Journal ArticleDOI
Overexpression of integrin β1 inhibits proliferation of hepatocellular carcinoma cell SMMC‐7721 through preventing Skp2‐dependent degradation of p27 via PI3K pathway
Yi Fu,Zhengyu Fang,Yulong Liang,Xiaodong Zhu,Peterbram Prins,Zengxia Li,Liying Wang,Lidong Sun,Jiawei Jin,Yong Yang,Xiliang Zha +10 more
TLDR
Results suggested that overexpression of integrin β1 inhibited cell proliferation by preventing the Skp2‐dependent degradation of p27Kip1 via PI3K pathway.Abstract:
Integrins may play important roles in many cellular events, such as cell proliferation, differentiation, and apoptosis. We showed previously that overexpression of integrin beta1 inhibits cell proliferation in SMMC-7721 cells. Here we reported that one of the cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) was involved in proliferation-inhibition induced by overexpression of integrin beta1. Overexpression of integrin beta1 upregulated p27(Kip1) at the protein level, but not mRNA level. The knock-down of p27(Kip1) expression restored cell growth in integrin beta1-overexpressing cells. Cycloheximide (Chx) treatment and pulse-chase experiments revealed that overexpression of integrin beta1 prolonged the half-life of p27(Kip1) by inhibiting its degradation. Proteasome inhibitor (MG132) treatment of the cells indicated that proteasome mediated degradation of p27, and Skp2-dependent degradation might be prevented. Overexpression of integrin beta1 decreased Skp2 at mRNA level, which was regulated by cell adhesion and the subsequent adhesion-dependent signaling. Overexpression of integrin beta1 reduced cell adhesion, accordingly, inactivated the phosphoinositide 3-kinase (PI3K) signaling. PI3K inhibitor LY294002 upregulated p27(Kip1) at post-translational level and downregulate Skp2 at mRNA level, which could mimic the effects of integrin beta1 overexpression on p27(Kip1) and Skp2. Together, these results suggested that overexpression of integrin beta1 inhibited cell proliferation by preventing the Skp2-dependent degradation of p27(Kip1) via PI3K pathway.read more
Citations
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Environment-mediated drug resistance: a major contributor to minimal residual disease
TL;DR: It is proposed that new therapeutic strategies targeting this interaction between tumour cells and the surrounding microenvironment should be applied during initial treatment to prevent the emergence of acquired resistance.
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The tumor microenvironment is a dominant force in multidrug resistance.
TL;DR: An additional perspective is proposed, one in which the tumor cells despite the malignant genome could find a microenvironment either within the tumor or as a dormant cell to remain polar and blend into an organized context.
Journal ArticleDOI
The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets.
TL;DR: The current knowledge about the role of the tumor microenvironment in pathogenesis of HCC, the role in the biologic and prognostic classification of H CC and efforts to develop treatments targeting the tumormicroenvironment are discussed.
Journal ArticleDOI
Cellular and molecular mechanisms of hepatocellular carcinoma: an update.
TL;DR: The current knowledge of HCC is discussed, focusing mainly on advances that have occurred during the past 5 years and on the development of novel therapeutics for liver cancer.
Journal ArticleDOI
The tumor microenvironment in hepatocellular carcinoma (review).
Giulia Costanza Leonardi,Saverio Candido,Melchiorre Cervello,Daria Nicolosi,Fabio Raiti,Salvatore Travali,Demetrios A. Spandidos,Massimo Libra +7 more
TL;DR: The tumor microenvironment in hepatocellular carcinoma (HCC) was explored by a review of studies on hepatitis virus infections and the consequent chronic inflammatory status of the liver, and the rationale for targeting tumor-stromal interface is summarized.
References
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Journal ArticleDOI
CDK inhibitors: positive and negative regulators of G1-phase progression
TL;DR: This work challenges previous assumptions about how the G1/S transition of the mammalian cell cycle is governed, helps explain some enigmatic features of cell cycle control that also involve the functions of the retinoblastoma protein (Rb) and the INK4 proteins, and changes the thinking about how either p16 loss or overexpression of cyclin D-dependent kinases contribute to cancer.
Journal ArticleDOI
Cancer Cell Cycles
TL;DR: Genetic alterations affecting p16INK4a and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development.
Journal ArticleDOI
Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27
Michele Pagano,Sun W. Tam,Anne M. Theodoras,Peggy Beer-Romero,Giannino Del Sal,Vincent Chau,P. Renee Yew,Giulio Draetta,Mark Rolfe +8 more
TL;DR: Compared with proliferating cells, quiescent cells exhibited a smaller amount of p27 ubiquitinating activity, which accounted for the marked increase of p 27 half-life measured in these cells, indicating that the abundance of p26 in cells is regulated by degradation.
Journal ArticleDOI
SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.
TL;DR: It is shown that the F-box protein SKP2 specifically recognizes p27 in a phosphorylation-dependent manner that is characteristic of an F- box-protein–substrate interaction and is subject to dual control by the accumulation of bothSKP2 and cyclins following mitogenic stimulation.
Journal ArticleDOI
AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.
TL;DR: It is concluded that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.