New research at The University of Texas MD Anderson Cancer Center has unearthed a previously unknown phenomenon: Key regulatory molecules are decreased when deprived of oxygen which leads to increased cancer progression in vitro and in vivo.
As tumors grow, they can outgrow their blood supply, leaving some of the tumor with areas where the tissue is oxygen starved, a condition known as tumor hypoxia. Conventional wisdom would suggest the lack of oxygen would slow growth. However, new information about hypoxia has been come to light in the MD Anderson study which looked at how certain enzymes were impacted. Surprisingly, hypoxia led to tumor progression. In short, cancer cells are wily and able to adapt in order to maintain continued growth.
“We showed that that hypoxia causes a downregulation of, or decrease in, quantities of Drosha and Dicer, enzymes that are necessary for producing microRNAs (miRNAs). MiRNAs are molecules naturally expressed by the cell that regulate a variety of genes,” said Anil Sood, M.D., professor of gynecologic oncology and reproductive medicine and cancer biology. “At a functional level, this process results in increased cancer progression when studied at the cellular level.”
Sood’s findings are published in this month’s issue of Nature Communications. Sood also was part of a study led by the Ontario Cancer Institute in Toronto, which reported in the same issue on hypoxia and regulation of DICER in breast cancer.
The investigation discovered that hypoxia-altered miRNA’s ability to mature in cells. Given that approximately one-third of the body’s genes are regulated by miRNA, Sood said that it was not surprising that cancer cells have altered miRNA levels and that miRNAs are extensively involved in cancer progression.
“Although global miRNA downregulation in cancer has been reported, the mechanism behind it has not been fully understood,” he said. “We already knew that downregulation of the enzymes Drosha and Dicer in ovarian, lung and breast cancer is associated with poor patient outcomes. In this study, we identified new methods for downregulation of miRNA.”
This chain of events stalled development of miRNA in its tracks, due to hypoxia leading to reduced levels of Drosha and Dicer. Rajesha Rupaimoole, a graduate student in the cancer biology program and first author of the study demonstrated that the disruption of molecular machinery depends on the transcription factors, ETS1 and ELK1 in order to successfully decrease one of the enzymes, Drosha, which consequently spur continued tumor growth. Transcription factors are proteins that turn genetic instructions on and off.
Sood’s team, however, demonstrated that ETS1 and ELK1 could be “silenced” when deprived of oxygen in vivo when they were targeted by specific RNA molecules known as small interfering RNA (siRNA).
“The rescue of Drosha by siRNAs targeting ETS1 and ELK1 led to significant tumor regression,” said Rupaimoole.
With a better understanding of how hypoxia regulates critical enzymes, Sood believes that there is potential for a new approach to halting tumor progression.
“Use of Drosha- and Dicer-independent siRNA-based gene targeting is an emerging strategy to develop therapies that target undruggable genes,” said Rupaimoole. “A comprehensive understanding of Drosha and Dicer downregulation under hypoxic conditions is an important leap towards comprehending how miRNA can go awry during cancer progression.”
MD Anderson participants in the study included Rajesha Rupaimoole, Sherry Wu, Ph.D., Sunila Pradeep, Ph.D., Cristina Ivan, Kshipra Gharpure, Archana Nagaraja, Guillermo Armaiz-Pena, Ph.D., Michael McGuire, Ph.D., Behrouz Zand, M.D., Heather Dalton, M.D., Justyna Filant, Ph.D., Justin Bottsford-Miller, M.D., Chunhua Lu, M.D., Ph.D., Nouara Sadaoui, Lingegowda Mangala, Ph.D., and Morgan Taylor, Ph.D., all of the department of gynecologic oncology and reproductive medicine; Cristian Rodriguez-Aguayo, Ph.D. , Gabriel Lopez-Berestein, M.D., and George Calin, M.D., Ph.D., all of the department of experimental therapeutics; Menashe Bar-Eli, Ph.D. and Li Huang, department of cancer biology; and Wei Zhang, Ph.D., department of pathology. Other participating institutions included the University of North Carolina, Chapel Hill, N.C., University Health Network, Toronto, and Indiana University, Indianapolis.
The study was funded by the National Institutes of Health (CA016672, CA109298, UH2TR000943-04, P50 CA083639, P50 CA098259, U54 CA151668, U24 CA143835, and CA155332), the National Cancer Institute (CA009666, T32 CA101642), the Cancer Prevention and Research Institute of Texas (RP110595, RP10152, and RP101489), the Ovarian Research Fund, Inc., and the Department of Defense (OC073399), the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The RGK Foundation, The Gilder Foundation, The Judi A. Rees Ovarian Cancer Research Fund, Mr. and Mrs. Daniel P., Gordon, the H.A. and Mary K. Chapman Charitable Foundation, The Blanton-Davis Ovarian Cancer Research Program, the Russell and the Diana Hawkins Family Foundation , and the Foundation for Women’s Cancer.
University of Texas MD Anderson Cancer