Every year approximately 40,000 Americans are diagnosed with RCC including military personnel, their family members, and U.S. Veteran population. It is expected that 54,390 new cases of kidney cancer would be diagnosed and 13,010 affected individuals would die in the U.S. in 2012. Approximately 50% of patients with metastatic RCC have a survival rate of less than one year. In addition, cancer contributes approximately 10% to mortality in diabetic patients. More than 23 million persons in the United States with diabetes and predicting by 2025 will be increase to 25 million and that may increase the risk of solid tumors including renal cell carcinoma. We show recently that 25.4 % of kidney cancer patients have history with diabetes from San Antonio Hospitals. The mechanism by which diabetes enhances certain pathways to develop cancer is largely unknown. In addition, there is no valid biomarker for the early detection of the incidence of cancer in diabetic patient. Hypothesis: we hypothesize that the chronic exposure to high glucose (hyperglycemia, HG) and/or insulin (hyperinsulinaemia, HI) activates the cell survival kinase, Akt and lead to inactivates tumor suppressor protein, tuberin (protein encodes by TSC2). Inactivation of tuberin resulted in (1) activation of mammalian target of rapamycin complex 1 (mTOR) mTORC1 to blocks and degrades insulin receptor substrate-1 (IRS- 1) and (2) activation of mTOC2 to activate Akt through feedback loop. On the other hand, activation of mTORC1/C2 resulting in downregulation of the DNA repair enzymes 8-oxoG-DNA glycosylase (OGG1) and poly (ADP-ribose) polymerase (PARP) to inactivates cell apoptosis. Inactivation of OGG1 and PARP resulted in accumulation of oxidative DNA, 8-oxodG. DNA damage (8-oxodG) enhances DNA methylation and mutagenesis and predisposes kidney and other organs to cancer. To better understand the mechanism of biological plausibility by which hyperglycaemia and/or hyperinsulinaemia increasing cancer risk and find a biomarker for early detection of cancer in diabetic patients, we proposed the following specific aims.
SPECIFIC AIM 1 : To determine the mechanisms by which chronic exposure of high glucose or high glucose+high insulin regulates cell survival/apoptosis/proliferation and DNA damage/repair pathways to prompt DNA methylation/mutations in proximal tubular cells, where renal cell carcinoma originates.
SPECIFIC AIM 2 : To explore the effect of hyperinsulinemia+hyperglycemia on the rate of development and severity of renal cell carcinoma in TSC2+/- in our new TSC2+/-/dbdb mouse model (model of type II diabetes).
SPECIFIC AIM 3 : To determine the relevant effect of hyperglycemia or hyperinsulinemia+ hyperglycemia identified in cell culture and animal to diabetic patients. In addition, find a candidate gene(s) that can be used as a biomarker for early detection of cancer in diabetic patients.
Cancer contributes approximately 13% to mortality in diabetic patients. More than 23 million persons in the USA with diabetes and predicting by 2025 will be increase to 25 million and expecting more risk of solid tumors in diabetic patients including renal cell carcinoma. We show recently that 25.4 % of kidney cancer patients (from San Antonio Hospitals) have history with diabetes. The mechanism by which diabetes enhances certain pathways to develop cancer is largely unknown. Our goal is to investigate the mechanisms by which hyperglycemia and/or hyperinsulinaemia enhances tumorigenesis. In addition, we will try to find a candidate gene that can be used as a biomarker for early detection of cancer in diabetic patients.
|Abu Aboud, Omran; Habib, Samy L; Trott, Josephine et al. (2017) Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging. Cancer Res 77:6746-6758|
|Ruan, Xinsen; Zuo, Qiao; Jia, Hao et al. (2015) P53 deficiency-induced Smad1 upregulation suppresses tumorigenesis and causes chemoresistance in colorectal cancers. J Mol Cell Biol 7:105-18|
|Habib, Samy L; Mohan, Sumathy; Liang, Sitai et al. (2015) Novel mechanism of transcriptional regulation of cell matrix protein through CREB. Cell Cycle 14:2598-608|
|Jia, H; Cong, Q; Chua, J F L et al. (2015) p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance. Oncogene 34:3568-81|
|Kosti, Adam; Harry Chen, Hung-I; Mohan, Sumathy et al. (2015) Microarray profile of human kidney from diabetes, renal cell carcinoma and renal cell carcinoma with diabetes. Genes Cancer 6:62-70|
|Habib, Samy L (2014) Tuberin in renal cell hypertrophy. Cell Cycle 13:869-70|
|Habib, Samy L; Liang, Sitai (2014) Hyperactivation of Akt/mTOR and deficiency in tuberin increased the oxidative DNA damage in kidney cancer patients with diabetes. Oncotarget 5:2542-50|
|Liang, Sitai; Salas, Tiffanie; Gencaslan, Emre et al. (2014) Tuberin-deficiency downregulates N-cadherin and upregulates vimentin in kidney tumor of TSC patients. Oncotarget 5:6936-46|