Hui Li
Assistant Professor of Pathology in the Cancer Center
Ph.D., Case Western Reserve University
Chimeric RNAs, role in normal and cancer cells

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Gene fusion is a common feature of cancer. The fusion products were believed to be unique to cancer cells until recently we demonstrated that abundant level of fusion products can also be present in normal cells. In these normal cells, the fusion products are made by a post-transcriptional process trans- to serve important functions. Our long-term hypotheses are that such trans-splicings are more than rare events and they play critical roles in normal physiology. In addition, mis-regulated trans-splicing machinery could generate highly abundant fusion products, which would promote oncogenesis the same way as the products made by traditional chromosomal rearrangements.

To discover more RNA trans-splicing events, we propose two approaches, a candidate gene approach and a genome-wide approach. The candidate gene approach would focus on the known gene fusions associated with chromosomal translocations in various tumors. We predict that at least some of the fusion products can also be detected in the normal corresponding cells at certain conditions. The key to look for such events. For the genome-wide approach, we propose a mate- combined paired- deep sequencing approach to document the whole transcriptome trans-splicing events in the cells of interest. To validate the candidates of trans-splicing, we are developing an intra-cellular based trans-splicing assay with high throughput potential. Our preliminary studies support the second part of the hypothesis that at least some fusions are the mis-regulated products of trans-splicing. Gain of function and loss of function approaches will be used to study the effect of the trans-spliced chimeric products on cancer development. Our proposed trans-splicing study will enhance our knowledge of the genetic information flow, suggest a novel oncogenic pathway, and provide additional links between cancer and its normal origin cells. In addition, the proposed study of trans-splicing will have both immediate and long-term clinical implications.

Selected References

Li H, Wang J, Ma X, Sklar J. (2009) "Gene fusions and RNA trans-splicing in normal and neoplastic human cells." Cell Cycle. Jan 8:218-22. Epub 2009 Jan 6. [PubMed]

Li H, Wang J, Mor G, Sklar J. (2008) "A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells." Science. Sep 321(5894):1357-61. [PubMed]

Li H, Ma X, Wang J, Koontz J, Nucci M, Sklar J. (2007) "Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival." Proc Natl Acad Sci U S A. Dec 104(50):20001-6. Epub 2007 Dec 6. [PubMed]

Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J,Rerko RM, Casey G, Issa JP, Willis J, Willson JK, Plass C, Markowitz SD. (2003) "SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers." Proc Natl Acad Sci U S A. Jul 100(14):8412-7. Epub 2003 Jun 26. [PubMed]

Li H, Myeroff L, Kasturi L, Krumroy L, Schwartz S, Willson JK, Stanbridge E,Casey G, Markowitz S. (2002) "Chromosomal autonomy of hMLH1 methylation in colon cancer." Oncogene. Feb 21:1443-9. [PubMed]