour Biology: the journal of the International Society for Oncodevelopmental Biology and Medicine, 37(9), 12193–12202.CrossRefGoogle Scholar
  117. 117.
    Hoshi, H., Sawada, T., Uchida, M., Saito, H., Iijima, H., Toda-Agetsuma, M., et al. (2011). Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer. International Journal of Oncology, 38(3), 619–627.PubMedGoogle Scholar
  118. 118.
    Yamazoe, S., Tanaka, H., Sawada, T., Amano, R., Yamada, N., Ohira, M., et al. (2010). RNA interference suppression of mucin 5AC (MUC5AC) reduces the adhesive and invasive capacity of human pancreatic cancer cells. Journal of Experimental & Clinical Cancer Research: CR, 29, 53.CrossRefGoogle Scholar
  119. 119.
    Chauhan, S. C., Ebeling, M. C., Maher, D. M., Koch, M. D., Watanabe, A., Aburatani, H., et al. (2012). MUC13 mucin augments pancreatic tumorigenesis. Molecular Cancer Therapeutics, 11(1), 24–33.CrossRefPubMedGoogle Scholar
  120. 120.
    Wissniowski, T. T., Meister, S., Hahn, E. G., Kalden, J. R., Voll, R., & Ocker, M. (2012). Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells. International Journal of Oncology., 40(5), 1581–1589.PubMedGoogle Scholar
  121. 121.
    Nath, S., Daneshvar, K., Roy, L. D., Grover, P., Kidiyoor, A., Mosley, L., et al. (2013). MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes. Oncogene, e51, 2.Google Scholar
  122. 122.
    Roy, L. D., Sahraei, M., Subramani, D. B., Besmer, D., Nath, S., Tinder, T. L., et al. (2011). MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene, 30(12), 1449–1459.CrossRefPubMedGoogle Scholar
  123. 123.
    Komatsu, M., Carraway, C. A., Fregien, N. L., & Carraway, K. L. (1997). Reversible disruption of cell-matrix and cell-cell interactions by overexpression of sialomucin complex. The Journal of Biological Chemistry, 272(52), 33245–33254.CrossRefPubMedGoogle Scholar
  124. 124.
    Komatsu, M., Tatum, L., Altman, N. H., Carothers Carraway, C. A., & Carraway, K. L. (2000). Potentiation of metastasis by cell surface sialomucin complex (rat MUC4), a multifunctional anti-adhesive glycoprotein. International Journal of Cancer, 87(4), 480–486.CrossRefPubMedGoogle Scholar
  125. 125.
    Price-Schiavi, S. A., Jepson, S., Li, P., Arango, M., Rudland, P. S., Yee, L., et al. (2002). Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. International Journal of Cancer, 99(6), 783–791.CrossRefPubMedGoogle Scholar
  126. 126.
    Nagy, P., Friedlander, E., Tanner, M., Kapanen, A. I., Carraway, K. L., Isola, J., et al. (2005). Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Research, 65(2), 473–482.PubMedGoogle Scholar
  127. 127.
    Komatsu, M., Yee, L., & Carraway, K. L. (1999). Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells. Cancer Research, 59(9), 2229–2236.PubMedGoogle Scholar
  128. 128.
    Mukherjee, P., Pathangey, L. B., Bradley, J. B., Tinder, T. L., Basu, G. D., Akporiaye, E. T., et al. (2007). MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model. Vaccine, 25(9), 1607–1618.CrossRefPubMedGoogle Scholar
  129. 129.
    Kimura, T., McKolanis, J. R., Dzubinski, L. A., Islam, K., Potter, D. M., Salazar, A. M., et al. (2013). MUC1 vaccine for individuals with advanced adenoma of the colon: a cancer immunoprevention feasibility study. Cancer Prevention Research (Philadelphia, Pa.), 6(1), 18–26.CrossRefGoogle Scholar
  130. 130.
    Leng, Y., Cao, C., Ren, J., Huang, L., Chen, D., Ito, M., et al. (2007). Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. The Journal of Biological Chemistry, 282(27), 19321–19330.CrossRefPubMedGoogle Scholar
  131. 131.
    Raina, D., Ahmad, R., Joshi, M. D., Yin, L., Wu, Z., Kawano, T., et al. (2009). Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Research, 69(12), 5133–5141.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Ahmad, R., Alam, M., Hasegawa, M., Uchida, Y., Al-Obaid, O., Kharbanda, S., et al. (2017). Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer. Molecular Cancer, 16(1), 33.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Choudhury, A., Singh, R. K., Moniaux, N., El-Metwally, T. H., Aubert, J. P., & Batra, S. K. (2000). Retinoic acid-dependent transforming growth factor-beta 2-mediated induction of MUC4 mucin expression in human pancreatic tumor cells follows retinoic acid receptor-alpha signaling pathway. The Journal of Biological Chemistry, 275(43), 33929–33936.CrossRefPubMedGoogle Scholar
  134. 134.
    Jain, M., Venkatraman, G., Moniaux, N., Kaur, S., Kumar, S., Chakraborty, S., et al. (2011). Monoclonal antibodies recognizing the non-tandem repeat regions of the human mucin MUC4 in pancreatic cancer. PLoS One, 6(8), e23344.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Gautam, S. K., Kumar, S., Cannon, A., Hall, B., Bhatia, R., Nasser, M. W., et al. (2017). MUC4 mucin—a therapeutic target for pancreatic ductal adenocarcinoma. Expert Opinion on Therapeutic Targets, 21(7), 657–669.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Moniaux, N., Nollet, S., Porchet, N., Degand, P., Laine, A., & Aubert, J. P. (1999). Complete sequence of the human mucin MUC4: a putative cell membrane-associated mucin. The Biochemical Journal, 338(Pt 2), 325–333.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Nollet, S., Moniaux, N., Maury, J., Petitprez, D., Degand, P., Laine, A., et al. (1998). Human mucin gene MUC4: organization of its 5′-region and polymorphism of its central tandem repeat array. The Biochemical Journal, 332(Pt 3), 739–748.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Bafna, S., Singh, A. P., Moniaux, N., Eudy, J. D., Meza, J. L., & Batra, S. K. (2008). MUC4, a multifunctional transmembrane glycoprotein, induces oncogenic transformation of NIH3T3 mouse fibroblast cells. Cancer Research, 68(22), 9231–9238.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Ponnusamy, M. P., Lakshmanan, I., Jain, M., Das, S., Chakraborty, S., Dey, P., et al. (2010). MUC4 mucin-induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells. Oncogene, 29(42), 5741–5754.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Piessen, G., Jonckheere, N., Vincent, A., Hemon, B., Ducourouble, M. P., Copin, M. C., et al. (2007). Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. The Biochemical Journal, 402(1), 81–91.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Mariette, C., Perrais, M., Leteurtre, E., Jonckheere, N., Hemon, B., Pigny, P., et al. (2004). Transcriptional regulation of human mucin MUC4 by bile acids in oesophageal cancer cells is promoter-dependent and involves activation of the phosphatidylinositol 3-kinase signalling pathway. The Biochemical Journal, 377(Pt 3), 701–708.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Pai, P., Rachagani, S., Dhawan, P., Sheinin, Y. M., Macha, M. A., Qazi, A. K., et al. (2016). MUC4 is negatively regulated through the Wnt/beta-catenin pathway via the Notch effector Hath1 in colorectal cancer. Genes & Cancer, 7(5–6), 154–168.Google Scholar
  143. 143.
    Komatsu, M., Jepson, S., Arango, M. E., Carothers Carraway, C. A., & Carraway, K. L. (2001). Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor. Oncogene, 20(4), 461–470.CrossRefPubMedGoogle Scholar
  144. 144.
    Jonckheere, N., Skrypek, N., & Van Seuningen, I. (2010). Mucins and pancreatic cancer. Cancers, 2(4), 1794–1812.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Jonckheere, N., Perrais, M., Mariette, C., Batra, S. K., Aubert, J. P., Pigny, P., et al. (2004). A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-beta in pancreatic carcinogenesis. Oncogene, 23(34), 5729–5738.CrossRefPubMedGoogle Scholar
  146. 146.
    Fauquette, V., Perrais, M., Cerulis, S., Jonckheere, N., Ducourouble, M. P., Aubert, J. P., et al. (2005). The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells. The Biochemical Journal, 386(Pt 1), 35–45.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Kaur, S., Sharma, N., Krishn, S. R., Lakshmanan, I., Rachagani, S., Baine, M. J., et al. (2014). MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-kappaB signaling in pancreatic cancer. Clinical Cancer Research: an official journal of the American Association for Cancer Research, 20(3), 688–700.CrossRefGoogle Scholar
  148. 148.
    Singh, A. P., Chauhan, S. C., Andrianifahanana, M., Moniaux, N., Meza, J. L., Copin, M. C., et al. (2007). MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms. Oncogene, 26(1), 30–41.CrossRefPubMedGoogle Scholar
  149. 149.
    Choudhury, A., Moniaux, N., Ulrich, A. B., Schmied, B. M., Standop, J., Pour, P. M., et al. (2004). MUC4 mucin expression in human pancreatic tumours is affected by organ environment: the possible role of TGFbeta2. British Journal of Cancer, 90(3), 657–664.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Joshi, S., Cruz, E., Rachagani, S., Guha, S., Brand, R. E., Ponnusamy, M. P., et al. (2016). Bile acids-mediated overexpression of MUC4 via FAK-dependent c-Jun activation in pancreatic cancer. Molecular Oncology, 10(7), 1063–1077.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Andrianifahanana, M., Singh, A. P., Nemos, C., Ponnusamy, M. P., Moniaux, N., Mehta, P. P., et al. (2007). IFN-gamma-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-gamma response. Oncogene, 26(51), 7251–7261.CrossRefPubMedGoogle Scholar
  152. 152.
    Iacobuzio-Donahue, C. A., Ashfaq, R., Maitra, A., Adsay, N. V., Shen-Ong, G. L., Berg, K., et al. (2003). Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Research, 63(24), 8614–8622.PubMedGoogle Scholar
  153. 153.
    Swartz, M. J., Batra, S. K., Varshney, G. C., Hollingsworth, M. A., Yeo, C. J., Cameron, J. L., et al. (2002). MUC4 expression increases progressively in pancreatic intraepithelial neoplasia. American Journal of Clinical Pathology, 117(5), 791–796.CrossRefPubMedGoogle Scholar
  154. 154.
    Chaturvedi, P., Singh, A. P., Chakraborty, S., Chauhan, S. C., Bafna, S., Meza, J. L., et al. (2008). MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Research, 68(7), 2065–2070.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Vasseur, R., Skrypek, N., Duchene, B., Renaud, F., Martinez-Maqueda, D., Vincent, A., et al. (2015). The mucin MUC4 is a transcriptional and post-transcriptional target of K-ras oncogene in pancreatic cancer. Implication of MAPK/AP-1, NF-kappaB and RalB signaling pathways. Biochimica et Biophysica Acta, 1849(12), 1375–1384.CrossRefPubMedGoogle Scholar
  156. 156.
    Rachagani, S., Torres, M. P., Kumar, S., Haridas, D., Baine, M., Macha, M. A., et al. (2012). Mucin (Muc) expression during pancreatic cancer progression in spontaneous mouse model: potential implications for diagnosis and therapy. Journal of Hematology & Oncology, 5, 68.CrossRefGoogle Scholar
  157. 157.
    Singh, A. P., Chaturvedi, P., & Batra, S. K. (2007). Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. Cancer Research, 67(2), 433–436.CrossRefPubMedGoogle Scholar
  158. 158.
    Torres, M. P., Chakraborty, S., Souchek, J., & Batra, S. K. (2012). Mucin-based targeted pancreatic cancer therapy. Current Pharmaceutical Design, 18(17), 2472–2481.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Carraway, K. L., Theodoropoulos, G., Kozloski, G. A., & Carothers Carraway, C. A. (2009). Muc4/MUC4 functions and regulation in cancer. Future Oncology (London, England), 5(10), 1631–1640.CrossRefGoogle Scholar
  160. 160.
    Jonckheere, N., & Van Seuningen, I. (2018). Integrative analysis of the cancer genome atlas and cancer cell lines encyclopedia large-scale genomic databases: MUC4/MUC16/MUC20 signature is associated with poor survival in human carcinomas. Journal of Translational Medicine, 16(1), 259.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Wei, J., Gao, W., Wu, J., Meng, K., Zhang, J., Chen, J., et al. (2008). Dendritic cells expressing a combined PADRE/MUC4-derived polyepitope DNA vaccine induce multiple cytotoxic T-cell responses. Cancer Biotherapy & Radiopharmaceuticals, 23(1), 121–128.CrossRefGoogle Scholar
  162. 162.
    Wu, J., Wei, J., Meng, K., Chen, J., Gao, W., Zhang, J., et al. (2009). Identification of an HLA-A*0201-restrictive CTL epitope from MUC4 for applicable vaccine therapy. Immunopharmacology and Immunotoxicology, 31(3), 468–476.CrossRefPubMedGoogle Scholar
  163. 163.
    Das, S., & Batra, S. K. (2015). Understanding the unique attributes of MUC16 (CA125): potential implications in targeted therapy. Cancer Research, 75(22), 4669–4674.CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    O’Brien, T. J., Beard, J. B., Underwood, L. J., Dennis, R. A., Santin, A. D., & York, L. (2001). The CA 125 gene: an extracellular superstructure dominated by repeat sequences. Tumour Biology: the journal of the International Society for Oncodevelopmental Biology and Medicine, 22(6), 348–366.CrossRefGoogle Scholar
  165. 165.
    O’Brien, T. J., Beard, J. B., Underwood, L. J., & Shigemasa, K. (2002). The CA 125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure. Tumour Biology: the journal of the International Society for Oncodevelopmental Biology and Medicine, 23(3), 154–169.CrossRefGoogle Scholar
  166. 166.
    Yin, B. W., Dnistrian, A., & Lloyd, K. O. (2002). Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. International Journal of Cancer, 98(5), 737–740.CrossRefPubMedGoogle Scholar
  167. 167.
    Haridas, D., Ponnusamy, M. P., Chugh, S., Lakshmanan, I., Seshacharyulu, P., & Batra, S. K. (2014). MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB Journal: official publication of the Federation of American Societies for Experimental Biology, 28(10), 4183–4199.CrossRefGoogle Scholar
  168. 168.
    Streppel, M. M., Vincent, A., Mukherjee, R., Campbell, N. R., Chen, S. H., Konstantopoulos, K., et al. (2012). Mucin 16 (cancer antigen 125) expression in human tissues and cell lines and correlation with clinical outcome in adenocarcinomas of the pancreas, esophagus, stomach, and colon. Human Pathology, 43(10), 1755–1763.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Aithal, A., Rauth, S., Kshirsagar, P., Shah, A., Lakshmanan, I., Junker, W. M., et al. (2018). MUC16 as a novel target for cancer therapy. Expert Opinion on Therapeutic Targets, 22(8), 675–686.CrossRefPubMedGoogle Scholar
  170. 170.
    Haridas, D., Chakraborty, S., Ponnusamy, M. P., Lakshmanan, I., Rachagani, S., Cruz, E., et al. (2011). Pathobiological implications of MUC16 expression in pancreatic cancer. PLoS One, 6(10), e26839.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Bafna, S., Kaur, S., & Batra, S. K. (2010). Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene, 29(20), 2893–2904.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Matte, I., Lane, D., Boivin, M., Rancourt, C., & Piche, A. (2014). MUC16 mucin (CA125) attenuates TRAIL-induced apoptosis by decreasing TRAIL receptor R2 expression and increasing c-FLIP expression. BMC Cancer, 14, 234.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Boivin, M., Lane, D., Piche, A., & Rancourt, C. (2009). CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis. Gynecologic Oncology, 115(3), 407–413.CrossRefPubMedGoogle Scholar
  174. 174.
    Berek, J. S., Taylor, P. T., Gordon, A., Cunningham, M. J., Finkler, N., Orr, J., Jr., et al. (2004). Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. Journal of Clinical Oncology: official journal of the American Society of Clinical Oncology, 22(17), 3507–3516.CrossRefGoogle Scholar
  175. 175.
    Sabbatini, P., Harter, P., Scambia, G., Sehouli, J., Meier, W., Wimberger, P., et al. (2013). Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO—the MIMOSA study. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology, 31(12), 1554–1561.CrossRefGoogle Scholar
  176. 176.
    Das, S., Majhi, P. D., Al-Mugotir, M. H., Rachagani, S., Sorgen, P., & Batra, S. K. (2015). Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying Golgi/post-Golgi compartments. Scientific Reports, 5, 9759.CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Garg, G., Gibbs, J., Belt, B., Powell, M. A., Mutch, D. G., Goedegebuure, P., et al. (2014). Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3. BMC Cancer, 14, 35.CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nature Reviews. Molecular Cell Biology, 7(2), 131–142.CrossRefPubMedGoogle Scholar
  179. 179.
    Thiery, J. P., Acloque, H., Huang, R. Y., & Nieto, M. A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139(5), 871–890.CrossRefPubMedGoogle Scholar
  180. 180.
    Ahmed, N., Abubaker, K., Findlay, J., & Quinn, M. (2010). Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Current Cancer Drug Targets, 10(3), 268–278.CrossRefPubMedGoogle Scholar
  181. 181.
    Lim, S., Becker, A., Zimmer, A., Lu, J., Buettner, R., & Kirfel, J. (2013). SNAI1-mediated epithelial-mesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance. PLoS One, 8(6), e66558.CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Voulgari, A., & Pintzas, A. (2009). Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochimica et Biophysica Acta, 1796(2), 75–90.PubMedGoogle Scholar
  183. 183.
    Yamada, S., Fuchs, B. C., Fujii, T., Shimoyama, Y., Sugimoto, H., Nomoto, S., et al. (2013). Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery, 154(5), 946–954.CrossRefPubMedGoogle Scholar
  184. 184.
    Ponnusamy, M. P., Seshacharyulu, P., Lakshmanan, I., Vaz, A. P., Chugh, S., & Batra, S. K. (2013). Emerging role of mucins in epithelial to mesenchymal transition. Current Cancer Drug Targets, 13(9), 945–956.CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Rajabi, H., Alam, M., Takahashi, H., Kharbanda, A., Guha, M., Ahmad, R., et al. (2014). MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition. Oncogene, 33(13), 1680–1689.CrossRefPubMedGoogle Scholar
  186. 186.
    Gnemmi, V., Bouillez, A., Gaudelot, K., Hemon, B., Ringot, B., Pottier, N., et al. (2014). MUC1 drives epithelial-mesenchymal transition in renal carcinoma through Wnt/beta-catenin pathway and interaction with SNAIL promoter. Cancer Letters, 346(2), 225–236.CrossRefPubMedGoogle Scholar
  187. 187.
    Gao, L., Liu, J., Zhang, B., Zhang, H., Wang, D., Zhang, T., et al. (2014). Functional MUC4 suppress epithelial-mesenchymal transition in lung adenocarcinoma metastasis. Tumour Biology: the journal of the International Society for Oncodevelopmental Biology and Medicine, 35(2), 1335–1341.CrossRefGoogle Scholar
  188. 188.
    Jonckheere, N., & Van Seuningen, I. (2014). Comment on: Functional MUC4 suppress epithelial-mesenchymal transition in lung adenocarcinoma metastasis. Gao L, Liu J, Zhang B, Zhang H, Wang D, Zhang T, Liu Y, Wang C. Tumour Biol. 2013, in press. Tumour Biology: the journal of the International Society for Oncodevelopmental Biology and Medicine, 35(4), 3941–3942.CrossRefGoogle Scholar
  189. 189.
    Comamala, M., Pinard, M., Theriault, C., Matte, I., Albert, A., Boivin, M., et al. (2011). Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells. British Journal of Cancer, 104(6), 989–999.CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Theriault, C., Pinard, M., Comamala, M., Migneault, M., Beaudin, J., Matte, I., et al. (2011). MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis. Gynecologic Oncology, 121(3), 434–443.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Colorectal SurgeryBeaumont HospitalDublin 9Ireland
  2. 2.Department of Physiology & Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland
  3. 3.Department of SurgeryRoyal College of Surgeons in IrelandDublin 2Ireland
  4. 4.Department of PathologyBeaumont HospitalDublin 9Ireland
  5. 5.Department of PathologyRoyal College of Surgeons in IrelandDublin 2Ireland

Personalised recommendations