Abstract
Epithelial-to-mesenchymal transition (EMT) plays an important role in invasion and metastasis of hepatocellular carcinoma (HCC). Our previous study found that atypical protein kinase C-ι (aPKC-ι) promoted the EMT process in HCC. However, how the aPKC-ι signaling pathway is regulated in HCC has not been elucidated. In this study, vector transfection was utilized to study the invasion of HCC cells, and the mechanism between P300 and aPKC-ι signaling pathways in regulating the EMT process of HCC was further elucidated in vitro and in vivo. We found both P300 and aPKC-ι were highly expressed in HCC and they were correlated with tumor progression and poor survival in HCC patients. P300 knockdown inhibited EMT, invasion and other malignant events of HCC cells but promoted cell apoptosis and cycle arrest. However, the effects mediated by P300 knockdown were abolished by aPKC-ι overexpression. Further studies showed that P300 upregulates aPKC-ι expression through increasing the transcription of Elk1, a transcriptional activator of aPKC-ι, and stabilizing Elk1 protein and its phosphorylation. In conclusion, our work uncovered the molecular mechanism by which oncogenic aPKC-ι is upregulated in HCC and suggests that P300, like aPKC-ι, may be used as a prognostic biomarker and therapeutic target in patients with HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common human malignancy and the second leading cause of cancer-related deaths world-wide[1,2]
Concomitant overexpression of P300 and Atypical protein kinase C-ι (aPKC-ι) correlates with HCC progression and a poor prognosis We examined the protein levels of P300 and aPKC-ι in 76 paired HCC and pericarcinoma tissue samples using Immunohistochemistry (IHC)
Both univariate and multivariate COX regression analyses indicated that P300, like TNM stage, AFP and tumor size, was an independent factor affecting the survival of HCC patients (Supplementary Table 4, P = 0.043). By combining this information with the TCGA database, we determined that there was a positive correlation between aPKC-ι and P300 in HCC patients. These data indicate that P300 and aPKC-ι interact to promote HCC progression and suggest that they may both act as potential prognostic indicators for predicting clinical outcomes for HCC patients
Summary
Hepatocellular carcinoma (HCC) is the sixth most common human malignancy and the second leading cause of cancer-related deaths world-wide[1,2]. Epithelial–mesenchymal transition (EMT) has been shown to be a pivotal mechanism contributing to cancer invasion and metastasis, as epithelial related transcription factors such as Snail, Twist, and zinc finger E-box binding protein 1 (ZEB1) have demonstrated involvement in the process of EMT in HCC5,6, the molecular mechanism underlying the regulation of EMT in HCC has not been fully elucidated. Atypical protein kinase C-ι (aPKC-ι) is a aPKC, which is regarded as a human oncogene and a potential therapeutic target in various human tumors, including HCC7. We previously reported that the expression of aPKC-ι was increased in HCC tumors when compared with peritumoral and normal liver tissues[8,9].
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