doi:10.1038/nindia.2010.31 Published online 16 March 2010
Researchers have pinpointed a new pathway to explain what genetic process happens inside benign tumor cells to tilt the balance towards malignancy, and changes them from epithelical to mesenchymal cells — a process essential for cancer progression.
Cancer progresses when benign tumor cells are converted into invasive ones that infiltrate surrounding tissues and ultimately spread to other organs – a process called metastasis. In the process, cells lose adhesion between themselves. The cells change from an epithelial cell type into a mesenchymal cell type — a phenomenon called epithelial mesenchymal transition (EMT).
A growth factor — the 'transforming growth factor-beta' (TGFβ) — is an important regulator of such transition. TGFβ actually functions as a tumor suppressor during early stages of tumorigenesis and as a tumor promoter in later stages.
The new pathway describes how this growth factor increases the translation of two genes required for EMT — Dab2 (Disabled2) and ILEI (Interleukin-like EMT Inducer) — by overriding a translation inhibition mechanism that keeps these two, and possibly other genes, silenced.
In cells that have not undergone EMT, these genes are not translated to produce the corresponding proteins, although the mRNAs encoded by these genes are abundantly present in the cells. This silencing is caused when a protein hnRNP E1 binds to a specific RNA structure (TGFβ-activated translation or BAT element) in the mRNAs.
The study provides insights into a new mechanism, where the presence of the BAT elements within the mRNAs of multiple EMT-promoting genes inhibits translation through the binding of hnRNP E1, thereby checking EMT. This, until the growth factor in tumor cells activates Akt2, which adds a phosphate to hnRNP E1 and causes it to fall off from the mRNAs. This tilts the balance towards EMT.
Coordinated translational regulation of the two genes (Dab2 and ILEI) indicates that this may constitute a post-transcriptional regulon inhibiting the expression of related EMT genes. "This system would exert a very fine-tuned control over EMT during development and tumor progression and might provide targets for anti-cancer therapeutic strategies in the future," says one of the authors, Partho Sarothi Ray.