Ovarian cancer is a devastating disease that afflicts approximately 22000 women and causes approximately 15,000 deaths in the United States each year. Progress has been made over the last three decades with improved 5-year survival due to better surgery and chemotherapy, but the overall cure rate remains an unacceptable 33%. Thus, there are pressing requirement for identification of novel biomarkers for prognosis and new therapeutic targets that can be used to improve outcome for ovarian cancer patients. ceRNA is a type of RNA that binds and inactivates microRNA (miR). Since miR have important roles in the initiation and progression of ovarian cancer, ceRNA could be an important regulator in ovarian cancer. The role of ceRNA in the regulation of miR in ovarian cancer represents an understudied opportunity to generate new biomarkers and new therapeutic opportunities.
Locus 3q26.2 of Chromosome 3, is highly amplified in a subset of high-grade serous epithelial ovarian cancer (HGSEOC), making it the most common copy number abnormality in the most aggressive and lethal form of ovarian cancer. Copy number variations (CNVs), a form of structural variation of the DNA in the cell, are frequent events in ovarian cancer. CNVs alter the amount of DNA for genes leading to changes in amounts of the proteins that influence the growth and behavior of ovarian cancer cells. Protein coding regions in CNVs have been well studied and characterized by our and other laboratories. Our high-throughput and high-resolution analysis recently showed that non-coding microRNAs named miR569 and miR551b in the 3q26.2 CNV are highly amplified and highly expressed in HGSEOC. Using cellular and molecular approaches we demonstrated the underlying oncogenic mechanism of action both miR569 and miR551b in ovarian cancer.
In the proposed study we will characterize the novel role of the CLDN11 gene, which is located close to miR569 and miR551b in the 3q26.2 locus. Our preliminary data demonstrates a novel action of CLDN11 mRNA on miR dynamics, that we have designated the ‘CLDN11 ceRNA effect’, which provides a growth advantage to ovarian cancer cells. Briefly, CLDN11 ceRNA acts as a sponge, which binds and inactivates important tumor suppressor microRNAs. Our studies will characterize the mechanism how CLDN11 ceRNA hijacks several tumor suppressor miR, and in turn increases the expression of important oncogenes resulting in activation of key tumorigenic pathways. Thus targeting CLDN11 ceRNA effect has the potential to inhibit the growth and metastasis of ovarian cancer cells. The role of ceRNA in human cancer is only beginning to emerge, thus our studies will provide novel therapeutic opportunities and biomarkers in ovarian cancer.
Dr. Pradeep Chaluvally-Raghavan is an Instructor in the Department of Systems Biology at The University of Texas MD Anderson Cancer Center. Dr. Chaluvally-Raghavan completed his Ph.D from the University of Calicut in India. During his graduate training, his research was focused on the roles of NF-kB transcription factor in melanoma metastasis. Soon after his Ph.D, Dr. Chaluvally-Raghavan started working in the lab of Dr. Yosef Yarden at the Weizmann Institute of Science, where he studied the role of EGFR family members in breast cancer. Later, he joined the lab of Dr. Gordon Mills as a postdoctoral fellow to study genomic aberrations in ovarian cancer. In recognition of his accomplishments and contributions, Dr. Chaluvally-Raghavan has been promoted to the faculty position in the Department of Systems Biology at MD Anderson Cancer Center.
During his research in the Department of Systems Biology, Dr. Chaluvally-Raghavan has received several honors and recognitions, including the Ann Schreiber Investigator Award from the Ovarian Cancer Research Fund in 2013, Young Investigator Award from the American Association of Indian Scientists in Cancer Research in 2013, Scientific Scholar Award from the Marsha Rivkin Foundation in 2014, and three different Scholar In Training awards from the American Association of Cancer Research in the years of 2009, 2013 and 2015. Pradeep has published several papers during his training, including his publications in Cancer Cell and Oncogene. His current research is focusing on the oncogenic roles of non-coding genetic aberrations in ovarian cancer. Successful completion of his research will add new microRNAs to the list of oncomiRs that can serve as biomarkers to predict the outcome of the disease as well as novel therapeutic targets to treat ovarian cancer. Receiving the Liz-Tilberis career development award from the Ovarian Cancer Research Foundation, which funds the best and brightest ovarian cancer researchers in the country, Dr. Chaluvally-Raghavan is on his way to establish his independent research program in ovarian cancer research.