Abstract
There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners. Increased expression of 14-3-3 proteins contributes to tumor progression of various malignancies. Several isoforms of 14-3-3 are overexpressed and associate with higher metastatic risks and poorer survival rates of hepatocellular carcinoma (HCC). 14-3-3β and 14-3-3ζ regulate HCC cell proliferation, tumor growth and chemosensitivity via modulating mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 signal pathways. Moreover, 14-3-3ε suppresses E-cadherin and induces focal adhesion kinase (FAK) expression, thereby enhancing epithelial-mesenchymal transition (EMT) and HCC cell migration. 14-3-3ζ forms complexes with αB-crystallin, which induces EMT and is the cause of sorafenib resistance in HCC. Finally, a recent study has indicated that 14-3-3σ induces heat shock protein 70 (HSP70) expression, which increases HCC cell migration. These results suggest that selective 14-3-3 isoforms contribute to cell proliferation, EMT and cell migration of HCC by regulating distinct targets and signal pathways. Targeting 14-3-3 proteins together with specific downstream effectors therefore has potential to be therapeutic and prognostic factors of HCC. In this article, we will overview 14-3-3’s regulation of its downstream factors and contributions to HCC EMT, cell migration and proliferation.
Highlights
There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners
These results reveal that 14-3-3ε may contribute to cell survival regulation, proliferation, epithelial-mesenchymal transition (EMT) migration, as well as hepatocellular carcinoma (HCC) invasion, which eventually lead to tumor growth and metastasis promotion
It was reported that overexpression of 14-3-3β induced cell proliferation, anchorage-independent growth and tumor growth of transformed cells via altering the activation of the mitogen-activated protein kinase (MAPK) signal pathway [17]
Summary
14-3-3 proteins comprise seven isoforms (β, ε, γ, η, σ, τ/θ and ζ) and share highly conserved homology among all eukaryotic cells. They exert their influence by binding with Ser/Thr phosphorylated intracellular proteins, thereby affecting conformation, activity, subcellular localization and protein complex stability [1,2,3,4,5]. An increasing number of reports have indicated that some 14-3-3 isoforms are overexpressed and that 14-3-3 proteins are implicated in regulating tumor progression of various types of human malignancies [9,10,11,12,13,14]. Elevated expression of selective 14-3-3 proteins is considered as having the potential to be tumor progression promoters
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