Amplification and/or activation of the c-Myc protooncogene 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 the mTORC1 complex, strongly inhibits c-Myc liver tumor formation. Also, p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/eukaryotic translation initiation factor 4E (4EBP1/eIF4E) signaling cascades downstream of mTORC1 are required for c-Myc-driven tumorigenesis. Intriguingly, microarray expression analysis revealed the upregulation of multiple amino acid transporters, including 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 HCC 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 mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of HCC with activated c-Myc signaling.

A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis / Liu, Pin; Ge, Mengmeng; Hu, Junjie; Li, Xiaolei; Che, Li; Sun, Kun; Cheng, Lili; Huang, Yuedong; Pilo, Maria G; Cigliano, Antonio; Pes, Giovanni M; Pascale, Rosa M; Brozzetti, Stefania; Vidili, Gianpaolo; Porcu, Alberto; Cossu, Antonio; Palmieri, Giuseppe; Sini, Maria C; Ribback, Silvia; Dombrowski, Frank; Tao, Junyan; Calvisi, Diego F; Chen, Ligong; Chen, Xin. - In: HEPATOLOGY. - ISSN 1527-3350. - 66:1(2017), pp. 167-181. [10.1002/hep.29183]

A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis

Pilo, Maria G;Cigliano, Antonio;Pes, Giovanni M;Pascale, Rosa M;Vidili, Gianpaolo;Porcu, Alberto;Cossu, Antonio;Palmieri, Giuseppe;Calvisi, Diego F;
2017-01-01

Abstract

Amplification and/or activation of the c-Myc protooncogene 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 the mTORC1 complex, strongly inhibits c-Myc liver tumor formation. Also, p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/eukaryotic translation initiation factor 4E (4EBP1/eIF4E) signaling cascades downstream of mTORC1 are required for c-Myc-driven tumorigenesis. Intriguingly, microarray expression analysis revealed the upregulation of multiple amino acid transporters, including 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 HCC 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 mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of HCC with activated c-Myc signaling.
2017
A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis / Liu, Pin; Ge, Mengmeng; Hu, Junjie; Li, Xiaolei; Che, Li; Sun, Kun; Cheng, Lili; Huang, Yuedong; Pilo, Maria G; Cigliano, Antonio; Pes, Giovanni M; Pascale, Rosa M; Brozzetti, Stefania; Vidili, Gianpaolo; Porcu, Alberto; Cossu, Antonio; Palmieri, Giuseppe; Sini, Maria C; Ribback, Silvia; Dombrowski, Frank; Tao, Junyan; Calvisi, Diego F; Chen, Ligong; Chen, Xin. - In: HEPATOLOGY. - ISSN 1527-3350. - 66:1(2017), pp. 167-181. [10.1002/hep.29183]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/210365
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