Protien Cyclin D1 governs microRNA processing in breast cancer

Nov. 29, 2013 — Cyclin D1, a protein that helps push a replicating cell through the cell cycle also mediates the processing and generation of mature microRNA (miRNA), according to new research publishing November 29 in Nature Communications. The research suggests that a protein strongly implicated in human cancer also governs the non-protein-coding genome. The non-coding genome, previously referred to as junk DNA, makes up most of the human genome, and unlike the coding genome, varies greatly between species.

"In addition to its role in regulating the cell cycle, cyclin D1 induces Dicer and thereby promotes the maturation of miRNA," says lead researcher Richard Pestell, M.D., Ph.D., Director of the Kimmel Cancer Center at Thomas Jefferson University and Chair of the Department of Cancer Biology. Dicer is a protein that converts inactive hairpin-structured microRNA precursors into their active single stranded form. "The work supports the idea that cancer-causing proteins like cyclin D1 may drive cancer progression in part via miRNA biogenesis."

Using antisense RNA, Dr. Pestell's group was the first to show that cyclin D1 drives mammary tumor growth in vivo. In prior work, they showed that cyclin D1 regulates the non coding genome, and that the non-coding genome, in turn, regulates expression of cyclin D1. Furthermore, the group showed that many cancer patients encode a form of cyclin D1 that evades negative feedback from the non coding genome. These attenuating feedback loops between the non coding and coding genome may be a common theme in cancer and other biological processes.

In the current study, the group sought to investigate the mechanism by which cyclin D1 regulates the biogenesis of non coding miRNA. Dr. Pestell and colleagues developed transgenic mice that could induce cyclin D1 expression in the breast and examined cells with cyclin D1 gene deleted. The researchers noticed that cells lacking cyclin D1 produced less of the miRNA-processing protein, Dicer, and therefore had reduced levels of mature miRNA.

The group also examined cells lacking Dicer, and noted many similarities between Dicer-lacking and cyclin D1-lacking cells, in addition to failure of miRNA processing, suggesting a deeper connection between these two processes.

In addition to the in vitro studies, the researchers also examined over 2,200 patient samples. They found that patients with the luminal A subtype of breast cancer had increased levels of expression of both cyclin D1 and Dicer. Luminal A subtype of breast cancer is the most common type and also has the best prognosis. The more aggressive basal-like subtype of breast cancers, however, exhibited lower levels of cyclin D1 and Dicer, which would in turn globally reduce the level of mature miRNA. Indeed, lower levels of miRNAs have been observed in a number of human cancers.

"By linking the decrease in miRNA levels to Dicer, we show that a global decrease in miRNA processing may be important in the initiation and progression of certain cancers," says first author, Zuoren Yu, Ph.D., who holds a joint appointment at Jefferson's Kimmel Cancer Center and Tongji University School of Medicine in Shanghai, China.

Because the cyclin D1 gene has been implicated in a variety of other human cancers these findings may have broad implications for processing of non coding RNA in human tumorigenesis.

View the original article here

Protien Cyclin D1 governs microRNA processing in breast cancer

Nov. 29, 2013 — Cyclin D1, a protein that helps push a replicating cell through the cell cycle also mediates the processing and generation of mature microRNA (miRNA), according to new research publishing November 29 in Nature Communications. The research suggests that a protein strongly implicated in human cancer also governs the non-protein-coding genome. The non-coding genome, previously referred to as junk DNA, makes up most of the human genome, and unlike the coding genome, varies greatly between species.

"In addition to its role in regulating the cell cycle, cyclin D1 induces Dicer and thereby promotes the maturation of miRNA," says lead researcher Richard Pestell, M.D., Ph.D., Director of the Kimmel Cancer Center at Thomas Jefferson University and Chair of the Department of Cancer Biology. Dicer is a protein that converts inactive hairpin-structured microRNA precursors into their active single stranded form. "The work supports the idea that cancer-causing proteins like cyclin D1 may drive cancer progression in part via miRNA biogenesis."

Using antisense RNA, Dr. Pestell's group was the first to show that cyclin D1 drives mammary tumor growth in vivo. In prior work, they showed that cyclin D1 regulates the non coding genome, and that the non-coding genome, in turn, regulates expression of cyclin D1. Furthermore, the group showed that many cancer patients encode a form of cyclin D1 that evades negative feedback from the non coding genome. These attenuating feedback loops between the non coding and coding genome may be a common theme in cancer and other biological processes.

In the current study, the group sought to investigate the mechanism by which cyclin D1 regulates the biogenesis of non coding miRNA. Dr. Pestell and colleagues developed transgenic mice that could induce cyclin D1 expression in the breast and examined cells with cyclin D1 gene deleted. The researchers noticed that cells lacking cyclin D1 produced less of the miRNA-processing protein, Dicer, and therefore had reduced levels of mature miRNA.

The group also examined cells lacking Dicer, and noted many similarities between Dicer-lacking and cyclin D1-lacking cells, in addition to failure of miRNA processing, suggesting a deeper connection between these two processes.

In addition to the in vitro studies, the researchers also examined over 2,200 patient samples. They found that patients with the luminal A subtype of breast cancer had increased levels of expression of both cyclin D1 and Dicer. Luminal A subtype of breast cancer is the most common type and also has the best prognosis. The more aggressive basal-like subtype of breast cancers, however, exhibited lower levels of cyclin D1 and Dicer, which would in turn globally reduce the level of mature miRNA. Indeed, lower levels of miRNAs have been observed in a number of human cancers.

"By linking the decrease in miRNA levels to Dicer, we show that a global decrease in miRNA processing may be important in the initiation and progression of certain cancers," says first author, Zuoren Yu, Ph.D., who holds a joint appointment at Jefferson's Kimmel Cancer Center and Tongji University School of Medicine in Shanghai, China.

Because the cyclin D1 gene has been implicated in a variety of other human cancers these findings may have broad implications for processing of non coding RNA in human tumorigenesis.

View the original article here

MicroRNA molecule found to be potent tumor-suppressor in lung cancer

Sep. 16, 2013 — New research shows that microRNA-486 is a potent tumor-suppressor molecule in lung cancer, and that the it helps regulate the proliferation and migration of lung-cancer cells, and the induction of programmed cell death, or apoptosis, in those cells.

The preclinical study was led by researchers at the Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James). It found that microRNA-486 (miR-486) directly targets the insulin growth-factor pathway, which is important for cell survival and proliferation. Alternations in the pathway are believed to play an early role in tumor initiation and progression.

The researchers further found that miR-486 is itself regulated by the tumor-suppressor gene p53, the most frequently altered gene in human cancers, and that activity of miR-486 is partially dependent upon functional p53.

Published in the Proceedings of the National Academy of Sciences, the study suggests that miR-486 might serve as a biomarker for lung-cancer patients who might respond to treatment with insulin-growth-factor inhibitors.

"It wasn't known whether miR-486 functioned as an oncogene or a tumor-suppressor gene in lung cancer," says co-corresponding author Patrick Nana-Sinkam, MD, associate professor of medicine and a researcher with the OSUCCC -- James Molecular Biology and Cancer Genetics Program.

"miR-486 appears to be a biomarker for lung cancer, but its mechanisms of action remain unclear," he says. "These findings show that miR-486 serves a tumor-suppressor function in lung cancer, and that miR-486 action is partially dependent on p53."

"This partial reliance of one tumor-suppressor on another was a surprise," says principal investigator and co-corresponding author Carlo M. Croce, MD, director of Ohio State's Human Cancer Genetics program and the John W. Wolfe Chair in Human Cancer Genetics at the OSUCCC -- James. "We don't know yet what implications, if any, this might have for the development of targeted therapies."

MicroRNAs are a class of short, non-coding RNAs that regulate the translation or degradation of messenger RNA and therefore the proteins that cells make. Research is showing that certain microRNAs are frequently dysregulated in cancer.

Nana-Sinkam and his colleagues examined lung-tumor samples from 81 patients with stage-1 nonsmall-cell lung cancer and tumor-cell lines. Analyses identified miR-486 as the most decreased of microRNAs in the cells, so the researchers chose it for further investigation.

View the original article here