CINCINNATI—In a study that is the first to explain how the Alpha-methylacyl-CoA racemase (AMACR) gene is regulated in cancer development, scientists from the University of Cincinnati (UC) have identified "hotspot" areas of deleted genetic data that play a critical role in regulating gene expression and influence colon cancer progression. According to the researchers, the hotspots could be used as a biomarker to predict a person's risk for colon cancer and how the disease may progress, paving the way for development of improved colon cancer diagnostic tools.
For the study, published in the Jan. 16 issue of PLoS Genetics, the UC researchers looked at the actions of the AMACR gene in human tissue. AMACR breaks down branched-chain fatty acids, a type of molecule only found in animals that eat plants. Previous research showed that plant-derived fatty acids, such as those found in red meat and dairy products, can accelerate cancer growth.
"Prior to this study, there were only immunohistochemistry studies showing increased protein expression of AMACR in a portion of colon cancer," says Dr. Shuk-mei Ho, chair of UC's Department of Environmental Health and senior author of the study. "There were no molecular studies on promoters of the gene. Most importantly, it was unknown as to how AMACR is turned on in colon cancer. There are one or two studies on prostate cancer cell lines studying how the gene might be regulated. AMACR was recently shown to have abnormal expression patterns in colon cancer, but not much was known about how it's regulated at the gene level. Uncovering how the gene is abnormally activated in cancer will give us a better understanding of how to treat the disease in the end."
To find these answers, the UC scientists, working with researchers at the University of Massachusetts, used Arcturus LCM microdissection instruments from MDS Analytical Technologies to enrich a homogenous population of cancer cells from colon carcinoma tissue, so that their data would not be obscured by non-carcinoma material that otherwise would be included in the analysis. Scientists analyzed a series of samples that represented the entire colon cancer progression, comparing the genetic sequences of the laser capture microdissected colon carcinoma cells with sequences from a general population. Comparative sequencing of the two groups of samples revealed the genetic variations that may be the triggers for abnormal protein expression found in colon cancer.
In addition to discovering the hotspots that trigger abnormal AMACR expression, they also identified transcription factors that would normally bind to the deleted sequences to maintain normal gene expression.
"From the colon tissues, we've identified two types of genetic deletions that may allow us to predict whether people will have a good or bad cancer outcome," says Dr. Xiang Zhang, first author of the study and UC environmental health research associate. "If a person carries one of the deletions, it may predispose him or her to a more aggressive type of colon cancer."
Although scientists have long believed that a diet high in red meat and low in fiber may lead to increased risk for colon cancer, the study suggests the disease may be the product of gene-environmental interaction, Ho says.
"We need to start paying closer attention to how the environment we live in and the things we put in our bodies interact with our genetic makeup to influence our cancer risk," she says.
The UC research team expects to expand this research into a multicenter study in the near future, and will use a similar method to study AMACR expression in prostate cancer. The project is currently funded by the National Institutes of Health and the U.S. Army Prostate Cancer Program.
For the study, Deletion Hotspots in AMACR Promoter CpG Island are Cis-Regulatory Elements Controlling the Gene Expression in the Colon, Ho and Zhang were joined by UC colleagues Ranjan Deka, Zhong Jiang, Irwin Leav, Mario Medevodic and Monica Revelo. DDN
For the study, published in the Jan. 16 issue of PLoS Genetics, the UC researchers looked at the actions of the AMACR gene in human tissue. AMACR breaks down branched-chain fatty acids, a type of molecule only found in animals that eat plants. Previous research showed that plant-derived fatty acids, such as those found in red meat and dairy products, can accelerate cancer growth.
"Prior to this study, there were only immunohistochemistry studies showing increased protein expression of AMACR in a portion of colon cancer," says Dr. Shuk-mei Ho, chair of UC's Department of Environmental Health and senior author of the study. "There were no molecular studies on promoters of the gene. Most importantly, it was unknown as to how AMACR is turned on in colon cancer. There are one or two studies on prostate cancer cell lines studying how the gene might be regulated. AMACR was recently shown to have abnormal expression patterns in colon cancer, but not much was known about how it's regulated at the gene level. Uncovering how the gene is abnormally activated in cancer will give us a better understanding of how to treat the disease in the end."
To find these answers, the UC scientists, working with researchers at the University of Massachusetts, used Arcturus LCM microdissection instruments from MDS Analytical Technologies to enrich a homogenous population of cancer cells from colon carcinoma tissue, so that their data would not be obscured by non-carcinoma material that otherwise would be included in the analysis. Scientists analyzed a series of samples that represented the entire colon cancer progression, comparing the genetic sequences of the laser capture microdissected colon carcinoma cells with sequences from a general population. Comparative sequencing of the two groups of samples revealed the genetic variations that may be the triggers for abnormal protein expression found in colon cancer.
In addition to discovering the hotspots that trigger abnormal AMACR expression, they also identified transcription factors that would normally bind to the deleted sequences to maintain normal gene expression.
"From the colon tissues, we've identified two types of genetic deletions that may allow us to predict whether people will have a good or bad cancer outcome," says Dr. Xiang Zhang, first author of the study and UC environmental health research associate. "If a person carries one of the deletions, it may predispose him or her to a more aggressive type of colon cancer."
Although scientists have long believed that a diet high in red meat and low in fiber may lead to increased risk for colon cancer, the study suggests the disease may be the product of gene-environmental interaction, Ho says.
"We need to start paying closer attention to how the environment we live in and the things we put in our bodies interact with our genetic makeup to influence our cancer risk," she says.
The UC research team expects to expand this research into a multicenter study in the near future, and will use a similar method to study AMACR expression in prostate cancer. The project is currently funded by the National Institutes of Health and the U.S. Army Prostate Cancer Program.
For the study, Deletion Hotspots in AMACR Promoter CpG Island are Cis-Regulatory Elements Controlling the Gene Expression in the Colon, Ho and Zhang were joined by UC colleagues Ranjan Deka, Zhong Jiang, Irwin Leav, Mario Medevodic and Monica Revelo. DDN
