Translational up-regulation of Aurora-A in EGFR-overexpressed cancer

J Cell Mol Med. 2010 Jun;14(6B):1520-31. doi: 10.1111/j.1582-4934.2009.00919.x. Epub 2009 Oct 3.

Abstract

Abnormal expression of Aurora-A and epidermal growth factor receptor (EGFR) is observed in different kinds of cancer and associated with poor prognosis in cancer patients. However, the relationship between Aurora-A and EGFR in tumour development was not clear. In previous reports, we found that EGFR translocates to nucleus to activate Aurora-A expression after EGF treatment in EGFR-overexpressed cells. However, we also observed that not all the EGFR-overexpressed cells have the nuclear EGFR pathway to mediate the Aurora-A expression. In this study, we demonstrated that EGF signalling increased the Aurora-A protein expression in EGFR-overexpressed colorectal cancer cell lines via increasing the translational efficiency. In addition, the overexpression of EGFR was also associated with higher expression of Aurora-A in clinical colorectal samples. Activation of the PI3K/Akt/mTOR and MEK/ERK pathways mediated the effect of EGF-induced translational up-regulation. Besides, only the splicing variants containing exon 2 of Aurora-A mRNA showed increased interaction with the translational complex to synthesize Aurora-A protein under EGF stimulus. Besides, the exon 2 containing splicing variants were the major Aurora-A splicing forms expressed in human colorectal cancers. Taken together, our results propose a novel regulatory mechanism for the abnormal expression of Aurora-A in EGFR-overexpressed cancers, and highlight the importance of alternative 5'-UTR splicing variants in regulating Aurora-A expression. Furthermore, the specific expression of exon 2 containing splicing variants in cancer tissues may serve as a potential target for cancer therapy in the future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Alternative Splicing / genetics
  • Aurora Kinases
  • Cell Line, Tumor
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Biosynthesis* / drug effects
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribosomes / drug effects
  • Ribosomes / metabolism
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*

Substances

  • 5' Untranslated Regions
  • RNA, Messenger
  • Epidermal Growth Factor
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases