Hepatocellular carcinoma (HCC) is the most common liver malignancy and accounts for a large proportion of cancer deaths worldwide. The disease develops after a long latency period as a complication of chronic liver injury and inflammation, primarily induced by alcohol use, viral hepatitis, or nonalcoholic fatty liver disease. Obesity and metabolic syndrome also increase the risk of HCC development. The therapeutic options for HCC are limited, with potential curative treatment available for less than one third of patients, due to the fact that HCC is, in general, refractory to chemotherapy treatment and becomes clinically symptomatic and detectable only at a late stage. This underscores the urgent need for further research on the mechanisms driving hepatic injury and on the molecular pathways that are vital to HCC progression and metastasis. Heat shock factor 1 (Hsf1), a major transactivator of stress proteins that protect cells against environmental stressors, has been implicated in the pathogenesis of cancer, but specific mechanisms by which Hsf1 may support cancer development remain elusive. During the previous funding period we discovered that genetic inactivation of Hsf1 in mouse cancer models leads to remarkable inhibition of HCC development. We have found a novel pathogenic mechanism whereby Hsf1 activation promotes growth of pre-malignant hepatocytes and HCC development by stimulating lipogenesis and perpetuating chronic hepatic metabolic disease induced by the carcinogen. Thus, Hsf1 is a potential target for control of hepatic steatosis, insulin resistance, and HCC development. In this application, we will test the hypothesis that tissue-specific or total body inactivation of Hsf1 wil result in HCC growth retardation and prevent cancer development by inhibiting tumor-promoting metabolic reprogramming. In addition, our hypothesis predicts that Hsf1 inactivation from total or metabolically active organs (e.g., liver, adipose tissues) will prevent or attenuate liver cancer development caused by dietary obesity and metabolic syndrome by interfering with tumor-promoting metabolic pathways as well as inflammation.
In Aim 1, development of liver tumors will be initiated by carcinogen, stable expression of oncogenes or by genetic manipulation of cultured embryonic liver progenitor cells followed by their re- transplantation into the livers of recipient mice. Extended analyses will address the clinically important question of whether systemic total body inactivation of Hsf1 can reverse HCC progression without eliciting adverse physiological consequences.
In Aim 2, we will determine the metabolic profile (glucose, glutamine, lipid metabolism and mitochondrial activity) of hsf1-proficient and hsf1-deficient liver cancer cells using a 13C isotopomer approach. Extended analyses will identify possible metabolic changes in liver tumors developed in cancer mouse models. In addition, we will determine the effects of tissue-specific Hsf1 ablation on dietary obesity-induced liver cancer. Thus, we will use unique mouse models and biochemical and genetic approaches to test the potential of Hsf1 targeting in human HCC.

Public Health Relevance

The results of our studies should have major implications for an understanding of heat shock transcription factor 1 (Hsf1) function in the regulation of tissue-specific and total body metabolism and inflammation, which are critical factors for malignant cell proliferation and cancer development. This research will provide the rationale to develop novel strategies to prevent, and perhaps treat, cancers, including HCC, that arise on the background of chronic hepatic injury due to impaired liver metabolism and proteostasis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01CA062130-19A1
Application #
8817986
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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