Li-Shu Wang, PhD

Li-Shu Wang, PhD

Presentation

Mechanisms of Tumor Suppressor Gene Demethylation in Colon Cancer by Berries (PDF)

Biography

Dr. Wang is a Research Scientist at the Medical College of Wisconsin and has worked previously at the Comprehensive Cancer Center at Ohio State University. She received her Ph.D. in Veterinary Biosciences in the College of Veterinary Medicine at Ohio State in June, 2006, and immediately joined Dr. Gary Stoner’s laboratory as a Post-doctoral researcher. She has experience in evaluating the effects of chemopreventive agents, including black raspberries, on gene expression in vitro (in mammary and colon cell culture systems) and in vivo (in the rat esophagus and in human colon). Using bio-directed fractionation, she showed that the anthocyanins in black raspberries are important for their chemopreventive effects and, recently, she provided evidence that the ellagitannins may be less important.

Using DNA microarray, Dr. Wang investigated the effects of a black raspberry diet on gene expression during the early and late stages of rat esophageal carcinogenesis and has shown that the berries exhibit a genome-wide effect on the expression of genes associated with multiple cellular processes including proliferation, apoptosis, inflammation, angiogenesis, cell cycling and cell adhesion, carbohydrate metabolism and cell differentiation. Recently, she has evidence that berries cause demethylation of tumor suppressor genes in rodent and human colon leading to their enhanced expression. Currently, she has 30 peer-reviewed publications including two manuscripts in press.

Abstract

Metabolomic profiling reveals a protective modulation on fatty acid metabolism in colorectal cancer patients following consumption of freeze-dried black raspberries

Authors: Li-Shu Wang, Matthew Young, Chieh-Ti Kuo, Christine Sardo, Mark Arnold, Edward Martin, Gary Stoner

Metabolic reprogramming which refers to altered nutrient uptake and use is thought to be essential for rapid cancer cell proliferation. Accelerated phospholipid biosynthesis is another metabolic signature of cancer because proliferating cells have a significant need for membrane production. Fatty acids that compose the hydrophobic tails of membrane phospholipids can regulate gene transcription through enzyme-mediated pathways, e.g., cyclooxygenase, lipoxygenase, and changing lipid raft composition that affect receptor-mediated signalings. We previously showed that dietary intervention with freeze-dried black raspberries (BRBs) decreased cell proliferation in colorectal tumors and IL-8, a pro-inflammatory cytokine, in plasma in colorectal cancer patients.

The goal of the current study was to determine if BRBs affect fatty acid metabolism which may contribute to their anti-proliferative and anti-inflammatory activities. Plasma samples were collected from 28 colorectal cancer patients before and after oral consumption of BRB powder (60g/day) for 1-to-9 wks for metabolomic profiling analysis. 421 biochemicals were analyzed using UHPLC/Gas chromatography and mass spectrometry. When data from all 28 patients were combined, the top 30 ranking biochemicals suggest that berry intervention led to alterations mostly in lipids, following by carbohydrates, amino acids, and cofactors and vitamins. Both monounsaturated fatty acids (MUFAs), e.g., eicosenoate (20:1n9 or 11), and polyunsaturated fatty acids (PUFAs), e.g., linoleate (18:2n6), arachidonate (20:4n6), were lower in the post plasma samples. PUFAs can be synthesized from linoleate and they also can be released by phospholipase A from phospholipid membrane. Therefore, berry intervention might alter activities of phospholipase A, elongases, and desaturases which in turn reduce levels of PUFAs. Alternatively, berry intervention increased secondary bile acids, e.g., glycodeoxycholate, produced by the action of enzymes existing in the microbial flora of the colonic environment, suggesting dietary BRBs could alter colonic microflora. Berry intervention associated alternations in bile acid metabolism could affect fat absorption and subsequently impact fatty acid metabolism. In conclusion, our results suggest that dietary berry consumption protectively modulates enzymes associated with fatty acid metabolism in the host as well as in gut microflora leading to decreased proliferation and inflammation in colorectal cancer patients.

Supported by R01 CA148818 to L-S Wang

Key words: Black raspberries, Colorectal cancer, Metabolomic profiling, Gut microflora.

References:
Wang LS, Arnold M, Huang YW, Sardo C, Seguin C, Martin E, Huang TH, Riedl K, Schwartz S, Frankel W, Pearl D, Xu Y, Winston J 3rd, Yang GY, Stoner G. Modulation of genetic and epigenetic biomarkers of colorectal cancer in humans by black raspberries: a phase I pilot study. Clin Cancer Res. 2011;17(3):598-610.
Mentor-Marcel RA, Bobe G, Sardo C, Wang LS, Kuo CT, Stoner G, Colburn NH. Plasma cytokines as potential response indicators to dietary freeze-dried black raspberries in colorectal cancer patients. Nutr Cancer. 2012;64:820-825.
Milburn MV, Lawton KA, McDunn JE, Ryals JA, Guo L. Chapter 12: Understanding cancer metabolism through global metabolomics. Genetics Meets Metabolomics: from experiment to systems biology. K. Suhre (ed.) 2012;p177-190
Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703-707.
Jump DB. Fatty acid regulation of gene transcription. Crit Rev Clin Lab Sci. 2004;41:41-78.