Selective disruption of oncogenic RET signaling in medullary thyroid carcinoma in vitro and in vivo is associated with loss of the neoplastic phenotype of medullary thyroid carcinoma and should be investigated further as the basis for new therapeutic approaches for this disease.
The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon. Functional inactivation of Smad4 is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth. Smad4 encodes an intracellular messenger common to all signalling cascades induced by members of the transforming growth factor-b (TGF-b) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-b/Smad signal transduction, little is known about Smad4 targets involved in the transition to malignancy. The hallmark of invasive growth is a breakdown of the basement membrane (BM), a specialized sheet of extracellular matrix produced through cooperation of epithelial and stromal cells. Laminin-5, a heterotrimeric epithelial-derived BM component, is commonly lost in carcinomas but not in premalignant tumors. Herein, we report that in human colon and pancreatic tumor cells, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-5. Coordinate re-expression of the three laminin-5 chains induced by reconstitution of Smad4 leads to secretion and deposition of the heterotrimeric molecule in BM-like structures. These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4.
Our results indicate that the identified ligand should be suitable to improve selectivity of adenoviral gene transfer to medullary thyroid tumors in vivo.
Contemporary protein microarrays such as the ProtoArray® are used for autoimmune antibody screening studies to discover biomarker panels. For ProtoArray data analysis, the software Prospector and a default workflow are suggested by the manufacturer. While analyzing a large data set of a discovery study for diagnostic biomarkers of the Parkinson’s disease (ParkCHIP), we have revealed the need for distinct improvements of the suggested workflow concerning raw data acquisition, normalization and preselection method availability, batch effects, feature selection, and feature validation. In this work, appropriate improvements of the default workflow are proposed. It is shown that completely automatic data acquisition as a batch, a re-implementation of Prospector’s pre-selection method, multivariate or hybrid feature selection, and validation of the selected protein panel using an independent test set define in combination an improved workflow for large studies.
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