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Autophagy-deficient mice develop multiple liver tumors
Open accessAbstract
Autophagy is a major pathway for degradation of cytoplasmic proteins and organelles, and has been implicated in tumor suppression. Here, we report that mice with systemic mosaic deletion of Atg5 and liver-specific Atg7⁻/⁻ mice develop benign liver adenomas. These tumor cells originate autophagy-deficient hepatocytes and show mitochondrial swelling, p62 accumulation, and oxidative stress and genomic damage responses. The size of the Atg7⁻/⁻ liver tumors is reduced by simultaneous deletion of p62. These results suggest that autophagy is important for the suppression of spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression.
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“we also observed the accumulation of p62/SQSTM [a hallmark of defective autophagy (Klionsky et al., 2012; Mizushima et al., 2010; Takamura et al., 2011)] in the Ulk1−/− RPE indicating that the enzymatic production of LC3-II was likely due to POS induced LAP as opposed to classical autophagy.”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Takamura et al., 2011
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“ATG7 deletion in mouse liver facilitates HCC development (Takamura et al., 2011).”
BackgroundNew Visions on Natural Products and Cancer Therapy: Autophagy and Related Regulatory Pathways
Martelli, A., Omrani, M., Zarghooni, M., Citi, V., Brogi, S., Calderone, V., Sureda, A., Lorzadeh, S., Rosa, S. C. D. S., Grabarek, B. O., et al. (2022) · Cancers · doi:10.3390/cancers14235839 · Cited by 40
Reactive Oxygen Species Modulation in the Current Landscape of Anticancer Therapies
Li, J., Justin, L. Y. S., Eu, J. Q., Chan, A. K. M. H., Goh, B. C., Wang, L., & Wong, A. L. (2024) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0445 · Cited by 42
“Accordingly, inhibition of autophagy via autophagy-related (ATG) proteins ATG5 or ATG7 deletion results in accumulation of damaged mitochondria, excess oxidative stress, and tumor initiation (Karantza-Wadsworth et al., 2007; Mathew et al., 2007; Takamura et al., 2011).”
Role of autophagy in the maintenance and function of cancer stem cells
Vitale, I., Manic, G., Dandrea, V., & Maria, R. D. (2015) · The International Journal of Developmental Biology · doi:10.1387/ijdb.150082iv · Cited by 39
“, 2007) and the deletion of Atg5 or Atg7 favors the development of liver hepatomas(Takamura et al., 2011).”
BackgroundInfluentialExploiting Nanomaterial‐Mediated Autophagy for Cancer Therapy
Wei, W., Rosenkrans, Z. T., Luo, Q., Lan, X., & Cai, W. (2018) · Small Methods · doi:10.1002/smtd.201800365 · Cited by 41
Bekos, C., Muqaku, B., Dekan, S., Horvat, R., Polterauer, S., Gerner, C., Aust, S., & Pils, D. (2019) · Cancers · doi:10.3390/cancers11050698 · Cited by 37
“Recently, in a mouse model ATG5 deficiency has been shown to be involved in tumorigenesis [48].”
BackgroundMonitoring autophagy in cancer: From bench to bedside
Long, M., & McWilliams, T. G. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.05.016 · Cited by 30
Bae, J., Jang, Y., Kim, H., Mahato, K., Schaecher, C., Kim, I. M., Kim, E., & Ro, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-50965-9 · Cited by 38
A tumor suppressor DLC1: The functions and signal pathways
Zhang, Y., & Li, G. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.29402 · Cited by 38
“Autophagy is often thought to act as a tumor inhibitor in the early stages of cancer, whereas autophagy promotes advanced cancer progression (Takamura et al., 2011).”
BackgroundWang, Q., Liu, H.-J., Zhao, Z., Zhang, Y., Wang, Z., Jiang, T., & Bao, Z. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s238332 · Cited by 37
“example, Takamura et al found that various liver tumors developed in a mouse model with deletion of autophagyrelated gene 5 (Atg5), which exhibited accumulation of p62, due to deficiency in autophagy, promoting tumor progression.(6) Various relationships between cancer and autophagy have been described.”
Vescovo, T., Pagni, B., Piacentini, M., Fimia, G. M., & Antonioli, M. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00047 · Cited by 40
“To this regard, Tanaka-Nakanishi et al. (2014) reported that HBz suppresses the pro-apoptotic protein Bim by negatively regulating its FoxO3a-mediated transcription.”
BackgroundSPIB promotes anoikis resistance via elevated autolysosomal process in lung cancer cells
Zhang, H., Wang, G., Zhou, R., Li, X., Sun, Y., Li, Y., Du, W., Yan, X., Yang, J., Chang, X., et al. (2020) · FEBS Journal · doi:10.1111/febs.15272 · Cited by 38
Autophagy: Mechanisms, regulation, and its role in tumorigenesis
Parkhitko, A. A., Favorova, O. O., & Henske, E. P. (2013) · Biochemistry (Moscow) · doi:10.1134/s0006297913040044 · Cited by 39
Wu, H., Xie, C., Lv, J., Qi, H.-Q., Wang, F., Zhang, S., Fang, Q., Wang, F., Lu, Y., & Yin, Z. (2018) · Laboratory Investigation · doi:10.1038/s41374-018-0062-3 · Cited by 37
The TRAF2-p62 axis promotes proliferation and survival of liver cancer by activating mTORC1 pathway
Liang, X., Yao, J., Cui, D., Zheng, W., Liu, Y., Lou, G., Ye, B., Shui, L., Sun, Y., Zhao, Y., et al. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01164-7 · Cited by 37
Dashti, Z. J. S., Yousefi, Z., Kiani, P., Taghizadeh, M., Maleki, M. H., Borji, M., Vakili, O., & Shafiee, S. M. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155811 · Cited by 38
Role of autophagy in cancer prevention, development and therapy
Helgason, G. V., Holyoake, T. L., & Ryan, K. M. (2013) · Essays in Biochemistry · doi:10.1042/bse0550133 · Cited by 38
Modeling progressive non-alcoholic fatty liver disease in the laboratory mouse
Riordan, J. D., & Nadeau, J. H. (2014) · Mammalian Genome · doi:10.1007/s00335-014-9521-3 · Cited by 36
“They allow a level of experimental control not possible with human studies, an essential factor in studying a complex, multifactorial condition such as NAFLD.”
BackgroundCorrea, R. J. M., Valdés, Y. R., Shepherd, T. G., & DiMattia, G. E. (2015) · Journal of Ovarian Research · doi:10.1186/s13048-015-0182-y · Cited by 38
“Furthermore, the tumor spectrum of Becn1 mice differs from other mouse models of autophagy disruption: Becn1 mice develop hepatocellular carcinomas, lung carcinomas, and lymphomas [9] whereas tissue-specific deletion of Atg7 or mosaic deletion of Atg5 led to only benign liver adenomas [49] and never the hepatocellular…”
Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay
Seiliez, I., Belghit, I., Gao, Y., Cassy, S., Dias, K., Cluzeaud, M., Rémond, D., Hafnaoui, N., Salin, B., Camougrand, N. M., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1117732 · Cited by 37
Novel pharmacological modulators of autophagy: an updated patent review (2012-2015)
Ha, J., & Kim, J. (2016) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2016.1217996 · Cited by 37
“In addition, accumulation of autophagy adaptor protein, p62/Sequestosome 1 (p62/SQSTM1), as a result of the inhibition of autophagy, was reported to be responsible for the tumorigenesis [42,43].”
BackgroundUbiquitin pathways regulate the pathogenesis of chronic liver disease
Park, J.-S., Ma, H., & Roh, Y. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114764 · Cited by 40
Sakaguchi, H., Tsuchiya, H., Kitagawa, Y., Tanino, T., Yoshida, K., Uchida, N., & Shiota, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020711 · Cited by 37
“Moreover, mice lacking Atg5 or Atg7 have been reported to develop liver cancers [29].”
BackgroundZhang, X., Wu, W. K. K., Xu, W., Man, K., Wang, X., Han, J., Leung, W. Y., Wu, R., Liu, K., & Yu, J. Q. (2017) · Theranostics · doi:10.7150/thno.19068 · Cited by 37
“The accumulation of ubiquitinated proteins is one of the hallmarks of autophagy deficiency (18).”
BackgroundEmerging role of LETM1/GRP78 axis in lung cancer
Tran, Q., Lee, H., Jung, J. H., Chang, S.-H., Shrestha, R., Kong, G., Park, J., Kim, S., Park, K., Rhee, H., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04993-5 · Cited by 37
“Regarding cancer initiation, autophagy performs an anti-tumorigenic role by clearing dysfunctional mitochondria and abnormal proteins [10, 11].”
BackgroundThe involvement of ROS-regulated programmed cell death in hepatocellular carcinoma
Cai, H., Meng, Z., & Yu, F. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104361 · Cited by 37
Mechanism and role of regulated cell death in tumor immunity and immunotherapy
Hu, J., Li, Y., Lian, B., Mao, Y., & Zhao, L. (2025) · 癌症：英文版 · doi:10.1002/cac2.70064 · Cited by 40
“…shift reveals autophagy’s dual role in cancer: defective autophagy initiates tumors (e.g., ATG5 deletion accelerates KRAS -driven lung carcinogenesis [262]), whereas advanced tumors exploit intact autophagy to sustain their malignant (e.g., liver-specific ATG7 knockout limits HCC malignancy [263]).”
Chen, Y., Wei, H., Liu, F., & Guan, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.526335 · Cited by 37
Metadata
- Authors
- Takamura, A., Komatsu, M., Hara, T., Sakamoto, A., Kishi, C., Waguri, S., Eishi, Y., Hino, O., Tanaka, K., & Mizushima, N.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Fukushima Medical University (JP)
- Juntendo University (JP)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-04-15
- Volume
- 25
- Issue
- 8
- Pages
- 795-800
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3078705
- OpenAlex
- W2116836791
- Cited by
- 1,342
- References
- 39
- Citations by year
- 2026: 34 · 2025: 68 · 2024: 87 · 2023: 66 · 2022: 110 · 2021: 129 · 2020: 108 · 2019: 120 · 2018: 93 · 2017: 80 · 2016: 95 · 2015: 77 · 2014: 85 · 2013: 106 · 2012: 57
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21659045, 21000012)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- autophagy, liver tumors, ATG5, ATG7, p62, tumor suppression, mitochondrial swelling, oxidative stress, genomic damage, spontaneous tumor development, hepatocytes
- MeSH terms
- Autophagy-Related Protein 5, Autophagy-Related Protein 7, Animals, Autophagy, Immunohistochemistry, Liver Neoplasms, Mice, Mutant Strains, Mice, Transgenic, Microscopy, Electron, Microtubule-Associated Proteins, Transcription Factors, Polymerase Chain Reaction, Adenoma, Liver Cell, Oxidative Stress, Mice, Transcription Factor TFIIH
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