Expression of the carboxy-terminal portion of MUC16/CA125 induces transformation and tumor invasion Journal Article

Authors: Rao, T. D. ; Tian, H.; Ma, X.; Yan, X.; Thapi, S.; Schultz, N.; Rosales, N.; Monette, S.; Wang, A.; Hyman, D. M.; Levine, D. A.; Solit, D.; Spriggs, D. R.
Article Title: Expression of the carboxy-terminal portion of MUC16/CA125 induces transformation and tumor invasion
Abstract: The CA125 antigen is found in the serum of many patients with serous ovarian cancer and has been widely used as a disease marker. CA125 has been shown to be an independent factor for clinical outcome in this disease. In The Cancer Genome Atlas ovarian cancer project, MUC16 expression levels are frequently increased, and the highest levels of MUC16 expression are linked to a significantly worse survival. To examine the biologic effect of the proximal portion of MUC16/CA125, NIH/3T3 (3T3) fibroblast cell lines were stably transfected with the carboxy elements of MUC16. As few as 114 amino acids from the carboxyterminal portion of MUC16 were sufficient to increase soft agar growth, promote matrigel invasion, and increase the rate of tumor growth in athymic nude mice. Transformation with carboxy elements of MUC16 was associated with activation of the AKT and ERK pathways. MUC16 transformation was associated with up-regulation of a number of metastases and invasion gene transcripts, including IL-1β, MMP2, and MMP9. All observed oncogenic changes were exclusively dependent on the extracellular "ectodomain" of MUC16. The biologic impact of MUC16 was also explored through the creation of a transgenic mouse model expressing 354 amino acids of the carboxy-terminal portion of MUC16 (MUC16c354). Under a CMV, early enhancer plus chicken β actin promoter (CAG) MUC16c354 was well expressed in many organs, including the brain, colon, heart, kidney, liver, lung, ovary, and spleen. MUC16c354 transgenic animals appear to be viable, fertile, and have a normal lifespan. However, when crossed with p53-deficient mice, the MUC16c354:p53+/- progeny displayed a higher frequency of spontaneous tumor development compared to p53+/- mice alone. We conclude that the carboxy-terminal portion of the MUC16/CA125 protein is oncogenic in NIH/3T3 cells, increases invasive tumor properties, activates the AKT and ERK pathways, and contributes to the biologic properties of ovarian cancer. © 2015 Rao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: cancer survival; controlled study; protein expression; unclassified drug; human cell; disease marker; mus; metastasis; ovary cancer; spleen; carboxy terminal sequence; gelatinase b; interleukin 1beta; protein; genetic transcription; protein p53; transgenic animal; animalia; mus musculus; ovary; liver; hybrid protein; nude mouse; brain; cancer cell; lung; amino acid; upregulation; ca 125 antigen; tumor growth; malignant transformation; heart; colon; fibroblast culture; gelatinase a; beta actin; tumor invasion; human; female; article; 3t3 cell line; muc16 protein
Journal Title: PLoS ONE
Volume: 10
Issue: 5
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2015-05-12
Start Page: e0126633
Language: English
DOI: 10.1371/journal.pone.0126633
PROVIDER: scopus
PMCID: PMC4429113
PUBMED: 25965947
Notes: Export Date: 2 July 2015 -- Source: Scopus
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MSK Authors
  1. David Solit
    435 Solit
  2. Douglas A Levine
    356 Levine
  3. Xun Ma
    9 Ma
  4. David Hyman
    187 Hyman
  5. Sebastien Monette
    76 Monette
  6. Huasong Tian
    8 Tian
  7. David R Spriggs
    314 Spriggs
  8. Nikolaus D Schultz
    202 Schultz
  9. Nestor S Rosales
    27 Rosales