Hepatocellular carcinoma (HCC) is the fifth most common cancer and the fourth leading cause of cancer death worldwide. For late state stage HCC, five year survival is less than 2%. Therefore prevention of HCC represents the most promising approach to reduce incidence and mortality from this cancer. Altered tumor metabolism has become appreciated as an early and important driver of many cancers including HCC. Increased lipogenesis is commonly found in patients with HCC, and is considered an early event. However, the mechanisms driving some of these metabolic changes/programs is not well understood. We recently showed that loss of the transcriptional coactivator PGC1 greatly reduced chemically induced hepatocellular carcinogenesis. PGC1? is a critical regulator of metabolism, playing a key role in control of oxidative metabolism. However, PGC1 has recently also been shown to regulate lipogenesis. Indeed, we also show that loss of PGC1 is associated with a reduction in the expression of genes driving fatty acid synthesis in the liver. Furthermore, we show that PGC1 promoted increased de novo fatty acid synthesis. Finally using established tumor xenografts, we show that inhibition of fatty acid synthesis blocks the ability of PGC1 to promote tumor growth. Based on this recent work as well as additional preliminary studies we hypothesize that control of energy and lipogenic pathways by PGC1 mediates its effects on HCC. In addition, diabetes, which is linked to an increased risk of HCC, displays many of these metabolic alterations even prior to tumor formation. This is significant since PGC1? is elevated in the livers of diabetic mice and humans, conditions associated with increased hepatic fatty acid synthesis and increased risk of HCC. Therefore we also hypothesize that PGC1 is an important player in the developed of HCC associated with diabetes. We will test these hypotheses in the following independent specific aims.
Specific Aim 1) To test the hypothesis that PGC1 promotes hepatocellular carcinogenesis via increasing fatty acid synthesis, Specific Aim 2) Determine whether regulation of AMPK activity by PGC1 is responsible for the effects of PGC1 on carcinogenesis, and Specific Aim 3) Determine whether PGC1? is responsible for the HCC associated with diabetes. Understanding how PGC1? controls metabolic alterations driving HCC and identifying a potentially relevant patient population to target for intervention with therapies directed against PGC1 would greatly reduce the incidence and hence mortality from this challenging cancer.

Public Health Relevance

Identifying how metabolic pathways control tumor development will lead to effective cancer therapies. PGC1 regulates key metabolic pathways implicated in cancer biology and is linked to metabolic diseases in the liver. Therefore, PGC1 represents a promising cancer prevention target. PGC1 is also associated with diabetes, a significant risk factor for hepatocellular carcinoma. Therefore these studies offer the promise of elucidating the mechanisms by which diabetes increases liver cancer risk and identification of a relevant patient population.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA169919-03
Application #
8657943
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Spalholz, Barbara A
Project Start
2012-07-09
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$348,615
Indirect Cost
$127,856
Name
State University New York Stony Brook
Department
Pathology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Bhalla, Kavita; Liu, Wan-Ju; Thompson, Keyata et al. (2014) Cyclin D1 represses gluconeogenesis via inhibition of the transcriptional coactivator PGC1?. Diabetes 63:3266-78