Evidence map›Paper›PMID 31062368›Full record

ArticleHepatology (Baltimore, Md.)2019

The mTORC2-Akt1 Cascade Is Crucial for c-Myc to Promote Hepatocarcinogenesis in Mice and Humans.

Zhong Xu, Meng Xu, Pin Liu, Shu Zhang, Runze Shang, Yu Qiao, Li Che, Silvia Ribback, Antonio Cigliano, Katja Evert and 6 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Hepatology (Baltimore, Md.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.

0numbers the graph read from it
0cells of the map it votes in
63citing papers in PubMed
4.3field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

63 citing papers in PubMed, 99 citations in OpenAlex.

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3 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors at 4 institutions in 4 countries.

Zhong XuDepartment of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, PR China.
Meng XuDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
Pin LiuDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
Shu ZhangDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
Runze ShangDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
Yu QiaoDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
Li CheDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.ORCID 0000-0001-7971-8725
Silvia RibbackInstitute of Pathology, University of Greifswald, Greifswald, Germany.
Antonio CiglianoInstitute of Pathology, University of Regensburg, Regensburg, Germany.
Katja EvertInstitute of Pathology, University of Regensburg, Regensburg, Germany.
Rosa M PascaleDepartment of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy.
Frank DombrowskiInstitute of Pathology, University of Greifswald, Greifswald, Germany.
Matthias EvertInstitute of Pathology, University of Regensburg, Regensburg, Germany.
Xi ChenDepartment of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China.
Diego F CalvisiInstitute of Pathology, University of Greifswald, Greifswald, Germany.
Xin ChenDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.ORCID 0000-0002-9588-0164
University of California, San Francisco · USGuizhou University · CNUniversität Greifswald · DEUniversity of Sassari · IT

Funding

UCSF Liver Core CenterP30DK026743 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Holger Willenbring · 1986 to 2026
$30.7M
Molecular Genetics of Liver CancersR01CA136606 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHEN, XIN · 2009 to 2016
$2.6M
Glutamine catabolism in c-Myc driven liver tumor developmentR21CA198490 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHEN, XIN · 2015 to 2016
$379k
China Scholarship Council 201408525080China Scholarship Council 201606280273China Scholarship Council 201703170154China Scholarship Council 201706240075National Natural Science Foundation of China 81860439NCI NIH HHS R01 CA136606NCI NIH HHS R21 CA198490NIDDK NIH HHS P30 DK026743
6 · The paper itself

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.

Indexed as

CarcinogenesisAnimalsCarcinoma, HepatocellularHumansLiver NeoplasmsMechanistic Target of Rapamycin Complex 2MiceProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-mycAKT1 protein, humanAkt1 protein, mouseMechanistic Target of Rapamycin Complex 2MYC protein, humanMyc protein, mouseProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-myc

Identifiers

PMID31062368
PMCPMC7195156
OpenAlexW2944267355

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.