[Title]
Elucidation of a novel mechanism for pathogenesis of hepatocellular carcinoma.
Aberrant activation of antioxidant response mechanisms caused by dysregulation of protein quality control.

[Summary]
 Research groups led by Masaaki Komatsu at the Tokyo Metropolitan Institute of Medical Science and led by Masayuki Yamamoto at Tohoku University Graduate School of Medicine successfully clarified that intracellular protein aggregates often observed in hepatocellular carcinoma activate a cytoprotection mechanism against oxidative stress.

 The Keap1-Nrf2 system is one of the fundamental defense mechanisms against oxidative and xenobiotic stresses. Recent study revealed that cancer cells often hijack this system and acquire the resistance against chemotherapy and the ability to proliferate more aggressively.

 p62 is a protein important for the autophagy, one of the mechanisms of protein quality control. Abnormal intracellular accumulation of p62 is frequently observed in malignant tumors, including hepatocellular carcinoma. However, its pathological significance had not been clarified.

 In this study, the research groups found that p62 activates Nrf2, demonstrating that cancer cells adopt a strategy to protect themselves from chemotherapeutic reagents and oxidative stress through accumulation of p62 and subsequent activation of Nrf2. Chemical compounds that inhibit expression or accumulation of p62 are expected to be effective for the anti-cancer therapy.

 The results were published online in Nature Cell Biology, British science journal, as an advanced publication. The paper’s title is “The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through Keap1-inactivation.”

[Contact]
(About the research)
Masaaki Komatsu, Researcher
The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan
Organization for Medical Research
Address: 1-6 Kamikitazawa 2-chome, Setagaya-ku, Tokyo156-8506, Japan
TEL: +81-3-5316-3244, FAX: +81-3-5316-3152
E-mail：komatsu-ms@igakuken.or.jp

Masayuki Yamamoto, Professor
Department of Medical Biochemistry, Tohoku University of Graduate School of Medicine
Address: 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan
TEL: +81-22-717-8084, FAX: +81-22-717-8090
E-mail: masiyamamoto@m.tains.tohoku.ac.jp