Positive feedback loop of FAM83A/PI3K/AKT/c-Jun induces migration, invasion and metastasis in hepatocellular carcinoma - 28/01/20
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Highlights |
• | FAM83A is highly expressed in hepatocarcinoma cells and plays a carcinogenic role. |
• | FAM83A induces EMT in hepatocarcinoma cells via PI3K/AKT/c-Jun signaling pathway. |
• | FAM83A is associated with sorafenib resistance and poor prognosis in HCC. |
• | There is a FAM83A/PI3K/AKT/c-Jun Positive feedback loop in HCC. |
Abstract |
FAM83A is part of an 8-member protein family of unknown function and is reported to be a cancer-promoting and treatment-resistance factor in several cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. Analysis of the Cancer Genome Atlas (TCGA) showed that FAM83A mRNA expression is upregulated in HCC, as are the protein expression levels in both HCC cell lines and tissues. Clinical data have demonstrated that high FAM83A expression is positively correlated with poor progression-free survival time, thus suggesting its cancer-promoting potential. Functional analyses showed that FAM83A overexpression promoted HCC cell migration and invasion in vitro and suppressed sorafenib sensitivity. Inhibiting FAM83A reversed these results. A pulmonary metastasis model further confirmed that FAM83A promoted HCC cell metastasis in vivo. Mechanistic analyses indicated that FAM83A activated the PI3K/AKT signaling pathway, its downstream c-JUN protein, and epithelial-to-mesenchymal transition (EMT)-related protein levels, including downregulation of E-cadherin and upregulation of Vimentin and N-cadherin. Interestingly, c-JUN induced FAM83A expression by directly binding to its promoter region and thus forming a positive-feedback loop for FAM83A/PI3K/AKT/c-JUN. In conclusion, we demonstrated that FAM83A, as a cancer-metastasis promoter, accelerates migration, invasion and metastasis by activating the PI3K/AKT/c-JUN pathway and inducing its self-expression via feedback, thus forming a FAM83A/PI3K/AKT/c-JUN positive-feedback loop to activate EMT signaling and finally promote HCC migration, invasion and metastasis.
El texto completo de este artículo está disponible en PDF.Abbreviations : TCGA, LIHC, HCC, PI3K, AKT, EMT, DUF, siRNA, TSS, AP-1, HEPA, GAPDH, NC, Lv, BF, GFP, WT, PCR, RT-PCR, qPCR
Keywords : HCC, FAM83A, PI3K/AKT, EMT, Metastasis
Esquema
Vol 123
Artículo 109780- mars 2020 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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