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2017 ; 66
(1
): 167-181
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A functional mammalian target of rapamycin complex 1 signaling is indispensable
for c-Myc-driven hepatocarcinogenesis
#MMPMID28370287
Liu P
; Ge M
; Hu J
; Li X
; Che L
; Sun K
; Cheng L
; Huang Y
; Pilo MG
; Cigliano A
; Pes GM
; Pascale RM
; Brozzetti S
; Vidili G
; Porcu A
; Cossu A
; Palmieri G
; Sini MC
; Ribback S
; Dombrowski F
; Tao J
; Calvisi DF
; Chen L
; Chen X
Hepatology
2017[Jul]; 66
(1
): 167-181
PMID28370287
show ga
Amplification and/or activation of the c-Myc proto-oncogene is one of the leading
genetic events along hepatocarcinogenesis. The oncogenic potential of c-Myc has
been proven experimentally by the finding that its overexpression in the mouse
liver triggers tumor formation. However, the molecular mechanism whereby c-Myc
exerts its oncogenic activity in the liver remains poorly understood. Here, we
demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is
activated and necessary for c-Myc-dependent hepatocarcinogenesis. Specifically,
we found that ablation of Raptor, the unique member of mTORC1, strongly inhibits
c-Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein
S6 and eukaryotic translation initiation factor 4E-binding protein 1/eukaryotic
translation initiation factor 4E signaling cascades downstream of mTORC1 are
required for c-Myc-driven tumorigenesis. Intriguingly, microarray expression
analysis revealed up-regulation of multiple amino acid transporters, including
solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake
of amino acids, including glutamine, into c-Myc tumor cells. Subsequent
functional studies showed that amino acids are critical for activation of mTORC1
as their inhibition suppressed mTORC1 in c-Myc tumor cells. In human
hepatocellular carcinoma specimens, levels of c-Myc directly correlate with those
of mTORC1 activation as well as of SLC1A5 and SLC7A6. CONCLUSION: Our current
study indicates that an intact mTORC1 axis is required for c-Myc-driven
hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters
may be an effective and novel therapeutic option for the treatment of
hepatocellular carcinoma with activated c-Myc signaling. (Hepatology
2017;66:167-181).
|Adaptor Proteins, Signal Transducing/metabolism
[MESH]
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