Decoding the Molecular Mechanisms of Ovarian Cancer Progression
Jefferson researchers identify specific lncRNAs overexpressed in aggressive ovarian cancer subtypes and link them to key metastatic process.
A new study from Sidney Kimmel Cancer Center (SKCC) investigator and Thomas Jefferson University Professor Christine Eischen, PhD provided important new insights into the mechanisms contributing to ovarian cancer. The findings were recently published in Nature Communications.
Ovarian cancer is the most lethal gynecologic malignancy in the United States, resulting in an estimated 14,100 deaths and 22,500 new cases in 2017 alone. This is primarily caused by the high rate of therapy resistance and the diagnosis of ovarian cancer after it has already metastasized, which occurs in approximately 80% of patients. In the new study, the Eischen group focused on the role of long non-coding RNAs (lncRNAs), which have emerged as key regulators of genes. By evaluating the molecular changes that occur in large cohorts of ovarian cancer patients, the researchers were able to identify several lncRNAs that are reproducibly altered in patients and which impact a critical developmental transition that contributes to the metastatic properties of their cancer cells.
The research was spearheaded by lead author and bioinformatician Ramkrishna Mitra, PhD, a postdoctoral associate in the Eischen laboratory. Mitra undertook a large-scale bioinformatics approach to evaluate over 700 ovarian cancer molecular profiles from four patient cohorts. This analysis led to the identification of several lncRNAs that are overexpressed in a particular subset of ovarian cancer: the one thought to be the most aggressive. Further analysis revealed that this lncRNA overexpression affects the expression of downstream proteins that regulate a well-known developmental process, termed the epithelial-to-mesenchymal transition (EMT).
EMT is important for cell migration and invasion, strongly suggesting that the link between lncRNAs and EMT contributes to the metastatic progression of ovarian cancer. Following up on this idea, the researchers found that one of the lncRNAs was directly implicated in patient outcomes. “Overexpression of one the lncRNAs, DNM30S, was significantly correlated with worse overall ovarian cancer patient survival,” said Eischen, Co-Leader of the Molecular Biology & Genetics Program at SKCC.
Based on these observations, the researchers suggested that targeting of the lncRNAs might represent a viable treatment strategy for ovarian cancer. To test this idea, they experimentally reduced the expression of the DNM30S lncRNA, which resulted in reduced ovarian cancer cell migration and invasion. In future work, the Eischen laboratory aims to further understand the role of lncRNAs in ovarian cancer and potentially translate their findings into clinical applications to reduce ovarian cancer metastasis.
This work was supported by NIH/NCI award R01CA177786 (to C.M.E), the Pellini Foundation Fund, and the Sidney Kimmel Cancer Center.
The authors declare no competing financial interests.
Article Reference: Ramkrishna Mitra, Xi Chen, Evan J. Greenawalt, Maulik, Ujjwal Maulik, Wei Jiang, Zhongming Zhao, Christine M. Eischen, “Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition” 2017, Nature Communications 8(1):1604. DOI: 10.1038/s41467-017-01781-0.