1410

CRYAB

Subretinal fibrosis is an end stage of neovascular age-related macular degeneration, characterized by fibrous membrane formation after choroidal neovascularization. An initial step of the pathogenesis is an epithelial-mesenchymal transition (EMT) of retinal pigment epithelium cells. alphaB-crystallin plays multiple roles in age-related macular degeneration, including cytoprotection and angiogenesis. However, the role of alphaB-crystallin in subretinal EMT and fibrosis is unknown. Herein, we showed attenuation of subretinal fibrosis after regression of laser-induced choroidal neovascularization and a decrease in mesenchymal retinal pigment epithelium cells in alphaB-crystallin knockout mice compared with wild-type mice. alphaB-crystallin was prominently expressed in subretinal fibrotic lesions in mice. In vitro, overexpression of alphaB-crystallin induced EMT, whereas suppression of alphaB-crystallin induced a mesenchymal-epithelial transition. Transforming growth factor-beta2-induced EMT was further enhanced by overexpression of alphaB-crystallin but was inhibited by suppression of alphaB-crystallin. Silencing of alphaB-crystallin inhibited multiple fibrotic processes, including cell proliferation, migration, and fibronectin production. Bone morphogenetic protein 4 up-regulated alphaB-crystallin, and its EMT induction was inhibited by knockdown of alphaB-crystallin. Furthermore, inhibition of alphaB-crystallin enhanced monotetraubiquitination of SMAD4, which can impair its nuclear localization. Overexpression of alphaB-crystallin enhanced nuclear translocation and accumulation of SMAD4 and SMAD5. Thus, alphaB-crystallin is an important regulator of EMT, acting as a molecular chaperone for SMAD4 and as its potential therapeutic target for preventing subretinal fibrosis development in neovascular age-related macular degeneration.CI - Copyright (c) 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Alpha B-crystallin (HspB5) is abnormally expressed in tumor tissues and portends a poor prognosis in cancer patients. However, the role of HspB5 in colorectal cancer (CRC) is still unclear. Seventy CRC patients and 40 healthy volunteers were sampled from August 2012 to March 2015 in order to determine the clinical significance of HspB5. In vitro cellular studies were used to validate its molecular mechanisms in CRC. Our clinical data indicated that HspB5 was up-regulated, and had a positive association with TNM stage CRC patients. The expression level of HspB5 in CRC patients was closely correlated with MMP7 and E-cadherin, two core epithelial-mesenchymal transition (EMT) gene products. The in vitro studies revealed that high HspB5 expression could prompt tumor cell proliferation and invasion, as well as EMT. Gene-microarray analysis suggested three significant signaling pathways (PI3K, p38 and ERK) were involved in HspB5-induced EMT. Signal transduction pathway inhibitors and HspB5 gene knockdown models suggested that HspB5 promotes CRC tumorigenesis and EMT progression through ERK signaling pathways. In summary, HspB5 maybe trigger the EMT in CRC by activating the ERK signaling pathway. It is a potential tumor biomarker for CRC diagnosis and prognosis.