Chronic oxidative stress and susceptibility to renal carcinogenesis

Kidneys are important target organ for oxidative stress mediated injury and oxidative stress has been suggested as a common pathway shared by multiple risk factors of kidney cancer. But there is no experimental evidence to show direct role of oxidative stress in kidney cancer. In this study, our main objective was to evaluate effect of H2O2-induced chronic oxidative stress on neoplastic transformation of normal human kidney epithelial cells. To achieve our study goals, we developed an in-vitro cell model by exposing the HK-2 cells (immortalized normal human kidney epithelial cells) to H2O2 for 6 months and then evaluated for the effects on cell growth, migration and in-vitro and in-vivo tumorigenic potential as well as changes in the expression of cell growth/survival, EMT and stem cell related genes. In addition, we also evaluated changes in epigenetic regulatory genes/proteins and effect of DNA demethylation on growth and transformation of cells. To further understand role of chronic oxidative stress on progression of renal cell cancer, we evaluated effect of chronic exposure to H2O2 on growth and tumorigenic potential of Cak-1, human renal cell carcinoma cell line and also confirmed the effects in MCF-7, ER-positive breast cancer cells. The result revealed that exposure to chronic oxidative stress induces growth and transformation of HK-2 and is associated with acquisition of EMT and stem cell characteristics. Significant alterations in epigenetic regulatory proteins and 5-aza 2' dC induced decrease in growth and tumorigenic potential further suggested possible role of DNA hypermethylation in chronic oxidative stress induced changes. Increased growth and tumorigenic potential of Caki-1 cells with up-regulation of metastasis and EMT related genes, further confirm role of chronic oxidative stress in progression of kidney cancer. In addition, increased growth and aggressiveness of MCF-7 cells with DNA hypermethylation mediated down regulation of ER-α after chronic exposure to H2O2 also revealed role of oxidative stress in progression of less aggressive ER-positive breast cancer into more aggressive ER-negative phenotype.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Environmental Toxicology

Grantor

Texas Tech University

Year dc:date.issued

2015

Author dc:creator

• Mahalingaiah, Prathap Kumar Salakatte

Chair dc:contributor.committeechair

• Singh, Kamaleshwar P.

Committee members dc:contributor.committeemember

• Mayer, Gregory D.
• Gollahon, Lauren
• Gao, Weimin

• Chronic oxidtaive stress
• Kidney cancer
• Epigenetics

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/2346/73694

OAI identifier oai:identifier

oai:ttu-ir.tdl.org:2346/73694