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American Liver Foundation
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American Liver Foundation Liver Scholar Award
University of California, San Diego, San Diego, California
“Contribution of mTOR and autophagy signaling to obesity-promoted hepatocarcinogenesis”
Approximately 90,000 people die each year in the US due to obesity-related cancers. Dr. Park’s previous study demonstrated that obesity acts as a tumor promoter for chemically-induced [diethylnitrosamine (DEN)] hepatocellular carcinoma (HCC) in mice and found that chronic liver inflammation associated with fat accumulation promotes HCC development. Obesity also induces activation of mammalian target of rapamycin (mTOR) signaling under the condition of insulin resistance, suggesting a contribution of mTOR signaling to obesity-promoted HCC development.
mTOR, a nutrient sensitive sensor, fulfills many critical functional roles in mediating not only cell growth, differentiation, and proliferation but also protein and lipid metabolism in response to various signals such as nutrients, hormones and growth factors by forming complexes with either Raptor (mTOR complex 1, mTORC1) or Rictor (mTORC2). Sustained activation of mTORC1 is a major cause of nutrient-induced obesity, insulin resistance, cardiac hypertrophy and tumors. mTORC1 activation also induces fat accumulation through lipogenic genes such as SREBP1 and PPARγ. mTORC1 negatively regulates autophagy, a type of programmed cell death, responsible for removal of unnecessary, damaged long-lived proteins or other organelles such as ER and mitochondria. Autophagy also regulates lipid metabolism. Thus, defective autophagy induces fat accumulation and insulin resistance as well as cancer development. However, it is not clear whether obesity-promoted liver cancer development is associated with mTOR and autophagy signaling.
From Dr. Park’s previous observation, he demonstrated that inflammation promotes HCC development, and mTOR signaling is associated with HCC development. However, the mechanism by which inflammation promotes liver cancer development through mTOR activation and autophagy is unknown. Therefore, Dr. Park will investigate the role of IL-6 and TNF in regulation of mTOR signaling in obesity-promoted HCC development, and the mechanism by which IL-6/STAT3 signaling regulates autophagy in obesity-promoted HCC development.
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