TSC-22 (TGF-beta stimulated clone-22): a novel molecular target for differentiation-inducing therapy in salivary gland cancer.

TSC-22 (Transforming growth factor-beta stimulated clone-22) was originally isolated as a TGF-beta-inducible gene in mouse osteoblastic cells. TSC-22 encodes a putative transcriptional regulator containing a leucine zipper-like structure. Several differentiation-inducing stimuli up-regulate the TSC-22 gene. Furthermore, TSC-22 acts as an effector that integrates multiple extracellular signals during embryogenesis of Drosophila and mouse. Separately, we identified TSC-22 cDNA as an anti-cancer drug (vesnarinone)-inducible gene in a human salivary gland cancer cell line, TYS. Vesnarinone is known to have a differentiation-inducing activity in several cell types. We showed that TSC-22 negatively regulated the growth of TYS cells, and that down-regulation of TSC-22 played a major role in the salivary gland tumorigenesis. Subsequently, we found that artificial overexpression of TSC-22 enhanced chemosensitivity and radiation-sensitivity by inducing apoptosis in TYS cells. Recently, we isolated TSC-22 genomic DNA and analyzed the transcriptional and post-transcriptional regulation of the TSC-22 gene. Then, we confirmed by the luciferase reporter assay that several differentiation-inducing stimuli directly activated the promoter region of TSC-22 gene. Now we are investigating the chemical compounds, which could enhance the transcription of the TSC-22 gene. Thus, because TSC-22 is a key molecule for differentiation of several cells, it can be used as a molecular target for cancer differentiation therapy in salivary gland cancer. Copyright 2004 Bentham Science Publishers Ltd.