UTR Shortening Found to Influence Tumour Suppression
Widespread mRNA 3′ UTR shortening through alternate polyadenylation1 promotes tumor development in vivo. A prevailing theory is that it induces proto-oncogene saying in cis through escaping microRNA-mediated repression.
Now, scientists at the University of Texas Medical Branch (UTMB) at Galveston and Baylor College of Medicine, have found that that a mechanism that brings by cancer development does not involve oncogene activation, but in turn, is largely due to the repression of tumor suppressor genes, or taking the foot off of the brake.
“Oncogenes and tumor suppressor genes have long been involved in tumor development,” said senior author Dr. Wei Li, professor at Baylor College of Medicine and member of the Dan L Duncan Comprehensive Cancer Center. “Traditionally, much attention has been focused on studying mutations in these genes that can lead to cancer development, but this approach has not been sufficient to explain all cancers. We took a different approach.”
The team led by Li, took a look at mechanisms that could disrupt the normal regulation of oncogenes or tumor suppressor genes’ expression. They particularly focused on a phenomenon widely spread in cancer cells called mRNA 3ʹUTR shortening.
“The prevailing hypothesis, which is based on studies of cancer cell lines grown in the laboratory, is that mRNA 3ʹUTR shortening induces oncogene activation, but recent data has challenged that view,” said co-first author Dr. Ping Ji, assistant professor of biochemistry and molecular biology at the University of Texas Medical Branch in Galveston. “Here, we studied samples from breast cancer patients and found evidence suggesting that the major role of mRNA 3ʹUTR shortening is in mediating repression of tumor suppressor genes, rather than inducing oncogene activation.”
“We combined a computational biology approach to analyze big data with classical molecular experiments in the laboratory,” said co-first author Dr. Hyun Jung Park, who was a postdoctoral associate in the Li lab during the development of this project and currently is an assistant professor of human genetics at the University of Pittsburgh. “Our statistical model accurately predicted gene expression changes mediated by mRNA 3ʹUTR shortening in human breast cancer.”
“This study is highly significant because it sheds light on new ways that tumors disrupt gene expression networks. It was shocking to me to see the lengths that cancers such as breast tumors will go in order to reduce the expression of tumor suppressor genes,” said co-senior author Dr. Eric Wagner, associate professor of biochemistry and molecular biology at UTMB. “My lab and the Li lab have collaborated for many years, and I hope that we will continue to drill down on the mechanisms underlying cancer gene expression regulation.”
“We think that our findings can lead to future ways to manipulate the 3’UTR shortening mechanism and thus regulate PTEN and other genes involved in breast cancer to prevent or treat this condition,” Li said.