Histone deacetylase (HDAC) 6 is a subtype of the HDAC family; it deacetylates a-tubulin and increases cell motility. Here, we investigate the impact of an alteration of HDAC6 expression in estrogen receptor a (ER)-positive breast cancer MCF-7 cells, as we identified that HDAC6 is a novel estrogen-regulated gene. MCF-7 treated with estradiol showed increased expression of HDAC6 mRNA and protein and a four-fold increase in cell motility in a migration assay. Cell motility was increased to the same degree by stably transfecting the HDAC6 expression vector into MCF-7 cells. In both cases, the cells changed in appearance from their original round shape to an axon-extended shape, like a neuronal cell. This HDAC6 accumulation caused the deacetylation of a-tubulin. Either the selective estrogen receptor modulator tamoxifen (TAM) or the pure antiestrogen ICI 182,780 prevented estradiol-induced HDAC6 accumulation and deacetylation of a-tubulin, leading to reduced cell motility. Tubacin, an inhibitory molecule that binds to the tubulin deacetylation domain of HDAC6, also prevented estradiol-stimulated cell migration. Finally, we evaluated HDAC6 protein expression in 139 consecutively archived human breast cancer tissues by immunohistochemical staining. The prognostic analyses for these patients revealed no significant differences based on HDAC6 expression. However, subset analysis of ERpositive patients who received adjuvant treatment with TAM (n ¼ 67) showed a statistically significant difference in relapse-free survival and overall survival in favor of the HDAC6-positive group (Po0.02 and Po0.05, respectively). HDAC6 expression was an independent prognostic indicator by multivariate analysis (odds ratio ¼ 2.82, P ¼ 0.047). These results indicate the biological significance of HDAC6 regulation via estrogen signaling.
Significant K-ras mutation occurs most frequently in the pancreatobiliary regions of patients with AIP. Autoimmune pancreatitis may be a risk factor of pancreatobiliary cancer.
Background-We previously identified INT6/eIF3e as a novel regulator of hypoxia-inducible factor 2␣ (HIF2␣) activity. Small interfering RNA (siRNA)-Int6 adequately stabilized HIF2␣, even under normoxic conditions, and thereby enhanced the expression of several angiogenic factors in vitro, suggesting that siRNA-Int6 may induce angiogenesis in vivo. Methods and Results-We demonstrated a 6-to 8-fold enhanced formation of normal arteries and veins in the subcutaneous regions of adult mice 5 days after a single siRNA-Int6 application. Subcutaneous fibroblasts were identified as the major source of secreted angiogenic factors that led to the formation of functional vessels during Int6 silencing. Fibroblasts transfected ex vivo with siRNA-Int6 induced potent neoangiogenesis when transplanted into a subcutaneous region of nude mice. Application of siRNA-Int6 promoted neoangiogenesis in the area surrounding the injury in wound healing models, including genetically diabetic mice, thereby accelerating the closure of the injury. HIF2␣ accumulation caused by siRNA-Int6 was confirmed as the unequivocal cause of the angiogenesis by an in vivo angiogenesis assay. Further analysis of the Int6 silencing-induced neoangiogenesis revealed that a negative feedback regulation of HIF2␣ stability was caused by HIF2␣-induced transcription of Int6 via hypoxia-response elements in its promoter. Thus, siRNA-Int6 temporarily facilitates an accumulation of HIF2␣ protein, leading to hypoxia-independent transcription of angiogenic factors and concomitant neoangiogenesis. Conclusions-We suggest that the pathway involving INT6/HIF2␣ acts as a hypoxia-independent master switch of functional angiogenesis; therefore, siRNA-Int6 application might be of clinical value in treating ischemic diseases such as heart and brain ischemia, skin injury, and diseases involving obstructed vessels. (Circulation. 2010;122:910-919.)Key Words: angiogenesis Ⅲ hypoxia Ⅲ molecular biology Ⅲ signal transduction Ⅲ siRNA T he process of vessel formation is complex but well coordinated, involving the combined action of numerous growth factors and related signaling pathways. 1 Nevertheless, a single angiogenic factor such as vascular endothelial growth factor (VEGF), 2 fibroblast growth factor (FGF), 3,4 or plateletderived growth factor 5 can induce neoangiogenesis, 6 -8 albeit with incomplete and leaky vessels. 6,9 The transgenic expression of angiopoietin-1 (ANG-1) and VEGF significantly increases both the size and number of blood vessels. 8 These results suggest that several angiogenic factors are essential for the formation of functional vessels and that they must be expressed in a complementary and coordinated manner 10 to strike a balance among many stimulatory and inhibitory signals. 11
Clinical Perspective on p 919The expression of various angiogenic factors such as VEGF, ANG-1, and pleiotrophin 12 is triggered by hypoxia through the action of hypoxia-inducible factors (HIFs); these angiogenic factors play important roles in blood vessel formation and oncogenesis. 13 ...
Gallbladder wall thickening with fibrosis and abundant infiltration of IgG4-positive plasma cells is frequently detected in patients with AIP. We propose the use of a new term, sclerosing cholecystitis, for these cases that are induced by the same mechanism as sclerosing pancreatitis or sclerosing cholangitis in AIP.
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