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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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Leonardi, L., Sibéril, S., Alifano, M., Cremer, I., & Joubert, P.-E. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.743780 · Cited by 16
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“In mice deficient for ATG5 and ATG7, we also observed the development of benign liver tumors, which are associated with genomic damage responses [66].”
Degradative and Non-Degradative Roles of Autophagy Proteins in Metabolism and Metabolic Diseases
Kuramoto, K., & He, C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.844481 · Cited by 16
“, 2003), systemic mosaic Atg5 deletion mice (Takamura et al., 2011), and liver- or pancreas-specific Atg5 or”
BackgroundThe cross-talk of autophagy and apoptosis in breast carcinoma: implications for novel therapies?
Seyrek, K., Wohlfromm, F., Espe, J., & Lavrik, I. N. (2022) · Biochemical Journal · doi:10.1042/bcj20210676 · Cited by 15
Unravelling the complexity of lncRNAs in autophagy to improve potential cancer therapy
Wang, Y., Fu, Y., Lu, Y., Chen, S., Zhang, J., Liu, B., & Yuan, Y. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188932 · Cited by 14
Walweel, N., & Aydin, Ö. F. (2024) · ACS Omega · doi:10.1021/acsomega.4c02234 · Cited by 15
Rahdan, F., Abedi, F., Dianat‐Moghadam, H., Sani, M. Z., Taghizadeh, M., & Alizadeh, E. (2024) · Clinical and Experimental Medicine · doi:10.1007/s10238-024-01527-5 · Cited by 15
“Specific KO of ATG5 impeded autophagy in the liver, caused oxidative DNA damage, and resulted in the growth of benign hepatic tumors with no discernible carcinoma [36].”
InfluentialAutophagy as a potential therapeutic target in regulating improper cellular proliferation
Kumar, P., Choudhary, A., Kinger, S., Jagtap, Y. A., Prajapati, V. K., Chitkara, D., Chinnathambi, S., Verma, R. K., & Mishra, A. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1579183 · Cited by 17
“Apart from this, the deletion of ATG7 can trigger tumorigenesis in the liver (Takamura et al., 2011).”
Noura, M., Matsuo, H., Koyama, A., Adachi, S., & Masutani, H. (2020) · FEBS Open Bio · doi:10.1002/2211-5463.12908 · Cited by 14
Construction Prognosis Model Based on Autophagy-Related Gene Signatures in Hepatocellular Carcinoma
Wang, J., Miao, Y., Ran, J., Yang, Y., Guan, Q., & Mi, D. (2020) · Biomarkers in Medicine · doi:10.2217/bmm-2020-0170 · Cited by 14
Köksal, A. R., Thevenot, P., Aydın, Y., Núñez, K., Sandow, T. A., Widmer, K., Nayak, L., Scott, J., Delk, M., Moehlen, M., et al. (2022) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s376210 · Cited by 14
“Liver-specific deletion of autophagy genes (ATG5 or ATG7) caused a spectrum of hepatic diseases including steatosis, inflammation, fibrosis, hepatomegaly, and HCC.(11,12) Moreover, impaired autophagy promotes tumorigenesis in Beclin1 or LkB1 gene knockout mice livers.”
BackgroundInfluentialMechanism and Physiological Significance of Growth Factor-Related Autophagy
Li, T. Y., Lin, S., & Lin, S. (2013) · Physiology · doi:10.1152/physiol.00023.2013 · Cited by 16
“Loss of autophagy by genetically targeting core autophagy machinery is also reported to result in tumor development (77, 108, 140).”
BackgroundABT-737, a Bcl-2 Selective Inhibitor, and Chloroquine Synergistically Kill Renal Cancer Cells
Yin, P., Jia, J.-P., Li, J., Song, Y., Zhang, Y., & Chen, F. (2016) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/096504016x14587366983838 · Cited by 14
“However, autophagy is also considered to have a cancer-suppressing role (31).”
BackgroundEmerging Players in Autophagy Deficiency-Induced Liver Injury and Tumorigenesis
Yang, H., Ni, H., & Ding, W. (2019) · Gene Expression · doi:10.3727/105221619x15486875608177 · Cited by 14
Cho, J., Lee, Y., Starost, M. F., Mansfield, B. C., & CHOU, J. Y. (2019) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12056 · Cited by 14
“Studies have shown that the autophagy impairment leads to accumulation of p62, an autophagy specific substrate that promotes tumorigenesis.(15,16) Indeed, compared to control mice, hepatic levels of p62 were markedly higher in L-G6pc−/− mice at both pre-tumor and tumor-developing stages (Figure 2B).”
BackgroundHexabromocyclododecanes promoted autophagy through the PI3K/Akt/mTOR pathway in L02 cells
Jin, Y., Shang, Y., Zhang, D., An, J., & Pan, D. (2019) · Journal of Environmental Management · doi:10.1016/j.jenvman.2019.05.031 · Cited by 14
Yeom, J., Ma, S., & Lim, Y. (2020) · Antioxidants · doi:10.3390/antiox9030214 · Cited by 14
“Autophagy deficiency promotes tumorigenesis [5,6] and causes neurodegenerative diseases [7] and chronic inflammation [8].”
BackgroundSuppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis
Kim, J., Lee, S., & Lee, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.832804 · Cited by 15
“Thus, a liver tumor develops in mice with tissue-specific or systemic mosaic deletion of autophagy-related 7 (Atg7) or Atg5, critical autophagy genes (8, 9), and the role of autophagy in the initiation or development of hepatocellular carcinoma has been an attractive issue appealing to the research interest of a numbe…”
BackgroundHiyama, M., Kusakabe, K. T., Takeshita, A., Sinji, S. U. G. I., Kuniyoshi, N., Imai, H., Kanô, K., & Kiso, Y. (2014) · Journal of Veterinary Medical Science · doi:10.1292/jvms.14-0490 · Cited by 14
“Autophagy has roles not only in starvation response, but also in keeping quality of protein and organelle, development, differentiation, antigen presentation, tumorigenesis, senescence and more [10, 21, 25, 26, 30, 32, 33, 38].”
BackgroundIdentification of Six Autophagy-Related-lncRNA Prognostic Biomarkers in Uveal Melanoma
Chen, Y., Chen, L., Wang, J., Tan, J., & Wang, S. (2021) · Disease Markers · doi:10.1155/2021/2401617 · Cited by 13
Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?
Gentile, D., Esposito, M., & Grumati, P. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.930223 · Cited by 13
“The absence of these genes impairs autophagy flux and promotes tumor initiation (Qu et al., 2003; Takamura et al., 2011).”
BackgroundJian, L., Wu, H., Zeng, H., Quan, T., Xia, F., Xiang, S., & Zhou, B. (2023) · Journal of Functional Foods · doi:10.1016/j.jff.2023.105770 · Cited by 13
Systems Biology and Cytokines Potential Role in Lung Cancer Immunotherapy Targeting Autophagic Axis
Khilwani, R., & Singh, S. (2023) · Biomedicines · doi:10.3390/biomedicines11102706 · Cited by 12
Li, C., Zhang, J., Dionigi, G., Liang, N., Guan, H., & Sun, H. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07084-9 · Cited by 13
“Our fi ndings illustrate that targeting the AdipoRon-AdipoR2-ULK/p-ULK1 axis may represent a new therapeutic strategy for PTC.”
BackgroundCheng, L., Hu, Z., Gu, J., Li, Q., Liu, J., Liu, M., Li, J., & Bi, X. (2024) · Pharmaceuticals · doi:10.3390/ph17111488 · Cited by 13
“In cancer, early studies suggested that autophagy acts as a tumor suppressor [117].”
NRF-mediated autophagy and UPR: Exploring new avenues to overcome cancer chemo-resistance
Dastghaib, S., Shafiee, S. M., Ramezani, F., Ashtari, N., Tabasi, F., Saffari‐Chaleshtori, J., Siri, M., Vakili, O., Igder, S., Zamani, M., et al. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.177210 · Cited by 18
Autophagy : Moving Benchside Promises to Patient Bedsides
Belaïd, A., Ndiaye, P. D., Filippakis, H., Roux, J., Röttinger, É., Graba, Y., Brest, P., Hofman, P. M., & Mograbi, B. (2015) · Current Cancer Drug Targets · doi:10.2174/156800961508151001102452 · Cited by 13
Clinicopathological Association of Autophagy Related 5 Protein with Prognosis of Colorectal Cancer
Hu, W., Yang, W., Liu, P., Liu, T., Morgan, P. M., Tsai, W., Pan, H., Lee, C., & Shu, C. (2021) · Diagnostics · doi:10.3390/diagnostics11050782 · Cited by 13
“Though the role of ATG5 is like a double-edged sword in cancer development and progression, the ATG5 knockout causes benign tumors in aged mice (19 month) [24].”
BackgroundTargeting autophagy drug discovery: Targets, indications and development trends
Jiang, M., Wu, W., Xiong, Z., Ye, Z., Ye, Z., & Wu, Z. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.116117 · Cited by 13
Dai, Y., Cros, M., Pontoizeau, C., Elena‐Herrmann, B., Bonn, G. K., & Hainaut, P. L. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt353 · Cited by 13
“Decreased p62 is a marker of protein digestion in autolysosomes (a later step in autophagy) (28,29).”
BackgroundChen, S., & Guan, J. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0664 · Cited by 13
Molecular mechanisms of interplay between autophagy and metabolism in cancer
Raj, S., Chandel, V., Kumar, A. J., Kesari, K. K., Asthana, S., Ruokolainen, J., Kamal, M. A., & Kumar, D. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118184 · Cited by 14
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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