AACR Spotlight on Cancer Center Research
April 23, 2010
A Nobel laureate highlighted the work of Norris Cotton Cancer Center researchers on April 19, at the annual meeting of the American Association for Cancer Research (AACR).
Dartmouth Medical School (DMS) alumnus Xi Liu, PhD, was lead author of a Cancer Center study on the uses of microRNAs (miRNAs) in cancer therapies while working in the laboratory of Ethan Dmitrovsky, MD, Co-Director of the Cancer Epidemiology and Chemoprevention Research Program, and a member of the Cancer Mechanisms Research Program. Dmitrovsky is also DMS's Andrew G. Wallace Professor of Pharmacology and Toxicology and of Medicine, as well as an American Cancer Society Professor.
"We have uncovered a previously unrecognized oncogenic microRNA in mouse and human lung cancers, miR-31, which exerts its effects by repressing the expression of specific tumor suppressors," said Liu, now a postdoctoral fellow at the National Cancer Institute (NCI), before the conference.
MiRNAs encode small RNAs that regulate gene expression, thus helping researchers better classify, diagnose, and potentially treat cancer. In their study, Liu and colleagues identified miRNAs that are over-expressed in lung cancers compared with those of normal lung tissues, and identified those that function as cancer-promoting miRNAs. The Journal of Clinical Investigation published the study, with Dmitrovsky as principal investigator, in its April 1 issue.
In addition to Liu's study of lung cancer, Nobel Prize-winner Philip A. Sharp, PhD, of the Massachusetts Institute of Technology (MIT), singled out - during a press conference at the end of the AACR gathering - three other cancer studies using miRNAs. The abstracts include a study of colorectal cancer from the University of Alabama-Birmingham, one of melanoma brain metastasis from the New York University School of Medicine, and one of breast cancer from the M.D. Anderson Cancer Center at the University of Texas.
"These abstracts are part of a revolution in cell biology that began in 2001 when the importance of miRNAs was recognized," said Sharp, a professor at MIT's Koch Institute for Integrative Cancer Research. "The science of miRNAs and related small RNAs will continue to generate new insights into cancer and possible future treatments."
Liu and his Dartmouth colleagues identified miR-31 target genes that included two tumor suppressors: large tumor suppressor 2 (LATS2), and PP2A regulatory subunit B alpha isoform (PPP2R2A). Expression of miR-31 was inversely related to LATS2 and PPP2R2A in both mouse and human lung cancers, according to Liu.
In a validation study, researchers detected 10 abundantly over-expressed miRNAs in a mouse model. Then, using human lung cancers available through Dartmouth tissue banks, they found that three miRNAs were significantly over-expressed - miR-31, miR-136, and miR-376a.
"It was surprising," Liu said, "that knock-down of only miR-31 repressed growth of mouse and human lung cancer cells and inhibited lung cancer formation in mice."
During his time in the Dmitrovsky Lab, Liu also co-authored a study showing how a cyclin dependent kinase (CDK) inhibitor represses lung-cancer growth. Fabrizio Galimberti, now a fourth-year PhD student at DMS, was lead author of the study, which appeared on the cover of the January 2010 edition of the AACR journal Clinical Cancer Research.
Dartmouth faculty collaborating with Liu and Dmitrovsky on the microRNA research include:
- Murray Korc, MD, chair of the DMS Department of Medicine, member of the Cancer Center's Molecular Therapeutics Research Program, and professor of Medicine and of Pharmacology & Toxicology
- Vincent A. Memoli, MD, professor of Pathology and a member of several oncology groups at the Cancer Center
- James DiRenzo, PhD, Scientific Co-Director of the Cancer Center's Comprehensive Breast Cancer Program, and associate professor of Pharmacology & Toxicology
- Konstantin H. Dragnev, MD, associate professor of Medicine and a member of the Cancer Center's Comprehensive Thoracic Oncology Program
- Angeline S. Andrew, PhD, DMS '01, assistant professor of Community and Family Medicine, member of the Cancer Center's Cancer Epidemiology and Chemoprevention Research Program, and member of Dartmouth's Toxic Metals Research Group
- Eugene Demidenko, PhD, research professor of Community and Family medicine and a member of the Cancer Center's Biostatistics Shared Resource
- Sarah J. Freemantle, PhD, assistant professor of Pharmacology & Toxicology
- Lorenzo F. Sempere, PhD, research associate in Biochemistry
Other Dartmouth contributors include postdoctoral fellows Meir Preis, MD, PhD, and Yue Luo, MS; Hua Li, PhD, a research associate in the Department of Pharmacology & Toxicology; and Dartmouth Medical School PhD students Haoxu Ouyang and Wei Shi.
- Read the study: "MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors," published in April 2010 in the Journal of Clinical Investigation.
- Read the study: "Targeting the Cyclin E-Cdk-2 Complex Represses Lung Cancer Growth by Triggering Anaphase Catastrophe," published in January 2010 in the journal Clinical Cancer Research.