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The mTORC2-Akt1 Cascade Is Crucial for c-Myc to Promote Hepatocarcinogenesis in Mice and Humans.
Xu, Zhong; Xu, Meng; Liu, Pin; Zhang, Shu; Shang, Runze; Qiao, Yu; Che, Li; Ribback, Silvia; Cigliano, Antonio; Evert, Katja; Pascale, Rosa M; Dombrowski, Frank; Evert, Matthias; Chen, Xi; Calvisi, Diego F; Chen, Xin.
Afiliação
  • Xu Z; Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, PR China.
  • Xu M; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
  • Liu P; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
  • Zhang S; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University.
  • Shang R; Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China.
  • Qiao Y; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
  • Che L; Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China.
  • Ribback S; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
  • Cigliano A; Department of Radiation Oncology and Department of Head & Neck Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
  • Evert K; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
  • Pascale RM; Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, PR China.
  • Dombrowski F; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
  • Evert M; Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, PR China.
  • Chen X; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
  • Calvisi DF; Institute of Pathology, University of Greifswald, Greifswald, Germany.
  • Chen X; Institute of Pathology, University of Regensburg, Regensburg, Germany.
Hepatology ; 70(5): 1600-1613, 2019 11.
Article em En | MEDLINE | ID: mdl-31062368
ABSTRACT
Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with limited treatment options. The c-Myc transcription factor is a pivotal player in hepatocarcinogenesis, but the mechanisms underlying c-Myc oncogenic activity in the liver remain poorly delineated. Mammalian target of rapamycin complex 2 (mTORC2) has been implicated in cancer by regulating multiple AGC kinases, especially AKT proteins. In the liver, AKT1 and AKT2 are widely expressed. While AKT2 is the major isoform downstream of activated phosphoinositide 3-kinase and loss of phosphatase and tensin homolog-induced HCC, the precise function of AKT1 in hepatocarcinogenesis is largely unknown. In the present study, we demonstrate that mTORC2 is activated in c-Myc-driven mouse HCC, leading to phosphorylation/activation of Akt1 but not Akt2. Ablation of Rictor inhibited c-Myc-induced HCC formation in vivo. Mechanistically, we discovered that loss of Akt1, but not Akt2, completely prevented c-Myc HCC formation in mice. Silencing of Rictor or Akt1 in c-Myc HCC cell lines inhibited phosphorylated forkhead box o1 expression and strongly suppressed cell growth in vitro. In human HCC samples, c-MYC activation is strongly correlated with phosphorylated AKT1 expression. Higher expression of RICTOR and AKT1, but not AKT2, is associated with poor survival of patients with HCC. In c-Myc mice, while rapamycin, an mTORC1 inhibitor, had limited efficacy at preventing c-Myc-driven HCC progression, the dual mTORC1 and mTORC2 inhibitor MLN0128 effectively promoted tumor regression by inducing apoptosis and necrosis.

Conclusion:

Our study indicates the functional contribution of mTORC2/Akt1 along c-Myc-induced hepatocarcinogenesis, with AKT1 and AKT2 having distinct roles in HCC development and progression; targeting both mTORC1 and mTORC2 may be required for effective treatment of human HCC displaying c-Myc amplification or overexpression.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article