Oxygen-deprived RNA molecules lead to tumor progression, study finds

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."