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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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Eşrefoğlu, M. (2024) · World Journal of Gastroenterology · doi:10.3748/wjg.v30.i24.3036 · Cited by 8
“Accordingly, defects of autophagic genes lead to increased production of reactive oxygen species (ROS) and accumulation of damaged organelles and DNA which in turn promote metabolic reprogramming and induce tumorigenesis[35].”
InfluentialYe, G. (2024) · American Journal of Cancer Research · doi:10.62347/ujvp4361 · Cited by 8
Celada, S. I., Li, G., Celada, L. J., Kanagasabai, T., Lu, W., Brown, L. K., Mark, Z. A., Izban, M. G., Ballard, B. R., Zhou, X., et al. (2024) · Science Signaling · doi:10.1126/scisignal.adk4122 · Cited by 8
The Ways to Die: Cell Death in Liver Pathophysiology
Cao, P., Jaeschke, H., Ni, H., & Ding, W. (2025) · Seminars in Liver Disease · doi:10.1055/a-2576-4332 · Cited by 11
Wolska, W., Gutowska, I., Wszołek, A., & Żwierełło, W. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104742 · Cited by 12
“However, mutations in essential genes regulating autophagy, such as Ambra1 [32], ATG5 [33], and ATG7 [34], may promote the onset of tumorigenesis by impairing the mechanisms that eliminate damaged cells.”
Autophagy modulation in cancer
Guilbaud, E., Ryan, K. M., Green, D. R., & Galluzzi, L. (2026) · Nature Reviews Drug Discovery · doi:10.1038/s41573-026-01449-9 · Cited by 11
“…develop spontaneous neoplasms that progress more slowly in the context of the concomitant deletion of Sqstm1 (which encodes a key autophagy adaptor) 65 ; (2) mice undergoing KRAS G12D -driven and BRAF V600E -driven pulmonary carcinogenesis in the context of conditional Atg5 or Atg7 deletion,…”
Yousefi, P., Tabibzadeh, A., Jwaziri, A. K., Mehrjoo, M., Akhavan, M., Allahqoli, L., & Salehiniya, H. (2024) · Immunity Inflammation and Disease · doi:10.1002/iid3.1182 · Cited by 7
“19 It was also found that ATG5 point mutations are identified in gastric cancer, colorectal cancer, and HCC. 43 In 2019, Shen and Lin 44 evaluated the relationship between 14 variants of ATGs (ATG3, ATG5, ATG10, ATG12, ATG16L1) in HCC development.”
BackgroundTargeting STAT3-mediated autophagy with small molecules in cancer treatment – A comprehensive review
Azad, S. M. A. K., Meem, J. N., Shaikat, A. H., Ali, M. L., Arif, M. S. R., Sabrin, S., Mostaq, M. S., Haque, M. R. U., Amin, M. N., & Mahmud, M. A. (2024) · Clinical Traditional Medicine and Pharmacology · doi:10.1016/j.ctmp.2024.200174 · Cited by 8
Autophagy and Tumorigenesis in Drosophila
Khezri, R., & Rusten, T. E. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-23629-8_7 · Cited by 8
Meng, Q., Zhang, Y., & Hu, L. G. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00886 · Cited by 8
Bortolami, M., Comparato, A., Benna, C., Errico, A., Maretto, I., Pucciarelli, S., Cillo, U., & Farinati, F. (2020) · PLoS ONE · doi:10.1371/journal.pone.0244356 · Cited by 8
“Research using mouse models shows that deletions of specific Atg genes (autophagy-related genes) induce a greater onset of hepatocellular carcinoma (HCC) [10].”
BackgroundAgrawal, Y., Sharma, T., Islam, S., Nadkarni, K. S., & Santra, M. K. (2022) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2022.106228 · Cited by 9
MIEAP and ATG5 are tumor suppressors in a mouse model of BRAFV600E-positive thyroid cancer
Hamada, K., Kurashige, T., Shimamura, M. I., Arakawa, H., Nakamura, Y., & Nagayama, Y. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.932754 · Cited by 8
“Accumulation of deformed and dysfunctional mitochondria was also observed in liver adenomas in liver–specific Atg7 mice mentioned above (34, 35).”
BackgroundWang, S., Wang, G., Lu, S., Zhang, J., Zhang, W., Han, Y., Cai, X. T., Zhuang, Y., Pu, F., Yan, X., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0276904 · Cited by 8
“In addition, the impairment of autophagy initiates spontaneous liver tumorigenesis in aged mice [30, 31].”
BackgroundNuta, G. C., Gilad, Y., Gershoni, M., Sznajderman, A., Schlesinger, T., Bialik, S., Eisenstein, M., Pietrokovski, S., & Kimchi, A. (2018) · Autophagy · doi:10.1080/15548627.2018.1525476 · Cited by 8
“Attenuation of autophagy at this stage leads to accumulation of defective mitochondria, promoting the production of reactive oxygen species (ROS) and DNA damage, which leads to tumorigenesis [4,5].”
BackgroundErcan, C., Coto‐Llerena, M., Gallon, J., Fourie, L., Marinucci, M., Hess, G. F., Vosbeck, J., Taha‐Mehlitz, S., Boldanova, T., Meier, M., et al. (2022) · Communications Medicine · doi:10.1038/s43856-022-00074-y · Cited by 8
Wang, Y., Liu, S., Ni, M., Chen, Y., Chen, R., Wang, J., Jiang, W., Zhou, T., Fan, S., Chang, J., et al. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.04.238 · Cited by 7
Dual Role of Lysosome in Cancer Development and Progression
Chen, X., Yang, Q., Chen, W., Chen, Z.-W., Guo, G.-H., Zhang, X., Sun, X.-M., Shen, T., Xiao, F., & Li, Y. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2911393 · Cited by 8
“Moreover, a growing body of findings have shown that a large number of autophagy-related genes (e.g., ATG5 , ATG12 ) are mutated or inactivated to evade the tumor suppressive effects of autophagy as tumor development progresses [88].”
Hamamoto, K., Liang, X., Ito, A., Lanza, M. R., Bui, V., Zhang, J., Opozda, D. M., Hattori, T., Chen, L., Haddock, D., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.115016 · Cited by 7
Lei, L., Zhang, J., Wei, R., Dong, B., Wang, X., & Zhou, Y. (2025) · Discover Oncology · doi:10.1007/s12672-025-02802-x · Cited by 8
“In a similar manner, the deletion of ATG5 in mice resulted in the production of benign liver tumors [36].”
Exploiting autophagy and related pathways: pioneering new horizons in cataract therapy
Hashemi, M., Asheghabadi, P. S., Moassesfar, M., Mohammadi, R. M., Rafedoust, N., Razeh, M., Esfahaniolasl, Y., Mirzayi, M., Keikhavani, S., Tajbakhsh, K., et al. (2025) · APOPTOSIS · doi:10.1007/s10495-025-02134-9 · Cited by 7
“Indeed, removing two autophagy regulators has been demonstrated to cause damaged proteins and organelles to accumulate, raising the production of ROS and causing intracellular damage [24–26].”
KRT4 suppresses oral squamous cell carcinoma development by reducing ATG4B-mediated autophagy
LI, X., WANG, Y., Fang, J., WANG, Z., Tao, X., Xia, J., & Cheng, B. (2021) · Biocell · doi:10.32604/biocell.2021.014844 · Cited by 7
Liu, X., Zhou, C., Cheng, B., Xiong, Y., Zhou, Q., Wan, E., & He, Y. (2024) · Scientific Reports · doi:10.1038/s41598-024-71123-w · Cited by 13
“According to Takamura et al. 48 , mice with liver-specific Atg7−/− and systemic mosaic deletion of Atg5 develop benign hepatic adenomas.”
BackgroundVPS34 in Autophagy, Cancer and Cancer Therapy
Bartolini, E., Janji, B., & Gao, R. (2026) · doi:10.20944/preprints202603.0323.v1 · Cited by 1
“Liver-specific deletion of downstream proteins of VPS34 (Atg5 or Atg7) leads to benign liver adenomas [91] and accelerates tumorigenesis once hydrides with other oncogenic drivers [92].”
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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