Autophagy-deficient mice develop multiple liver tumors

Akito Takamura; Masaaki Komatsu; Taichi Hara; Ayako Sakamoto; Chieko Kishi; Satoshi Waguri; Yoshinobu Eishi; Okio Hino; Keiji Tanaka; Noboru Mizushima

doi:10.1101/gad.2016211

Autophagy-deficient mice develop multiple liver tumors

¹Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
²Department of Medicine and Rheumatology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
³Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
⁴Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan;
⁵Department of Human Pathology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
⁶Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo 113-8421, Japan;
⁷Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan

↵8 These authors contributed equally to this work.

↵9 Present address: Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.

Abstract

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.