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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgia Regents University
Schools of Medicine
United States
Zip Code
Yang, Zheqiong; Peng, Min; Cheng, Liang et al. (2016) GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer. Am J Pathol 186:1340-50
Eroglu, Binnur; Min, Jin-Na; Zhang, Yan et al. (2014) An essential role for heat shock transcription factor binding protein 1 (HSBP1) during early embryonic development. Dev Biol 386:448-60
Hong, Yuan; Peng, Yibing; Guo, Z Sheng et al. (2014) Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology 59:1448-58
Eroglu, Binnur; Kimbler, Donald E; Pang, Junfeng et al. (2014) Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury. J Neurochem 130:626-41
Peng, Min; Zhang, Hao; Jaafar, Lahcen et al. (2013) Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations. J Biol Chem 288:33387-97
Bradley, Eric; Bieberich, Erhard; Mivechi, Nahid F et al. (2012) Regulation of embryonic stem cell pluripotency by heat shock protein 90. Stem Cells 30:1624-33
Xi, Caixia; Hu, Yanzhong; Buckhaults, Phillip et al. (2012) Heat shock factor Hsf1 cooperates with ErbB2 (Her2/Neu) protein to promote mammary tumorigenesis and metastasis. J Biol Chem 287:35646-57
Jin, Xiongjie; Eroglu, Binnur; Cho, Wonkyoung et al. (2012) Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo. Mol Cancer Res 10:523-34
Wu, Juan; Li, Jiaqi; Salcedo, Rosalba et al. (2012) The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res 72:3977-86
Antonov, Alexander S; Antonova, Galina N; Munn, David H et al. (2011) ýýVýý3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-ýýB activation. J Cell Physiol 226:469-76

Showing the most recent 10 out of 38 publications