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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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“The role of autophagy in malignancy is complicated, with conflicting reports on its role in different contexts([23-27]).”
BackgroundInterplay of autophagy and cancer stem cells in hepatocellular carcinoma
Wong, M. M.-T., Chan, H.-Y., Aziz, N. A., Ramasamy, T. S., Bong, J. J., Ch’ng, E. S., Armon, S., Peh, S., & Teow, S. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06334-9 · Cited by 28
Autophagy in Cancer Therapy—Molecular Mechanisms and Current Clinical Advances
Ganzleben, I., Neurath, M. F., & Becker, C. (2021) · Cancers · doi:10.3390/cancers13215575 · Cited by 30
“However, the resulting neoplastic lesions were benign and not malignant [40].”
BackgroundATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis
Long, J. S., Kania, E., McEwan, D. G., Barthet, V. J. A., Brucoli, M., Ladds, M. J. G. W., Nössing, C., & Ryan, K. M. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113465119 · Cited by 28
Transient Systemic Autophagy Inhibition Is Selectively and Irreversibly Deleterious to Lung Cancer
Khayati, K., Bhatt, V. D., Lan, T., Alogaili, F., Wang, W., Lopez, E., Hu, Z. S., Gokhale, S., Cassidy, L. D., Narita, M., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1039 · Cited by 28
Emerging roles of mitochondria and autophagy in liver injury during sepsis
Aki, T., Unuma, K., & Uemura, K. (2017) · Cell Stress · doi:10.15698/cst2017.11.110 · Cited by 28
“Development of multiple liver tumors has also been reported in mice with partial deletion of atg5 [8].”
BackgroundWang, Y., Sun, L., Qiu, W., Qi, W., Qi, Y., Liu, Z., Liu, S., & Lv, J. (2020) · Aging · doi:10.18632/aging.103013 · Cited by 28
“Some studies have shown that autophagy might protect the genome from damage and inhibit tumorigenesis, but this process also activates metabolic stress responses [19, 20].”
Yu, X., Elfimova, N., Müller, M., Bachurski, D., Koitzsch, U., Drebber, U., Mahabir, E., Hansen, H. P., Friedman, S. L., Klein, S., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.02.013 · Cited by 27
“Moreover, inhibition of autophagy in hepatocytes leads to development of hepatocellular carcinoma.(23,24) Therefore, the therapeutic impact of inhibition of miR-29a release from HSC to the bloodstream should be ideally shown on experimental fibrosis in HSC-specific, autophagy-deficient mice.”
BackgroundAutophagy and oxidative stress in solid tumors: Mechanisms and therapeutic opportunities
Carretero-Fernández, M., Cabrera-Serrano, A. J., Sánchez‐Maldonado, J. M., Ruiz-Durán, L., Jiménez-Romera, F., García‐Verdejo, F. J., González‐Olmedo, C., Cardús, A., Díaz-Beltrán, L., Gutiérrez‐Bautista, J. F., et al. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104820 · Cited by 37
“For instance, in models lacking ATG5 or ATG7 , p62 aggregation promotes ROS accumulation and tumorigenesis (Takamura et al., 2011).”
Autophagy in HCV Infection: Keeping Fat and Inflammation at Bay
Vescovo, T., Refolo, G., Romagnoli, A., Ciccosanti, F., Corazzari, M., Alonzi, T., & Fimia, G. M. (2014) · BioMed Research International · doi:10.1155/2014/265353 · Cited by 27
“liver damage, which leads to the development of hepatic cancer via persistent activation of the Nrf2 pathway [117–119].”
BackgroundWang, R., Shen, Z., Liu, Y., Yin, M.-L., Zheng, W., Wu, B., Liu, T., & Song, H. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3121 · Cited by 27
“Swelling and structural damage of mitochondria in the liver of transgenic mice with autophagic defects have been reported (33).”
Yu, Z., Ma, J., Li, X., Liu, Y., Li, M., Wang, L., Zhao, M., He, H., Zhang, Y., Rao, Q., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-28369-y · Cited by 27
Sun, S., Wu, Y., Fu, H., Yang, M., Ge, X., Zhu, J. X., Xuan, F., & Wu, X. (2019) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2018.12.079 · Cited by 27
Anti-tumor immunity influences cancer cell reliance upon ATG7
Arensman, M. D., Yang, X. S., Zhong, W., Bisulco, S., Upeslacis, E., Rosfjord, E. C., Deng, S., Abraham, R. T., & Eng, C. H. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1800162 · Cited by 27
“Other studies have found that autophagy loss can promote tumor growth.(20,21)”
BackgroundNanotherapeutics in autophagy: a paradigm shift in cancer treatment
Negi, S., Chaudhuri, A., Kumar, D. N., Dehari, D., Singh, S. K., & Agrawal, A. K. (2022) · Drug Delivery and Translational Research · doi:10.1007/s13346-022-01125-6 · Cited by 27
“In contrast to the embryonic death in the case of BECN1, it was found that mice with systemic mosaic deletion of Atg5 and liverspecific Atg7 − / − mice develop benign liver adenomas [21, 22].”
BackgroundCrosstalk between cGAS-STING pathway and autophagy in cancer immunity
Lu, Q., Chen, Y., Li, J., Zhu, F., & Zheng, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1139595 · Cited by 28
“Defects in autophagy in vivo have been linked to an increased risk of tumor initiation (92).”
BackgroundHydrogen Sulfide and Liver Health: Insights into Liver Diseases
Nguyen, T. T. P., Nguyen, P. L., Park, S., Jung, C. H., & Jeon, T. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0404 · Cited by 27
Mitophagy: Therapeutic Potentials for Liver Disease and Beyond
Lee, S., & Js, K. (2014) · Toxicological Research · doi:10.5487/tr.2014.30.4.243 · Cited by 26
“Indeed, in livers of autophagy-deficient mice, mitochondrial damage is evident such as swelling and ROS formation (5).”
BackgroundTargeting autophagy in gastrointestinal malignancy by using nanomaterials as drug delivery systems
Raju, G. S. R., Pavitra, E., Merchant, N., Lee, H., Prasad, G. L. V., Nagaraju, G. P., Huh, Y. S., & Han, Y. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.01.044 · Cited by 27
The interplay between probiotics and host autophagy: mechanisms of action and emerging insights
Sadeghloo, Z., Nabavi-Rad, A., Zali, M. R., Klionsky, D. J., & Yadegar, A. (2024) · Autophagy · doi:10.1080/15548627.2024.2403277 · Cited by 26
“Mitochondrial damage, SQSTM1 aggregation, and oxidative stress in mice with systemic atg5 deletion and liver-specific knockout of Atg7 promote tumor progression in the liver [201].”
Farah, B. L., Yen, P. M., & Koeberl, D. D. (2019) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2019.11.005 · Cited by 26
“Moreover, ATG7 and VPS34 liver knockout, ATG5 mosaic deletion [58] and BCN1 haploinsufficent mice all showed evidence of increased hepatic triglyceride levels, suggesting the important role of lipophagy in normal lipid metabolism.”
BackgroundRole of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress
Pecoraro, A., Pagano, M., Russo, G., & Russo, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197334 · Cited by 26
Dual Roles of Autophagy and Their Potential Drugs for Improving Cancer Therapeutics
Shin, D. W. (2020) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2020.155 · Cited by 27
Yan, S., Khambu, B., Chen, X., Dong, Z., Guo, G. L., & Yin, X. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.10.011 · Cited by 26
“Autophagy deficiency in the liver causes hepatomegaly, chronic injury, and tumorigenesis.(9,10) Mechanically, consistent activation of NRF2 by sequestosome-1 (SQSTM1) is critical for pathologic changes induced by hepatic Atg5 or Atg7 deletion,(9,12,13) yet how SQSTM1-NRF2 signaling leads to hepatocyte death remains un…”
BackgroundNlp promotes autophagy through facilitating the interaction of Rab7 and FYCO1
Xiao, W., Yeerken, D., Li, J., Li, Z., Jiang, L., Li, D., Fu, M., Ma, L., Song, Y., Zhang, W., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00543-1 · Cited by 26
“Liver-specific deletion of ATG5 and ATG17 mice display hepatic metabolic dysfunction which results in liver injury, hepatomegaly, inflammation, fibrosis and benign tumors.(33,41) When autophagy is impaired, p62 accumulates and binds to KEAP1, which negatively regulates and stabilizes NRF2, that leads to a deleteriousl…”
BackgroundSenescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver
Huda, N., Khambu, B., Liu, G., Nakatsumi, H., Yan, S., Chen, X., Ma, M., Dong, Z., Nakayama, K. I., & Yin, X. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.04.003 · Cited by 27
Interactions of Autophagy and the Immune System in Health and Diseases
Pant, A., Yao, X., Lavedrine, A., Viret, C., Dockterman, J., Chauhan, S. C., Shi, C.-S., Manjithaya, R. R., Cadwell, K., Kufer, T. A., et al. (2022) · Autophagy Reports · doi:10.1080/27694127.2022.2119743 · Cited by 28
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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