KRT8 phosphorylation regulates the epithelial‐mesenchymal transition in retinal pigment epithelial cells through autophagy modulation

Abstract

Proliferative vitreoretinopathy (PVR) is a severe ocular disease which results in complex retinal detachment and irreversible vision loss. The epithelial‐mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is considered to be critical in the pathogenesis of PVR. In this study, we focused on the potential impact of keratin 8 (KRT8) phosphorylation and autophagy on TGF‐β2–induced EMT of RPE cells and explored the relationship between them. Using immunofluorescence and Western blot analysis, the co‐localization of KRT8 and autophagy marker, as well as the abundance of phosphorylated KRT8 (p‐KRT8) expression, was observed within subretinal and epiretinal membranes from PVR patients. Moreover, during TGF‐β2–induced EMT process, we found that p‐KRT8 was enhanced in RPE cells, which accompanied by an increase in autophagic flux. Inhibition of autophagy with pharmacological inhibitors or specific siRNAs was associated with a reduction in cell migration and the synthesis of several EMT markers. In the meantime, we demonstrated that p‐KRT8 was correlated with the autophagy progression during the EMT of RPE cells. Knockdown the expression or mutagenesis of the critical phosphorylated site of KRT8 would induce autophagy impairment, through affecting the fusion of autophagosomes and lysosomes. Therefore, this study may provide a new insight into the pathogenesis of PVR and suggests the potential therapeutic value of p‐KRT8 in the prevention and treatment of PVR.

Modification of STIM2 by m6A RNA methylation inhibits metastasis of cholangiocarcinoma

“…Our mechanistic investigation revealed that the STIM2-KRT8 axis is critical in CCA metastasis. KRT8 (keratin 8) is an epithelial marker and one of the most important keratin proteins (28). KRT8 and its filament partner, KRT18, have been found to control the cellular response to stress stimuli and contribute to cell resistance to apoptosis, in addition to maintaining cell mechanical integrity (29).…”

KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMT via NF-κB Signaling

“…Although aberrant KRT8 expression has been studied in a variety of malignancies ( 9 , 12 – 15 , 17 , 18 ), the underlying mechanisms and role of KRT8 in LUAD still remain unclear. KRT8 plays a key role in lung disease, such as lung fibrosis ( 10 , 11 ).…”

“…Epithelial-to-mesenchymal transition (EMT) is a biologic phenomenon that can alter the state of cells along a phenotypic spectrum and cause transcriptional rewiring to produce distinct tumor cell subpopulations ( 25 ). It is reported that KRT8 can participate in cell migration and invasion through EMT ( 18 ). In LUAD, the results indicated that KRT8 knockdown downregulated EMT.…”

“…KRT8 is upregulated in clear cell renal cell carcinoma ( 13 ), gastric cancer ( 9 ), breast cancer ( 14 ), and lung cancer ( 15 , 16 ). Aberrantly high expression of KRT8 has been found to be associated with multiple tumor progressions including cell migration ( 9 , 13 , 15 , 17 , 18 ). However, the role and mechanisms of these KRT8-mediated processes in LUAD have not been fully clarified.…”

Yes‐associated protein is essential for proliferative vitreoretinopathy development via the epithelial‐mesenchymal transition in retinal pigment epithelial fibrosis

“…It has been shown that these floating pigment cells, presumably RPE cells, attach to the surface of the retina, undergo EMT and migrate as fibrotic cells 29 . Miao et al 30 found that the loss of cell‐cell adhesion was the cause of EMT process and RPE cell proliferation. The epithelial markers, involving E‐cadherin and ZO‐1, have been proven to play an important role in maintaining cell proliferation and epithelial differentiation 31,32 .…”