TGF-beta is a pleiotropic cytokine that has both growth suppressive and growth promoting activates in oncogenesis. During the early stages of tumorigenesis TGF-beta acts as a tumor suppressor, however at later stages of neoplasia, this tumor suppressive role is lost and tumor cells become more motile, more invasive and more resistant to apoptosis. A comprehensive mechanism to describe the effects that TGF-beta has on invasion and metastasis is lacking. A recent study has shown that TGF-beta signaling is responsible for increased processing of the microRNA mlR-21. miR-21 is over expressed in a number of solid tumors including pancreatic cancer and has been shown to suppress the translation of a number of genes that inhibit invasion and metastasis (e.g. TIMP3, PDCD4, RECK and maspin). This project proposes a role for TGF-beta signaling in invasion and metastasis of pancreatic cancer through the increased processing of microRNAs miR-21 and miR-181.
Our first aim will study the effects of TGF-beta on the processing of miR-21 and miR-181 in pancreatic cancer cells.
Aim 2 will investigate the role of the receptor SMADs (e.g. SMAD2 and SMADS) and the inhibitory SMAD7 on TGF-beta induced miRNA processing will be investigated.
Aim 3 focuses on defining the contribution of the TGF-beta/SMAD/miRNA pathway on invasion and metastasis. This will be carried out using in vitro cell migration assays in the presence of antisense or pre-miR oligonucleotides to miR- 21 and miR-181. Finally, our fifth aim will attempt to discover additional microRNAs that are regulated by TGF-beta signaling by profiling the expression of over 740 microRNAs in cells stimulated with TGF-beta. Successful completion of this study will provide a microRNA link between TGF-beta signaling and cell invasion/metastasis. Relevance Pancreatic adenocarcinoma is one of the most lethal types of cancer and is approximately 99% fatal. Better understanding of the mechanism(s) responsible for pancreatic cancer metastasis could lead to improved treatment options. Data acquired from this study my lead to the development of new therapeutic targets to treat metastatic disease.
Pancreatic adenocarcinoma is one of the most lethal types of cancer and is approximately 99% fatal. Better understanding of the mechanism(s) responsible for pancreatic cancer metastasis could lead to improved treatment options. Data acquired from this study may lead to the development of new therapeutics targets to treat metastatic disease.
|Henry, Jon C; Azevedo-Pouly, Ana Clara P; Schmittgen, Thomas D (2011) MicroRNA replacement therapy for cancer. Pharm Res 28:3030-42|