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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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BackgroundInfluentialp62/ SQSTM 1: ‘Jack of all trades’ in health and cancer
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Eng, C. H., Wang, Z., Tkach, D., Toral‐Barza, L., Ugwonali, S., Liu, S., Fitzgerald, S., George, E., Frias, E., Cochran, N. R., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1515617113 · Cited by 229
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Selective Autophagy Regulates Cell Cycle in Cancer Therapy
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BackgroundInfluentialTXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation
Park, H.-S., Song, J.-W., Park, J.-H., Lim, B.-K., Moon, O.-S., Son, H.-Y., Lee, J.-H., Gao, B., Won, Y.-S., & Kwon, H.-J. (2021) · Autophagy · doi:10.1080/15548627.2020.1834711 · Cited by 219
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Mathiassen, S. G., Zio, D. D., & Cecconi, F. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00051 · Cited by 214
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Lin, L., & Baehrecke, E. H. (2015) · Molecular & Cellular Oncology · doi:10.4161/23723556.2014.985913 · Cited by 206
The Autophagy Lysosomal Pathway and Neurodegeneration
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Jiang, X., Overholtzer, M., & Thompson, C. B. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73942 · Cited by 202
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Tumor Suppression and Promotion by Autophagy
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ResultMutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
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BackgroundFOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway
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BackgroundInfluentialHepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation
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Ballesteros‐Álvarez, J., & Andersen, J. K. (2021) · Aging Cell · doi:10.1111/acel.13431 · Cited by 187
“Defective autophagy leads to increased DNA- damaging reactive oxygen species production, genomic instability, and generalized inflammation which can promote tumor initiation (Komatsu et al., 2007; Takamura et al., 2011).”
BackgroundZhou, J., Farah, B. L., Sinha, R. A., Wu, Y., Singh, B. K., Bay, B., Yang, C. S., & Yen, P. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087161 · Cited by 182
p62 at the Interface of Autophagy, Oxidative Stress Signaling, and Cancer
Nezis, I. P., & Stenmark, H. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4394 · Cited by 186
Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy
Liu, T., Liu, X. Z., & Li, W. (2016) · Oncotarget · doi:10.18632/oncotarget.8315 · Cited by 176
“Evidence has shown that autophagy is important in normal growth control and may be defective in cancer cells [66, 67].”
BackgroundNi, H., Boggess, N., McGill, M. R., Lebofsky, M., Borude, P. C., Apte, U. M., Jaeschke, H., & Ding, W. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs133 · Cited by 174
“Mice with the systemic mosaic deletion of Atg5, in which only 10–40% of cells have the deletion of Atg5, develop spontaneous benign tumors in the liver (Takamura et al., 2011).”
BackgroundAutophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia
Watson, A., Riffelmacher, T., Stranks, A. J., Williams, O., de Boer, J., Cain, K., MacFarlane, M., McGouran, J. F., Kessler, B. M., Khandwala, S., et al. (2015) · Cell Death Discovery · doi:10.1038/cddiscovery.2015.8 · Cited by 179
Autophagy-Regulating microRNAs and Cancer
Gözüaçık, D., Akkoç, Y., Öztürk, D. G., & Koçak, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00065 · Cited by 180
“Similarly, Atg5 and Atg7 deletions in the liver resulted in the formation of liver adenomas (108).”
BackgroundRegulation of the Keap1–Nrf2 pathway by p62/SQSTM1
Katsuragi, Y., Ichimura, Y., & Komatsu, M. (2016) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2016.09.005 · Cited by 174
Autophagy in colorectal cancer: An important switch from physiology to pathology
Burada, F. (2015) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v7.i11.271 · Cited by 171
Autophagy and CancerPreprint
Mah, L. Y., & Ryan, K. M. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008821 · Cited by 169
“Moreover, the mosaic loss of Atg5 in other tissues did not have any effect on tumor formation—either benign or malignant (Takamura et al. 2011).”
Autophagy as a pro‐death pathway
Denton, D., Xu, T., & Kumar, S. (2014) · Immunology and Cell Biology · doi:10.1038/icb.2014.85 · Cited by 168
Autophagy and intermittent fasting: the connection for cancer therapy?
Antunes, F., Erustes, A. G., Costa, A. J., Nascimento, A. C., Bincoletto, C., Ureshino, R. P., Pereira, G. J. S., & Smaili, S. S. (2018) · Clinics · doi:10.6061/clinics/2018/e814s · Cited by 179
“However, autophagy impairment due to a mosaic deletion of ATG5 induces benign liver tumors, demonstrating that different tissues have different responses to autophagy impairment (35).”
BackgroundAutophagy in Protein and Organelle TurnoverPreprint
Mizushima, N. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.011023 · Cited by 170
“Of importance, concomitant deletion of p62 reduces the size of the liver tumors, although it does not completely suppress tumor formation (Takamura et al. 2011).”
BackgroundTAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis
Inokuchi‐Shimizu, S., Park, E. J., Roh, Y. S., Yang, L., Zhang, B., Song, J., Liang, S., Pimienta, M., Taniguchi, K., Wu, X., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74068 · Cited by 166
Kang, R., Loux, T., Tang, D., Schapiro, N. E., Vernon, P., Livesey, K. M., Krasinskas, A., Lotze, M. T., & Zeh, H. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113865109 · Cited by 163
“For example, autophagy inhibits the development of breast (27) and liver cancers (28), but it promotes the growth of pancreatic cancer (12) and BCR-Abl–associated leukemia (29).”
BackgroundMolecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma
Vescovo, T., Refolo, G., Vitagliano, G., Fimia, G. M., & Piacentini, M. (2016) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2016.07.019 · Cited by 172
“factor Nrf2, which regulates the expression a variety of cytoprotective genes [54,55].”
BackgroundHou, J., Han, Z.-P., Jing, Y.-Y., Yang, X., Zhang, S.-S., Sun, K., Hao, C., Meng, Y., Yu, F.-H., Liu, X.-Q., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.338 · Cited by 163
Autophagy in hepatic adaptation to stress
Hazari, Y., Bravo-San Pedro, J. M., Hetz, C., Galluzzi, L., & Kroemer, G. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.08.026 · Cited by 151
Khan, A. Q., Rashid, K., AlAmodi, A. A., Agha, M. V., Akhtar, S., Hakeem, I., Raza, S. S., & Shahab Uddin, M. S. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112142 · Cited by 164
McMahon, J. J., Huang, X., Yang, J., Komatsu, M., Yue, Z., Qian, J., Zhu, X. C., & Huang, Y. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2392-12.2012 · Cited by 156
“…invasion (Mizushima et al., 2008), antigen presentation (Deretic and Levine, 2009), tumor suppression (Chen and Debnath, 2010; Komatsu, 2011; Takamura et al., 2011), homeostasis of axons (Komatsu et al., 2007), and neurodegeneration (Komatsu et al., 2005, 2006; Hara et al., 2006;…”
BackgroundThe role of autophagy in hepatocellular carcinoma: friend or foe
Liu, L., Liao, J., He, X., & Li, P. (2017) · Oncotarget · doi:10.18632/oncotarget.17202 · Cited by 158
“This kind of mice developed Atg5-deficient hepatocytes derived tumors only in liver which revealed the hepatic specific antitumor effect of autophagy [87].”
BackgroundResultMitochondria and autophagy: Critical interplay between the two homeostats
Okamoto, K., & Kondo‐Okamoto, N. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.08.001 · Cited by 155
Cicchini, M., Chakrabarti, R., Kongara, S., Price, S. M., Nahar, R., Lozy, F., Zhong, H., Vázquez, A., Kang, Y., & Karantza, V. (2014) · Autophagy · doi:10.4161/auto.34398 · Cited by 159
The role of autophagy induced by tumor microenvironment in different cells and stages of cancer
Yang, X. F., Yu, D., Yan, F., Jing, Y., Han, Z., Sun, K., Liang, L., Hou, J., & Wei, L. (2015) · Cell & Bioscience · doi:10.1186/s13578-015-0005-2 · Cited by 155
“Liver-specific deletion of Atg7 also leads to benign liver tumors in a mice model [102].”
BackgroundAutophagy: More Than a Nonselective Pathway
Reggiori, F., Komatsu, M., Finley, K. D., & Simonsen, A. (2012) · International Journal of Cell Biology · doi:10.1155/2012/219625 · Cited by 161
Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization
Pérez-Hernández, M., Arias, A., Martínez‐García, D., Pérez‐Tomás, R., Quesada, R., & Soto‐Cerrato, V. (2019) · Cancers · doi:10.3390/cancers11101599 · Cited by 158
“For instance, the suppression of ATG proteins in mice has been shown to provoke multiple benign tumors in liver [28].”
BackgroundGlutaminolysis and autophagy in cancer
Villar, V. H., Merhi, F., Djavaheri-Mergny, M., & Durán, R. V. (2015) · Autophagy · doi:10.1080/15548627.2015.1053680 · Cited by 143
Lu, J., He, L., Behrends, C., Araki, M., Araki, K., Jun Wang, Q., Catanzaro, J. M., Friedman, S. L., Zong, W.-X., Fiel, M. I., et al. (2014) · Nature Communications · doi:10.1038/ncomms4920 · Cited by 148
“Conditional deletion of autophagy-related genes in a tissue-specific manner shows severe pathologies in the liver, including hepatomegaly, hepatic steatosis, liver tumors, and oxidative stress 16, 29, 30 .”
Russo, M., & Russo, G. L. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.02.007 · Cited by 148
Autophagy supports genomic stability by degrading retrotransposon RNA
Guo, H., Chitiprolu, M., GAGNON, D. R., Meng, L., Perez‐Iratxeta, C., Lagace, D. C., & Gibbings, D. (2014) · Nature Communications · doi:10.1038/ncomms6276 · Cited by 154
Kudo, Y., Sugimoto, M., Arias, E., Kasashima, H., Cordes, T., Linares, J. F., Durán, Á., Nakanishi, Y., Nakanishi, N., L’Hermitte, A., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.05.018 · Cited by 147
“, 2010), which has been postulated to be a tumor suppressor at least during cancer initiation (Takamura et al., 2011).”
BackgroundAutophagy Required for Hepatitis B Virus Replication in Transgenic Mice
Tian, Y., Sir, D., Kuo, C.-F., Ann, D. K., & Ou, J. J. (2011) · Journal of Virology · doi:10.1128/jvi.06064-11 · Cited by 149
“2A to C), results which were also consistent with the results of previous reports (7, 16, 20).”
ResultFunctional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62
DeJesus, R., Moretti, F., McAllister, G., Wang, Z., Bergman, P., Liu, S., Frias, E., Alford, J., Reece-Hoyes, J. S., Lindeman, A., et al. (2016) · eLife · doi:10.7554/elife.17290 · Cited by 140
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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