Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1864663 (HCC)
 2,985 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Motility and invasiveness events require specific intracellular signaling cascade activations. In cancer liver cells, one of these mechanisms could involve the MAPK MEK/ERK cascade activation which has been shown over expressed and activated in hepatocellular carcinoma. To study whether the MEK/ERK cascade is involved in the motility of HCC, we examined the effect of MEK inhibitor and ERK2 silencing using monolayer wound-healing assays and fluoroblock invasion systems. Evidence was provided that the MAPK cascade is a key transduction pathway which controls HCC cells motility and invasiveness. We could disconnect proliferation to motility using mitomycin C and we established that RNAi-mediated inhibition of ERK2 led to strongly reduced cell motility. To improve our understanding, we analysed the regulation and the role of urokinase receptor (uPAR) in this process. We provided evidence that uPAR was under a MEK/ERK dependent mechanism and blocking uPAR activity using specific antagonist or inhibiting its expression by RNA interference which resulted in complete inhibition of motility. Moreover, we found in MAPK inhibited cultures and in uPAR silencing cells that p70S6K phosphorylation on residue Thr-389 was significantly reduced, whereas Ser-421/Thr-424 phosphorylation did not change. We highlighted that the FRAP/mTOR pathway did not affect motility and Thr-389 phosphorylation. Furthermore, we demonstrated that p70S6K inhibition by RNA interference completely inhibited hepatocarcinoma cell motility. Therefore, targeting uPAR and/or MEK/ERK/S6K by RNA interference could be a major therapeutic strategy for the future treatment of invasive hepatocarcinoma cells.
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PMID:MEK/ERK-dependent uPAR expression is required for motility via phosphorylation of P70S6K in human hepatocarcinoma cells. 1742 99

Liver-specific deletion of autophagy-related genes in mice leads to hepatomegaly, liver injury and spontaneous liver tumorigenesis. Accumulating evidence indicates that p62/SQSTM1-mediated NFE2L2/Nrf2/(nuclear factor, erythroid 2 like 2) activation plays a critical role in promoting liver injury and tumorigenesis in autophagy-defective livers. However, the mechanisms of how persistent NFE2L2 activation induces liver injury and tumorigenesis are unknown. In a recent study, it was found that deletion of Mtor (mechanistic target of rapamycin kinase) or Rptor/Raptor attenuates hepatomegaly and liver injury in young liver-specific atg5 knockout mice but accelerates liver tumorigenesis in old mice likely due to feedback AKT activation. Overall, these findings suggest that both hyper- and hypo-activation of MTOR are detrimental to the liver resulting in the development of liver tumors. A balanced MTOR activity is critical to maintain the normal physiological functions of the liver, and caution should be exercised when treating hepatocellular carcinomas using MTOR inhibitors. Abbreviations: Atg5: autophgy related 5; DKO: double-knockout; HCC: hepatocellular carcinoma; INS: insulin; INSR: insulin receptor; KEAP1: kelch-like ECH-associated protein 1; KO: knockout; MTOR: mechanistic target of rapamycin kinase; NFE2L2: nuclear factor, erythroid 2 like 2; raptor: regulatory associated protein of MTOR, complex 1; SQSTM1: sequestosome 1: tsc1: TSC complex subunit 1.
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PMID:The double-edged sword of MTOR in autophagy deficiency induced-liver injury and tumorigenesis. 3121 56