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Transcription co-activator P300 activates Elk1-aPKC-ι signaling mediated epithelial-to-mesenchymal transition and malignancy in hepatocellular carcinoma.
Oncogenesis ( IF 6.2 ) Pub Date : 2020-03-06 , DOI: 10.1038/s41389-020-0212-5
Chaoqun Ma 1 , Shuhong Huang 2 , Lei Xu 1 , Li Tian 1 , Yan Yang 3 , Jianming Wang 1, 4
Affiliation  

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.

中文翻译:

转录共激活因子P300激活肝细胞癌中Elk1-aPKC-1信号传导介导的上皮-间充质转化和恶性肿瘤。

上皮-间质转化(EMT)在肝细胞癌(HCC)的侵袭和转移中起着重要作用。我们先前的研究发现非典型蛋白激酶C-1(aPKC-1)促进了HCC中的EMT过程。然而,尚未阐明在肝癌中如何调节aPKC-1信号传导途径。在这项研究中,利用载体转染研究了HCC细胞的侵袭,并在体内和体外进一步阐明了P300和aPKC-1信号通路之间调节HCC EMT过程的机制。我们发现P300和aPKC-1均在HCC中高表达,并且它们与HCC患者的肿瘤进展和不良的存活相关。P300抑制可抑制HCC细胞的EMT,侵袭和其他恶性事件,但可促进细胞凋亡和周期停滞。然而,通过aPKC-1过表达消除了由P300敲低介导的作用。进一步的研究表明,P300通过增加Elk1(aPKC-1的转录激活因子)的转录并稳定Elk1蛋白及其磷酸化来上调aPKC-1的表达。总之,我们的工作揭示了致癌性aPKC-1在肝癌中被上调的分子机制,并暗示P300像aPKC-1一样可以用作HCC患者的预后生物标志物和治疗靶标。
更新日期:2020-03-06
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