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肝癌細胞線粒體在ROS生成下HSP60介導並調控MAPK信號傳遞的分子機制

為了解決3M pr的問題，作者JayaPrakash Mandal 這樣論述：

Our previous studies showed that mitogen-activated protein kinases (MAPKs) are activated by the interaction of protein kinase C (PKC) and reactive oxygen species (ROS) for hepatocellular carcinoma (HCC) progression. However, the relevant mechanisms remained to be clarified in more detail. In this s

tudy, we used two hepatoma cell lines HepG2 and HCC340 as models to investigate the comprehensive ROS-PKC signaling triggered by tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Since mitochondria-derived reactive oxygen species (mtROS) signaling is well known to be involved in tumor prog

ression, we examined whether TPA triggers the generation of mtROS that can crosstalk with PKC. By mtROS assay, TPA maximally induced mtROS generation at 10 min, which could be prevented by the mitochondria-specific scavenger of mtROS, MitoTEMPO. By western blot, we observed TPA induced transient pho

sphorylation of ERK/JNK and expression of transcriptional factors c-jun/c-fos. Using inhibitors of PKC isozymes and mitoTEMPO, the signal pathway was proved to be transmitted in mtROS/PCK-dependent manner. By BIAM-labeling coupled with LC-MS/MS, heat shock protein 60 (HSP60) was identified as the m

ajor oxidative target. Moreover, suppression of HSP60 by HSP60shRNA, HSP60 inhibitor mizoribine, and expression of dominant-negative HSP60 Cys-mutant prevented TPA-induced phosphorylation of MAPKs and expression of c-jun. In the mechanistic study, for oxidation of HSP60 leading to MAPK activation, w

e found Raf kinase inhibitor protein (RKIP), a negative regulator of MAPK and well-known metastatic suppressor, was involved. Using immunoprecipitation (IP)/Western blot analysis, we found TPA induced the dissociation RKIP from HSP60 within 30 min in both HCCs which can be attenuated by inhibitor of

PKC delta, mtROS scavenger and HSP60 Cys-mutant. At the same time, translocation of HSP60 coupled with MAPK from mitochondria to cytosol was observed. These were closely associated with the robust phosphorylation of MAPKs in the cytosol. By transwell migration assay and cell cycle analysis, TPA ind

uced G1 cell cycle arrest and cell migration, respectively, two dichotomous phenotypical changes of HCCs. Such phenotypes were prevented by the inhibitor of mtROS and knockdown of PKC and HSP60. Several migratory genes such as MMP1/3 (matrix metalloproteinase), LAMC2 (laminin????2), Hic-5 (hydrogen

peroxide inducible clone-5), and a miR-6134, targeting CCNE1 (cyclin E1) were upregulated by TPA. In addition, transcriptional system AP-1 (c-jun/c-fos) regulated TPA-induced migratory genes and miR-6134.In conclusion, we established TPA-induced PKC-mtROS-HSP60 (RKIP)-MAPK-(AP-1) signal axis requi

red for regulating gene expressions triggering dichotomous phenotype in HCCs. Several key players in this pathway such as PKCδ, RKIP, and HSP60 are promising candidates for targeted therapy to prevent HCC progression.