A genetic misfire called the 3q26.2 amplicon can cause real havoc. In fact, it is among the most frequent chromosomal aberrations seen in many cancers, including ovarian and breast cancers.
Researchers behind a study at The University of Texas MD Anderson Cancer Center believe they may have found a molecule-based approach to halting 3q26.2's destructive nature. By manipulating a non-coding microRNA (miRNA) known as miR569 that is part of the amplicon, scientists were able to increase cell death in vitro and in vivo. MicroRNAs are short, non-coding RNA molecules that are important to controlling gene expression.
The study was featured in this month's issue of Cancer Cell.
"Small non-coding miRNAs represent underexplored targets of genetic aberrations and emerging therapeutic targets," said study lead Gordon Mills, M.D., Ph.D., professor and chair of Systems Biology at MD Anderson. "We demonstrated that miR569, which is overexpressed in a subset of ovarian and breast cancers due in part to the 3q26.2 amplicon, can impact cell survival and proliferation."
In order for miR69 to halt 3q26.2's penchant for molecular mayhem, it must first alter expression levels of the tumor protein known as TP53INP1.
"The study results clearly show that TP53INP1 is a key target of miR569 both in vitro and in vivo," said Mills. "An increase in miR569 levels subsequently decreased TP53INP1 levels which was associated with worsened outcomes for ovarian patients."
However, when miR569 expression was "silenced" or decreased, TP53INP1 levels were increased and survivability outcomes improved. In effect, targeting miR569 sensitizes ovarian and breast cancer cells overexpressing miR569 to the commonly used chemotherapy agent cisplatin, which impacts its effectiveness.
"The discovery that miRNAs are potent regulators of RNA stability and translation dramatically change our understanding of the mechanisms controlling protein levels, and further provided a therapeutic approach to a number of targets that have previously been designated as 'undruggable'," said Mills.
MD Anderson study participants included Pradeep Chaluvally-Raghavan, Ph.D., Fan Zhang, Tyler Moss, Ph.D., Yiling Lu, M.D., Shuangxing Yu, M.D., Dong Zhang, Ph.D., and Prahlad Ram, Ph.D., all with the department of systems biology; Sunila Pradeep, Ph.D., Rajesha Rupaimoole, and Anil Sood, M.D., gynecologic oncology; Chad Pecot, M.D., thoracic, head and neck oncology; Cristian Rodriguez-Aguayo, Ph.D., and Gabriel Lopez-Berestein, M.D., experimental therapeutics; Avinashnarayan Venkatanarayan, biochemistry and molecular biology; Mihai Gagea, D.V.M., veterinary medicine and surgery; and Wenbin Liu, bioinformatics and computational biology. Other participating institutions included Baylor College of Medicine, Houston; the University of Oslo, Norway; Aix-Marseille University, Marseille, France; and Oregon Health & Science University, Portland, Ore.
The study was funded by the National Cancer Institute (2P50CA083639-11, 5P50CA083639-11, 5R01CA123219-01, P50CA58207, U54CA112970, P50CA083639, P50CA098258, and U54CA151668); Stand Up to Cancer/American Association of Cancer Research (SU2C-AACR-DT0209); and the Komen Promise Grant (KG081694). Chaluvally-Raghavan, the first author of the study, was supported by the Ann Schreiber Program for Excellence grant from Ovarian Cancer Research Fund and the Scientific Scholar Award from the Marsha Rivkin Center for Ovarian Cancer Research.