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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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Brimson, J. M., Prasanth, M. I., Malar, D. S., Thitilertdecha, P., Kabra, A., Tencomnao, T., & Prasansuklab, A. (2021) · Pharmaceuticals · doi:10.3390/ph14100982 · Cited by 53
Gungor, M. Z., Uysal, M., & Şentürk, Ş. (2022) · Cancers · doi:10.3390/cancers14040940 · Cited by 53
“, wherein genetically engineered mouse models with deletions of autophagy-related genes (ATG5 and ATG7) had impaired autophagy and developed benign tumors in the liver, suggesting that an intact autophagy program in mice may suppress inappropriate proliferation in the liver [110].”
BackgroundLactylation modification in cancer: mechanisms, functions, and therapeutic strategies
Lv, M., Huang, Y., Chen, Y., & Ding, K. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00622-x · Cited by 54
“…there is now also a lot of evidence revealing the bidirectional effect of autophagy in tumors, not only the traditional idea that tumor development can be inhibited through autophagy [62], but also the role of autophagy in promoting cancer, regulating tumor metabolism, and cancer metastasis [63].”
Patulin induces pro-survival functions via autophagy inhibition and p62 accumulation
Guo, X., Dong, Y., Yin, S., Zhao, C., Huo, Y., Fan, L., & Hu, H. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.349 · Cited by 51
Rajas, F., Labrune, P., & Mithieux, G. (2013) · Diabetes & Metabolism · doi:10.1016/j.diabet.2013.03.002 · Cited by 58
“[88] Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, et al.”
BackgroundKwanten, W. J., Vandewynckel, Y., Martinet, W., Winter, B. Y. D., Michielsen, P. P., Hoof, V. O. V., Driessen, A. L. C., Timmermans, J., Bédossa, P., Vlierberghe, H. V., et al. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00418.2015 · Cited by 49
“Hepatocyte-specific knockout of autophagy causes a severe hepatomegaly and hepatic injury as already partially reported in other studies (22, 25, 28, 32, 37, 47, 49).”
ResultManent, J., Banerjee, S., Simoes, R. D. M., Zoranovic, T., Mitsiades, C. S., Penninger, J. M., Simpson, K. J., Humbert, P. O., & Richardson, H. E. (2017) · Oncogene · doi:10.1038/onc.2017.175 · Cited by 50
Jung, D., Khurana, A., Roy, D., Kalogera, E., Bakkum-Gamez, J. N., CHIEN, J. R., & Shridhar, V. (2018) · Scientific Reports · doi:10.1038/s41598-018-20531-w · Cited by 51
MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and suppresses Nrf2 signaling
Tan, C. T., Chang, H., Zhou, Q., Yu, C., Fu, N. Y., Sabapathy, K., & Yu, V. C. K. (2021) · EMBO Reports · doi:10.15252/embr.202050854 · Cited by 49
“…in the livers of hepatocellular carcinoma (HCC) patients in the form of Mallory – Denk bodies and intracellular hyaline granules, is implicated to play a role in the development of HCC (Zatloukal et al , 2002; Mathew et al , 2009; Inami et al , 2011; Takamura et al , 2011; Umemura et al , 2016).”
Therapeutic strategies targeting AMPK-dependent autophagy in cancer cells
Yuan, W., Fang, W., Zhang, R., Lyu, H., Xiao, S., Guo, D. S., Ali, D. W., Michalak, M., Chen, X., Zhou, C., et al. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119537 · Cited by 53
Pimentel, J. M., Zhou, J. Y., & Wu, G. S. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217285 · Cited by 55
Identification of a lung cancer cell line deficient in atg7-dependent autophagy
Mandelbaum, J., Rollins, N., Shah, P., Bowman, D., Lee, J. Y., Tayber, O., Bernard, H., Leroy, P. J., Li, P., Koenig, E. M., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1056966 · Cited by 49
Obesity, autophagy and the pathogenesis of liver and pancreatic cancers
Aghajan, M., Li, N., & Karin, M. (2012) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2011.07008.x · Cited by 48
Farah, B. L., Sinha, R. A., Wu, Y., Singh, B. K., Zhou, J., Bay, B., & Yen, P. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098155 · Cited by 49
“In this connection, recent studies have shown an increase in hepatic steatosis in mice lacking epinephrine [18], as well as in mice that are defective in autophagy [31].”
BackgroundResultSeiwert, N., Neitzel, C., Stroh, S., Frisan, T., Audebert, M., Toulany, M., Kaina, B., & Fahrer, J. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.418 · Cited by 54
“autophagy regulator beclin-1 or deletion of atg5 resulted in increased tumorigenesis.(5,6) On the other hand, autophagy”
BackgroundJi, E., Kim, C., Kang, H., Ahn, S., Jung, M., Hong, Y., Tak, H., Lee, S., Kim, W., & Lee, E. K. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00508-18 · Cited by 50
“For example, autophagy deficiency resulted from the depletion of ATG5 and ATG7, and p62 accumulation promoted tumor growth in hepatocytes (61, 62).”
BackgroundGuarino, M., Kumar, P., Felser, A., Terracciano, L., Guixé‐Muntet, S., Humar, B., Foti, M., Nuoffer, J., St–Pierre, M. V., & Dufour, J. (2020) · Cancers · doi:10.3390/cancers12061407 · Cited by 48
“Hence, since autophagy is, in turn, stimulated by exercise [31] (Figure 8), we attribute the lower steatosis in the CD-HFD exercised group in part to an increase in autophagic processes.”
BackgroundThe role of FOXOs and autophagy in cancer and metastasis—Implications in therapeutic development
Farhan, M., Silva, M., Li, S., Yan, F., Fang, J., Peng, T., Hu, J., Tsao, M., Little, P. J., & Zheng, W. (2020) · Medicinal Research Reviews · doi:10.1002/med.21695 · Cited by 50
“139‐141 In addition, the deletion of vital autophagy genes Atg5 and Atg7 in mice induced the development of benign liver tumors.(142) Possible mechanisms behind the autophagy tumor suppressive role have been already identified.”
BackgroundTargeting the Metabolic Rewiring in Pancreatic Cancer and Its Tumor Microenvironment
Yamamoto, K., Iwadate, D., Kato, H., Nakai, Y., Tateishi, K., & Fujishiro, M. (2022) · Cancers · doi:10.3390/cancers14184351 · Cited by 52
“For example, mosaic deletion of autophagy-related (Atg)-5 in the whole body or liver-specific deletion of Atg7 leads to the spontaneous formation of benign tumors (adenoma) in the mouse liver [83,84].”
BackgroundCao, M., & Zhong, Q. (2015) · Cilia · doi:10.1186/s13630-016-0027-3 · Cited by 50
“Interestingly, only premalignant tumors, but not malignant tumors, are observed in autophagy-deficient mice by knockout of atg5 or atg7, two autophagy essential genes, suggesting a suppressive role of autophagy in cell transformation [87].”
BackgroundRelevance of autophagy to fatty liver diseases and potential therapeutic applications
Yan, S., Huda, N., Khambu, B., & Yin, X. (2017) · Amino Acids · doi:10.1007/s00726-017-2429-y · Cited by 47
“In mouse models with hepatic deletion of Atg7 or Atg5, protein aggregates and subcellular organelles are massively accumulated, leading to liver enlargement, severe liver injury, inflammation, fibrosis, cirrhosis, and tumorigenesis (Komatsu et al. 2005; Takamura et al. 2011; Ni et al. 2014).”
InfluentialDenisenko, T. V., Pivnyuk, A. D., & Zhivotovsky, B. (2018) · Cancers · doi:10.3390/cancers10050148 · Cited by 51
“Consequently, autophagy inhibition, following ATG5 or ATG7 deletion, leads to chronic oxidative stress, accumulation of damaged mitochondria, tissue damage and inflammation which all favor tumor initiation [69,70].”
BackgroundMore Than Skin Deep: Autophagy Is Vital for Skin Barrier Function
Sil, P., Wong, S., & Martinez, J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01376 · Cited by 48
Sircana, A., Paschetta, E., Saba, F., Molinaro, F., & Musso, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071745 · Cited by 46
“A study in autophagy-deficient mice with mosaic deletion of Atg5, showed the ‘double-edged sword’ of autophagy, since it is important for suppression of tumorigenesis in the liver but at the same time it promotes tumor progression because of accumulation of harmful protein aggregated [74].”
BackgroundOn ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns
Agrotis, A., & Ketteler, R. (2019) · Cells · doi:10.3390/cells9010053 · Cited by 47
“For instance, it has been noted that ATG5 defective cells can induce the formation of spontaneous liver tumours [5].”
Background
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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