Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Recent epidemiological studies revealed that obesity results in a substantial increase in cancer risk including HCC. Accordingly, it was described that obesity promotes liver inflammation and tumorigenesis in mice by enhancing circulating levels of inflammatory cytokines such as IL-6 and TNF?. Therefore, in obesity associated cancers an ideal molecular target is the one whose inhibition should a) suppress cancer cell proliferation, and b) reduce body adiposity and circulating inflammatory cytokines. Id1 (inhibitor of DNA binding 1) is a helix-loop-helix (HLH) transcription factor that functions as a negative regulator f basic helix-loop-helix (bHLH) transcription factors. Id1 promotes cell proliferation and inhibits cellular differentiation. It was shown that Id1 is overexpressed in many human cancers including HCC, however, the specific role of Id1 in HCC initiation and progression is not known. Recently, I discovered that Id1 is highly expressed in adipose tissues, especially in brown adipose tissue (BAT), and Id1-deficiency in mice resulted in enhanced thermogenesis due to induced expression of PGC1? and UCP1, critical regulators of thermogenesis. These studies together suggest that Id1 functions as a critical regulator in two different cellular processes;cell proliferation and cellular metabolism. Taken together, I hypothesize that deletion of Id1 suppresses obesity associated HCC by two mechanisms: 1. Id1 is required for cancer cell proliferation, and deletion of Id1 suppresses liver tumor growth. 2. Deletion of Id1 enhances thermogenesis, reduces body adiposity and circulating inflammatory cytokines, therefore, prevents liver inflammation that contributes to liver tumor growth. The objective of this proposal is to investigate the specific role of Id1 in obesity associated liver tumorigenesis. In pursuit of this two specific aims are proposed.
Aim 1 : I will investigate the consequence of loss of Id1 in the regulation of PGC1? and UCP1 in BAT mediated thermogenesis. For this purpose, I generated Id1fl/fl conditional knockout mice and adipose tissue specific deletion of Id1 will be achieved by crossing with aP2Cre mice which will allow me to investigate the impact of loss of Id1 in the regulation of thermogenic pathway and body adiposity.
Aim 2 :
The second aim will investigate the effect of loss and overexpression of Id1 in liver tumorigenesis, and identify potential cooperating partners of Id1 that are involved in HCC progression. For this purpose I will use Id1fl/flAlbCre mice, and generate a new transgenic model (Alb- Id1Tg) to evaluate the consequence of liver specific loss and overexpression of Id1 on HCC initiation and progression. In addition, by combined deletion of Id1 in adipose tissue and liver, and by utilizing high fat die (HFD) model of obesity, I will investigate if lack of Id1 prevents obesity associated HCC.

Public Health Relevance

Liver cancer is one of the leading causes of cancer deaths worldwide. Recent epidemiological studies revealed that obesity results in a substantial increase in cancer risk including liver cancer. In support of these studies, researchers discovered that obesity promotes liver inflammation and tumorigenesis by enhancing the levels of inflammatory molecules in the body circulation. Therefore, in obesity associated cancers an ideal drug target is the one whose inhibition must a) suppress cancer cell proliferation, and b) reduce body adiposity and circulating inflammatory molecules. Id1 (inhibitor of DNA binding 1) is a transcription factor that promotes cell proliferation and inhibits cellular differentiation. It was shown that Id1 is highly expressed in many human cancers including liver cancer, however, the specific role of Id1 in liver cancer initiation and progression is unknown. Recently, I discovered that Id1 is highly expressed in mouse fat (adipose) tissues, especially in brown adipose tissue (BAT), and when we deleted Id1 gene in mice by genetic approaches, we detected enhanced thermogenesis (heat production) due to induced expression of PGC1αand UCP1 proteins, which are critical regulators of thermogenesis. These studies together suggest that Id1 functions as a critical regulator in two different cellular mechanisms;cell proliferation and cellular metabolism. Taken together, I hypothesize that deletion of Id1 suppresses obesity associated liver tumorigenesis by two mechanisms: 1. Id1 is required for cancer cell proliferation and deletion of Id1 suppresses liver tumor growth, and 2. Deletion of Id1 enhances thermogenesis, reduces body adiposity and circulating inflammatory molecules, therefore, prevents liver inflammation that contributes to liver tumor growth. The objective of my proposal is to investigate the specific role of Id1 in obesity associated liver tumorigenesis. In pursuit of this I am proposing two specific aims: Aim 1: I will investigate the consequence of specific deletion of Id1 gene in adipose tissues on the regulation of PGC1αand UCP1 in BAT mediated thermogenesis. For this purpose, I generated a novel Id1 knockout mouse which will allow me to investigate the impact of loss of Id1 in the regulation of thermogenesis and body adiposity. Aim 2: The second aim will investigate the effect of loss and overexpression of Id1 gene in liver tumorigenesis, and identify potential co-operating partners of Id1 that are involved in liver tumor progression. Public health relevance: After lung and stomach cancer, liver cancer is the third leading cause of cancer deaths worldwide with more than 600,000 people die annually. Although hepatitis B and C infections are the major risk factors of liver cancer, obesity is rapidly emerging as a significant risk factor of liver cancer and is growing at an alarming rate with ~60% of US adults are overweight or obese, and ~300 million people are obese worldwide. Currently, FDA approved sorafenib which showed some promise in inhibiting unresectable liver cancers. However, it is causing many side effects suggesting the need to discover other more effective drug targets to inhibit liver cancer. Id1 protein is highly expressed in human liver cancer samples, but the specific role of Id1 in cancer initiation and progression is not known. My proposed studies in highly sophisticated knockout and transgenic mouse models will uncover the specific role of Id1 in liver tumorigenesis, energy balance and obesity associated liver cancer. Therefore, my proposed study will explore if Id1 emerges as a novel drug target to treat not only liver cancer but also obesity mediated metabolic disorders and liver disease.

Agency
National Institute of Health (NIH)
Type
Career Transition Award (K22)
Project #
5K22CA168828-02
Application #
8708001
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Patil, Mallikarjun; Sharma, Bal Krishan; Satyanarayana, Ande (2014) Id transcriptional regulators in adipogenesis and adipose tissue metabolism. Front Biosci (Landmark Ed) 19:1386-97
Sharma, Bal Krishan; Patil, Mallikarjun; Satyanarayana, Ande (2014) Negative regulators of brown adipose tissue (BAT)-mediated thermogenesis. J Cell Physiol 229:1901-7