TRIP-1 regulates TGF-β1-induced epithelial-mesenchymal transition of human lung epithelial cell line A549.

Abstract

Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells undergo conversion to a mesenchymal phenotype contributing to wound repair by fibrosis and to cancer cell acquisition of invasive ability. Recently, we showed that type II TGF-β receptor interacting protein-1 (TRIP-1), a protein identified as a phosphorylation target of the TGF-β type II receptor kinase and as a functional component of eukaryotic translation initiator factor 3 (eiF3) multiprotein complex, is a novel modulator of fibroblast collagen contraction, an important step in wound repair stimulated by TGF-β1 action. TGF-β1 drives EMT, but it is not known whether TRIP-1 expression influences EMT induction. To investigate whether TRIP-1 plays a role in EMT induction we studied the effect of downregulating TRIP-1 expression in the well-characterized A549 model of TGF-β1 induction of EMT. Here we report that short hairpin RNA (shRNA)-mediated depletion of TRIP-1 gene transcripts in A549 cells promotes EMT as assessed by changes in phenotypic markers, morphology, and migrative ability. Knockdown of TRIP-1 dramatically increased A549 responsiveness to TGF-β1 induction of EMT. Mechanistically, a pathway involving increased TGF-β type II receptor level, enhanced Smad3 phosphorylation, and the transcription factor SLUG is implicated. Altogether, the findings point to regulation of endogenous TRIP-1 protein expression as a potential strategy to target EMT, and related invasive behavior, in cancer cells.

• Authors: Ricardo E Perez, Angels Navarro, Mohammad H Rezaiekhaligh, Sherry M Mabry, Ikechukwu I Ekekezie
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 300 Issue 5 Pg. L799-807 (May 2011) ISSN: 1522-1504 [Electronic] United States
• PMID: 21378021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Eukaryotic Initiation Factor-3
• RNA, Small Interfering
• SMAD3 protein, human
• Smad3 Protein
• Transforming Growth Factor beta1
• EIF3I protein, human

Topics

• Cell Line, Tumor
• Down-Regulation
• Epithelial Cells (cytology)
• Epithelial-Mesenchymal Transition (drug effects)
• Eukaryotic Initiation Factor-3 (genetics, metabolism)
• Humans
• Lung
• RNA, Small Interfering (pharmacology)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (metabolism, pharmacology)