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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In Ulk1−/− RPE, p62/SQSTM accumulates, indicating defective autophagy.
“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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“Loss of p62 reduces liver damage and hepatoma formation resulting from autophagy deficiency, indicating that aberrant accumulation of p62 is largely the cause (Komatsu et al., 2010; Takamura et al., 2011).”
BackgroundObesity, inflammation, and liver cancer
Sun, B., & Karin, M. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.09.020 · Cited by 496 · see citing works
“Curiously, disruption of autophagy, as occurs in ATG7 or ATG5 knockout mice, leads to spontaneous HCC development[146, 147].”
BackgroundAutophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations
Yang, A., Rajeshkumar, N. V., Wang, X., Yabuuchi, S., Alexander, B. M., Chu, G. C., Von Hoff, D. D., Maitra, A., & Kimmelman, A. C. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0362 · Cited by 486 · see citing works
“Mosaic deletion of Atg5 predisposes mice to benign liver adenomas which do not progress to malignant tumors (5).”
BackgroundChloroquine in Cancer Therapy: A Double-Edged Sword of Autophagy
Kimura, T., Takabatake, Y., Takahashi, A., & Isaka, Y. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2464 · Cited by 494 · see citing works
“Liver-specific Atg7-deficient mice and mice with systemic mosaic deletion of Atg5 develop benign liver adenomas (23, 24).”
BackgroundUmemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.04.006 · Cited by 438 · see citing works
“Of note, whole-body p62 disruption suppresses benign adenomas in autophagy-deficient livers (Takamura et al., 2011).”
BackgroundInfluentialInside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462 · see citing works
Functions of autophagy in normal and diseased liver
Czaja, M. J., Ding, W., Donohue, T. M., Friedman, S. L., Js, K., Komatsu, M., Lemasters, J. J., Lemoine, A., Lin, J. D., Ou, J. J., et al. (2013) · Autophagy · doi:10.4161/auto.25063 · Cited by 435 · see citing works
Strohecker, A. M., Guo, J. Y., Karsli-Uzunbas, G., Price, S. M., Chen, G. J., Mathew, R., McMahon, M., & White, E. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0397 · Cited by 435 · see citing works
“HBSS: 0 1 2 3 0 1 2 3 5078(2) #2 5078(2) #3 5079(2) #2 5079(3) #1 5125(1) #2 5125(1) #5 5311(2) #10 5317(1) #5”
InfluentialPlasma cells require autophagy for sustainable immunoglobulin production
Pengo, N., Scolari, M., Oliva, L., Milan, E., Mainoldi, F., Raimondi, A., Fagioli, C., Merlini, A., Mariani, E., Pasqualetto, E., et al. (2013) · Nature Immunology · doi:10.1038/ni.2524 · Cited by 427 · see citing works
Kenzelmann Broz, D., Spano Mello, S., Bieging, K. T., Jiang, D., Dusek, R. L., Brady, C. A., Sidow, A., & Attardi, L. D. (2013) · Genes & Development · doi:10.1101/gad.212282.112 · Cited by 443 · see citing works
“…are susceptible to tumorigenesis, including Becn1 +/À mice, Atg4c À/À mice, and mice lacking Atg5 or Atg7 in the liver, which develop spontaneous tumors, chemical carcinogen-induced tumors, and benign liver tumors, respectively (Morgan and Kastan 1997; Yue et al. 2003; Takamura et al. 2011).”
BackgroundCrosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System
Kocatürk, N. M., & Gözüaçık, D. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00128 · Cited by 415 · see citing works
“For example, inhibition of proteasomal activity by the proteasome inhibitor and chemotherapy agent bortezomib led to an increase in the expression of autophagy genes ATG5 and ATG7, and induced autophagy.”
InfluentialAutophagy in tumour immunity and therapy
Xia, H., Green, D. R., & Zou, W. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00344-2 · Cited by 411 · see citing works
Regulation and Function of Autophagy during Cell Survival and Cell DeathPreprint
Das, G., Shravage, B. V., & Baehrecke, E. H. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008813 · Cited by 413 · see citing works
“Significantly, loss of Atg5 leads to benign adenomas in livers, but this phenotype is not observed in other tissues (Takamura et al. 2011).”
BackgroundObesity and cancer: inflammation bridges the two
Kolb, R. H., Sutterwala, F. S., & Zhang, W. (2016) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2016.07.005 · Cited by 411 · see citing works
PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond
Fattahi, S., Amjadi‐Moheb, F., Tabaripour, R., Ashrafi, G. H., & Akhavan‐Niaki, H. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118513 · Cited by 403 · see citing works
Diverse Cellular Roles of Autophagy
Morishita, H., & Mizushima, N. (2019) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100818-125300 · Cited by 376 · see citing works
Self-citationMaycotte, P., & Thorburn, A. M. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.11.2.14627 · Cited by 394 · see citing works
Autophagy as a molecular target for cancer treatment
Kocatürk, N. M., Akkoç, Y., Kığ, C., Bayraktar, O., Gözüaçık, D., & Kutlu, Ö. (2019) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2019.04.011 · Cited by 388 · see citing works
Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function
Jaber, N. L., Dou, Z., Chen, J., Catanzaro, J. M., Jiang, Y.-P., Ballou, L. M., Selinger, E. S., Ouyang, X., Lin, R. Z., Zhang, J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112848109 · Cited by 386 · see citing works
Tanaka, S., Hikita, H., Tatsumi, T., Sakamori, R., Nozaki, Y., Sakane, S., Shiode, Y., Nakabori, T., Saito, Y., Hiramatsu, N., et al. (2016) · Hepatology · doi:10.1002/hep.28820 · Cited by 376 · see citing works
“beclin1, generates liver inflammation and tumorigenesis,((40-42)) indicating the importance of basal levels of autophagy for maintaining liver integrity.”
BackgroundAutophagy: An Essential Degradation Program for Cellular Homeostasis and Life
Chun, Y., & Kim, J. (2018) · Cells · doi:10.3390/cells7120278 · Cited by 385 · see citing works
“Additionally, a positive correlation between tumor progression and autophagy adaptor p62/SQSTM1 protein level was documented in vivo [208].”
BackgroundAutophagy in liver diseases: Time for translation?
Allaire, M., Rautou, P.-E., Codogno, P., & Lotersztajn, S. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.01.026 · Cited by 378 · see citing works
Autophagy in liver diseases: A review
Qian, H., Chao, X., Williams, J. A. R., Fulte, S., Li, T., Yang, L., & Ding, W. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.100973 · Cited by 377 · see citing works
Matsuzawa, Y., Hwang, S., & Cadwell, K. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042617-053253 · Cited by 378 · see citing works
Autophagy and disease: unanswered questions
Yang, Y., & Klionsky, D. J. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-019-0480-9 · Cited by 369 · see citing works
Saito, T., Ichimura, Y., Taguchi, K., Suzuki, T., Mizushima, T., Takagi, K., Hirose, Y., Nagahashi, M., Iso, T., Fukutomi, T., et al. (2016) · Nature Communications · doi:10.1038/ncomms12030 · Cited by 364 · see citing works
“Purified Keap1 (1 mM) was pre-treated with or without the indicated compounds in pull-down assay buffer (20mM Tris-HCl (pH 7.5), 150mM NaCl, 0.5% NP-40, 0.5mM TCEP), and then 6 His-GST-Neh2(1-56) (1 mM) or 6 His-GST-Neh2(D17-51) (1 mM) was added to the mixture.”
BackgroundMethodInfluentialAutophagy and apoptosis in liver injury
Wang, K. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1038685 · Cited by 363 · see citing works
“Autophagy through a cell-intrinsic mechanism is an important mediator for the suppression of tumorigenesis.(49) Furthermore, autophagy defect is associated with a poor prognosis of HCC.”
BackgroundAutophagy maintains tumour growth through circulating arginine
Poillet-Perez, L., Xie, X., Zhan, L., Yang, Y., Sharp, D. W., Hu, Z. S., Su, X., Maganti, A., Jiang, C., Lu, W., et al. (2018) · Nature · doi:10.1038/s41586-018-0697-7 · Cited by 363 · see citing works
Obesity and Cancer: The Oil that Feeds the Flame
Font-Burgada, J., Sun, B., & Karin, M. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.015 · Cited by 354 · see citing works
“Systemic mosaic deletion of Atg5 or liver-specific deletion of Atg7 results in liver damage and the development of benign liver adenomas (Komatsu et al., 2005; Takamura et al., 2011).”
BackgroundNoncanonical autophagy promotes the visual cycle
Kim, J.-Y., Zhao, H., Martinez, J., Doggett, T. A., Kolesnikov, A. V., Tang, P. H., Ablonczy, Z., Chan, C.-C., Zhou, Z., Green, D. R., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.012 · Cited by 347 · see citing works
“phagocytosis is maximal, we detected LC3-II (Figure 6A); however, 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 POSinduced L…”
Gukovsky, I., Li, N., Todoric, J., Gukovskaya, A. S., & Karin, M. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.02.007 · Cited by 346 · see citing works
Cellular metabolic and autophagic pathways: Traffic control by redox signaling
Dodson, M. B., Darley-Usmar, V. M., & Zhang, J. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.05.014 · Cited by 325 · see citing works
Targeting autophagy using natural compounds for cancer prevention and therapy
Deng, S., Shanmugam, M. K., Kumar, A. P., Yap, C. T., Sethi, G., & Bishayee, A. (2019) · Cancer · doi:10.1002/cncr.31978 · Cited by 322 · see citing works
“leads to the formation of multiple, benign tumors developed in the liver of mice.(78) Atg7 is also involved in liver tumor development, because liver-specific knockout of Atg7 increases the rate of liver tumors in mice.”
BackgroundActivating autophagy to potentiate immunogenic chemotherapy and radiation therapy
Galluzzi, L., Bravo-San Pedro, J. M., Demaria, S., Formenti, S. C., & Kroemer, G. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.183 · Cited by 314 · see citing works
Khandia, R., Dadar, M., Munjal, A. K., Dhama, K., Karthik, K., Tiwari, R., Yatoo, M. I., Iqbal, H. M. N., Singh, K. P., Joshi, S. K., et al. (2019) · Cells · doi:10.3390/cells8070674 · Cited by 323 · see citing works
“…through inhibiting- high mobility group box 1 protein (HMGB1) Tang et al., 2010 [288] Autophagy deficiency- leads to benign hepatoma cell death Takamura et al., 2011 [291] Autophagy induced by PTEN and TSC, the tumor suppressor protein Feng et al., 2005 [301];Tsuchihara et al., 2009…”
BackgroundInfluentialTherapeutic targets in cancer cell metabolism and autophagy
Cheong, H., Lü, C., Lindsten, T., & Thompson, C. B. (2012) · Nature Biotechnology · doi:10.1038/nbt.2285 · Cited by 316 · see citing works
Regulation of Liver Metabolism by Autophagy
Madrigal‐Matute, J., & Cuervo, A. M. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.09.042 · Cited by 312 · see citing works
Hallmarks of Aging in the Liver
Hunt, N. J., Kang, S. W., Lockwood, G. P., Couteur, D. G. L., & Cogger, V. C. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.07.021 · Cited by 315 · see citing works
“Macroautophagy is the most important for maintaining hepatic homeostasis [34].”
BackgroundAutophagy and human disease: emerging themes
Schneider, J. L., & Cuervo, A. M. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2014.04.003 · Cited by 303 · see citing works
“Whereas primary loss of autophagy predisposes to malignant transformation [45], autophagic activation may confer tumor cells a survival advantage in metabolically stressful environments or in response to anti-oncogenic therapeutics injury [12].”
p62/SQSTM1/A170: Physiology and pathology
Komatsu, M., Kageyama, S., & Ichimura, Y. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.07.004 · Cited by 301 · see citing works
Kageyama, S., Gudmundsson, S. R., Sou, Y., Ichimura, Y., Tamura, N., Kazuno, S., Ueno, T., Miura, Y., Noshiro, D., Abe, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20185-1 · Cited by 290 · see citing works
The autophagic network and cancer
Rybstein, M. D., Pedro, J. M. B., Kroemer, G., & Galluzzi, L. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0042-2 · Cited by 287 · see citing works
Watch What You (Self-) Eat: Autophagic Mechanisms that Modulate Metabolism
Lahiri, V., Hawkins, W. D., & Klionsky, D. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.03.003 · Cited by 286 · see citing works
“Inhibition of autophagy in mice by mosaic deletion of Atg5 or Atg7 promotes the development of liver neoplasms (Takamura et al., 2011; Inami et al., 2011).”
BackgroundAutophagy-Dependent Production of Secreted Factors Facilitates Oncogenic RAS-Driven Invasion
Lock, R., Kenific, C. M., Leidal, A. M., Salas, E., & Debnath, J. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0841 · Cited by 280 · see citing works
“In addition, although liver-specific deletion of ATG7 or ATG5 initiates the development of benign adenomas, these tumors are unable to progress to adenocarcinomas, suggesting that autophagy is required for advanced tumor progression (42, 43).”
p62/SQSTM1 – steering the cell through health and disease
Sánchez‐Martín, P., & Komatsu, M. (2018) · Journal of Cell Science · doi:10.1242/jcs.222836 · Cited by 280 · see citing works
“A physiological problem arises with this non-canonical mechanism, referred to as the SQSTM1-mediated Keap1–Nrf2 pathway, when autophagy is defective, as accumulation of SQSTM1 leads to persistent activation of Nrf2, which causes tissue damage and tumorigenesis in liver of hepatocyte-specific Atg7-knockout mice (Ichimu…”
BackgroundThe Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases
Wang, H., Liu, Y., Wang, D., Xu, Y., Dong, R., Yang, Y., Lv, Q., Chen, X., & Zhang, Z. (2019) · Cells · doi:10.3390/cells8121597 · Cited by 281 · see citing works
Role and Mechanisms of Mitophagy in Liver Diseases
Ma, X., McKeen, T., Zhang, J., & Ding, W. (2020) · Cells · doi:10.3390/cells9040837 · Cited by 279 · see citing works
“Subsequent findings from mice with liver-specific deletion of either Atg5 or Atg7 show spontaneous liver tumors, unequivocally indicating that autophagy is a bona fide tumor suppressor [196,197].”
BackgroundEmerging strategies to effectively target autophagy in cancer
Rebecca, V. W., & Amaravadi, R. K. (2015) · Oncogene · doi:10.1038/onc.2015.99 · Cited by 283 · see citing works
Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins
Klionsky, D. J., & Schulman, B. A. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2787 · Cited by 274 · see citing works
Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy
Ni, H.-M., Woolbright, B. L., Williams, J., Copple, B., Cui, W., Luyendyk, J. P., Jaeschke, H., & Ding, W.-X. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.04.043 · Cited by 270 · see citing works
“Previous studies, including ours, showed that loss of autophagy in livers caused persistent activation of Nrf2 by activating the noncanonical p62-Keap1-Nrf2 pathway [2, 13, 15].”
InfluentialRole of tumor and host autophagy in cancer metabolismPreprint
Poillet-Perez, L., & White, E. (2019) · Genes & Development · doi:10.1101/gad.325514.119 · Cited by 269 · see citing works
“In tissues such as the pancreas and liver, where tumor initiation is caused by chronic tissue damage and inflammation, ablation of Atg7 or Atg5 leads to induction of benign pancreatic intraepithelial neoplasia (PANIN) in Kras mice and spontaneous liver adenomas, respectively, that fail to progress to malignancy (Takam…”
BackgroundAutophagy: shaping the tumor microenvironment and therapeutic response
Maes, H., Rubio, N., Garg, A. D., & Agostinis, P. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.04.005 · Cited by 266 · see citing works
Jiao, L., Zhang, H., Li, D., Yang, K.-L., Tang, J., Li, X., Ji, J., Yu, Y., Wu, R.-Y., Senthilkumar, R., et al. (2017) · Autophagy · doi:10.1080/15548627.2017.1381804 · Cited by 265 · see citing works
“liver-specific deletion of either the Atg5 or Atg7 gene in mice results in benign liver adenomas [6].”
BackgroundAutophagy and organelle homeostasis in cancer
Miller, D. R., & Thorburn, A. M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.02.010 · Cited by 264 · see citing works
Cianfanelli, V., Fuoco, C., Lorente, M., Salazar‐Roa, M., Quondamatteo, F., Gherardini, P. F., Zio, D. D., Nazio, F., Antonioli, M., D’Orazio, M., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3072 · Cited by 258 · see citing works
“First, autophagy represents a preventive mechanism against the accumulation of damaged organelles and genome, so counteracting tumour formation.35–38 Second, autophagy supplies fuel essential for established tumour growth.45–47 Considering AMBRA1’s place in the cascade of events leading to…”
Therapeutic Targeting of Autophagy in Disease: Biology and Pharmacology
Cheng, Y., Ren, X., Hait, W. N., & Yang, J. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007120 · Cited by 258 · see citing works
“Mice with a systemic mosaic deletion of Atg5 or mice with a liver-specific Atg7 deficiency developed benign tumors in the liver, suggesting that autophagy is critical for suppression of spontaneous tumorigenesis in this model (Takamura et al., 2011).”
Background
- 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
- Health Sciences › Medicine › Epidemiology › 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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