Loss of p53 and MCT-1 overexpression synergistically promote chromosome instability and tumorigenicity

Ravi Kasiappan, Hung Ju Shih, Kang Lin Chu, Wei Ti Chen, Hui Ping Liu, Shiu Feng Huang, On Choy Chik, Chung Li Shu, Richard Din, Jan Show Chu, Hsin Ling Hsu

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16 Citations (Scopus)

Abstract

MCT-1 oncoprotein accelerates p53 degradation by means of the ubiquitin-dependent proteolysis. Our present data show that induction of MCT-1 increases chromosomal translocations and deregulated G 2-M checkpoint in response to chemotherapeutic genotoxin. Remarkably, increases in chromosome copy number, multinucleation, and cytokinesis failure are also promoted while MCT-1 is induced in p53-deficient cells. In such a circumstance, the Ras-mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase signaling activity and the expression of metastatic molecules are amplified. Given a p53-silencing background, MCT-1 malignantly transforms normal breast epithelial cells that are satisfactory for stimulating cell migration/ adhesion and tumorigenesis. Detailed analyses of MCT-1 oncogenicity in H1299 p53-null lung cancer cells have shown that ectopically expressed MCT-1 advances xenograft tumorigenicity and angiogenesis, which cannot be completely suppressed by induction of p53. MCT-1 counteracts mutually with p53 at transcriptional levels. Clinical validations confirm that MCT-1 mRNA levels are differentially enriched in comparison between human lung cancer and nontumorigenic tissues. The levels of p53 mRNA are comparatively reduced in a subset of cancer specimens, which highly present MCT-1 mRNA. Our results indicate that synergistic promotions of chromosomal imbalances and oncogenic potency as a result of MCT-1 expression and p53 loss play important roles in tumor development.

Original languageEnglish
Pages (from-to)536-548
Number of pages13
JournalMolecular Cancer Research
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 1 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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  • Cite this

    Kasiappan, R., Shih, H. J., Chu, K. L., Chen, W. T., Liu, H. P., Huang, S. F., Chik, O. C., Shu, C. L., Din, R., Chu, J. S., & Hsu, H. L. (2009). Loss of p53 and MCT-1 overexpression synergistically promote chromosome instability and tumorigenicity. Molecular Cancer Research, 7(4), 536-548. https://doi.org/10.1158/1541-7786.MCR-08-0422