Abstract
Knockdown of T-cell intracellular antigens TIA1 and TIAR in transformed cells triggers cell proliferation and tumor growth. Using a tetracycline-inducible system, we report here that an increased expression of TIA1 or TIAR in 293 cells results in reduced rates of cell proliferation. Ectopic expression of these proteins abolish endogenous TIA1 and TIAR levels via the regulation of splicing of their pre-mRNAs, and partially represses global translation in a phospho-eukaryotic initiation factor 2 alpha-dependent manner. This is accompanied by cell cycle arrest at G1/S and cell death through caspase-dependent apoptosis and autophagy. Genome-wide profiling illustrates a selective upregulation of p53 signaling pathway-related genes. Nude mice injected with doxycycline-inducible cells expressing TIA1 or TIAR retard, or even inhibit, growth of xenotumors. Remarkably, low expressions of TIA1 and TIAR correlate with poor prognosis in patients with lung squamous cell carcinoma. These findings strongly support the concept that TIA proteins act as tumor suppressor genes.
Highlights
Though the known importance of T-cell intracellular antigens (TIA) proteins in inflammation and the stress response, their role(s) in proliferation/
Results showed that the expression of tetracycline-inducible TIA1, TIA1ΔQ, TIAR, TIARΔQ and HuR proteins was consistent with their well-established patterns of nucleocytoplasmic and nuclear localizations for endogenous TIA1, TIAR and HuR, respectively (Figure 1a and refs 27,28)
Ectopic TIA1 or TIAR expression promoted the depletion of endogenous TIA proteins (Figures 1b,c and Supplementary Figure S2A)
Summary
Though the known importance of TIA proteins in inflammation and the stress response, their role(s) in proliferation/. We previously reported that a reduction of TIA expression in HeLa cells enhances proliferation, invasion and tumor growth.[21,26] Further, TIA proteins are downregulated in a subset of human epithelial tumors. These observations suggest that TIA proteins could act as inhibitors of tumorigenesis.[21,26] these capabilities have never been established. We clearly showed that TIA proteins function as cell growth and tumor suppressor genes. TIA proteins may have potential as biomarkers and prognosis factors in human lung cancer
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