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The thyroid hormone, 3,3 0 ,5-triiodo-L-thyronine (T 3 ), mediates several physiological processes, including embryonic development, cellular differentiation, metabolism and regulation of cell proliferation. Thyroid hormone (T 3 ) and its receptor (TR) are involved in metabolism and growth. In addition to their developmental and metabolic functions, TRs play a tumor suppressor role, and therefore, their aberrant expression can lead to tumor transformation. Aberrant epigenetic silencing of tumor suppressor genes promotes cancer progression. The epigenetic regulator, Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), is overexpressed in various cancers. In our study, we demonstrated that T 3 negatively regulates UHRF1 expression, both in vitro and in vivo. Our results further indicate that UHRF1 regulation by T 3 is indirect and mediated by Sp1. Sp1-binding elements of UHRF1 were identified at positions 2664/2505 of the promoter region using the luciferase and chromatin immunoprecipitation assays. Notably, UHRF1 and Sp1 levels were elevated in subgroups of hepatocellular carcinoma patients and inversely correlated with TRa1 expression. Knockdown of UHRF1 expression should therefore provide a means to inhibit hepatoma cell proliferation. Expression of UHRF1 was downregulated by TRs, in turn, relieving silencing of the UHRF1 target gene, p21. Based on the collective findings, we propose that T 3 /TR signaling induces hepatoma cell growth inhibition via UHRF1 repression.The thyroid hormone, 3,3 0 ,5-triiodo-L-thyronine (T 3 ), is an important regulator of several physiological processes, including embryonic development, cellular differentiation, proliferation and metabolism. 1 The actions of T 3 are mediated by nuclear thyroid hormone receptors (TRs), ligand-dependent transcription factors that comprise modular functional domains mediating hormone binding (ligands), DNA binding, receptor homodimerization and heterodimerization and interactions with other transcription factors and cofactors. 2 TRs normally act by binding, generally as heterodimers with the retinoid X receptor, to thyroid hormone response elements located in regulatory regions of target genes. 3 Using cDNA microarray, we previously showed that the Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) oncogene is negatively regulated by T 3 in a TRa1-overexpressing hepatoma cell line. 4 Accumulating evidence supports an association of aberrant TR regulation or mutation of TR genes with human neoplasia. 5 Lin et al. 6 identified truncated TRa1 and TRb1 cDNA fragments in 53% of human hepatocellular carcinomas (HCCs). Moreover, high frequency of multiple point mutations in TRs was observed (89 and 46% for TRa1 and TRb1, respectively). 6 Many of these mutant TRs exhibited loss of T 3 binding and aberrant DNA binding activity. Accumulating evidence has revealed that the thyroid hormone receptor is a potent suppressor of tumorigenesis, invasiveness and metastasis formation. 1 In mammals, DNA methylation plays a crucial role in regulation of gene e...

Background & Aims : Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths worldwide. Many studies indicate that disruption of cellular thyroid hormone signaling promotes HCC progression. However, the mechanisms underlying the regulation of genes downstream of thyroid hormone actions in HCC have remained elusive. In the current study, we identified NUPR1 (nuclear protein-1), a stress-induced protein that overexpresses in various neoplasia, is upregulated by triiodothyronine/thyroid hormone receptor (T 3 /TR) signaling and aimed to elucidate its role in angiogenesis in cancer progression. Methods : Quantitative reverse transcription-PCR, luciferase promoter and chromatin immunoprecipitation assays were performed to identify the NUPR1 regulatory mechanism by T 3 /TR. In vitro and In vivo vascular formations were performed to detect the angiogenic function of NUPR1. Human angiogenesis arrays were performed to identify the downstream angiogenic pathway. The sorafenib resistant ability of TR/NUPR1 was further examined in vitro and in vivo . Clinical relevance of TR, NUPR1 and platelet-derived growth factor A (PDGFA) were investigate in HCC samples using qRT-PCR and western blot. Results : Our experiments disclosed positive regulation of NUPR1 expression by T 3 /TR through direct binding to the -2066 to -1910 region of the NUPR1 promoter. Elevated NUPR1 and TR expression link to poor survival in clinical HCC specimens. An analysis of clinicopathological parameters showed that expression of NUPR1 is associated with vascular invasion and pathology stage. Functional studies revealed that NUPR1 induced endothelial cell angiogenesis in vitro and in vivo . Using a human angiogenesis array, we identified PDGFA as a target of NUPR1 in the downstream angiogenic pathway. NUPR1 induced transcription of PDGFA through direct binding to the corresponding promoter region, and inhibition of the PDGFA signaling pathway impaired angiogenesis in human umbilical vein endothelial cells (HUVECs). Notably, the angiogenic effects of NUPR1/PDGFA were mediated by the MEK/ERK signaling pathway. TR/NUPR1 expression increased cell viability and resistance to sorafenib treatment. Moreover NUPR1 expression was positively correlated with TRα, TRβ, and PDGFA expression. Conclusions : We propose that the T 3 /TR/NUPR1/PDGFA/MEK/ERK axis has a vital role in hepatocarcinogenesis and suggest NUPR1 as a potential therapeutic target in HCC.

An unusual heavy coastal rainfall event ([231 mm day -1 ) occurred during the period of 24-25 June 1987 over the lowland (elevation less than 200 m) and coastal areas in northwest and central Taiwan. The Weather Research and Forecasting (WRF) model is used to investigate the role of synoptic forcing, orographic effects and the diurnal heating cycle on the generation of a prefrontal localized low-level convergence zone offshore leading to the observed coastal rainfall maximum. This case is well simulated by the control experiment initialized at 0000 UTC (0800 LST) 24 June 1987 using the European Centre for Medium-Range Weather Forecasts data. A model sensitivity test without Taiwan's terrain fails to reproduce the observed coastal rainfall maximum. It is apparent that for this case, synoptic forcing by the Mei-Yu jet/front system is inadequate to initiate deep convection leading to the development of coastal heavy precipitation. The generation of the localized low-level convergence zone is closely related to the simulated strong winds with a large southwesterly wind component (or the barrier jet) along the northwestern coast as the surface front approaches. The development of the simulated barrier jet is due to a 50-60% increase in the meridional pressure gradient as a result of orographic blocking. The diurnal heating cycle also impacts the strength of the simulated barrier jet over the northwestern Taiwan coast. The simulated barrier jet is stronger (*3 m s -1 ) in the early morning than in the afternoon as orographic blocking is most significant when the surface air is the coldest. The representation of the terrain in the model impacts the simulated barrier jet and rainfall. With a coarse horizontal resolution (45 km), orographic blocking is less significant than the control run with a much weaker meridional wind component over the northwestern coast of Taiwan. The coarse resolution model fails to reproduce the observed rainband off the northwestern coast. Thus, to successfully simulate this type of event, high-resolution mesoscale models adequately depicting Taiwan's terrain are required.Responsible editor: M. Kaplan.