Oxygen-Deprived RNA Molecules Found to Lead to Tumor Progression

New research has discovered 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 inhibit growth. However, new insights into hypoxia has been gleaned in a study by investigators from the University of Texas MD Anderson Cancer Center (Houston, TX, USA), which examined at how specific enzymes were impacted. Unexpectedly, hypoxia led to tumor progression. Meaning, cancer cells are clever and able to modify to maintain sustained 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, MD, 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.”

Dr. Sood’s findings were published October 2014 in the journal Nature Communications. Dr. Sood also was part of a study led by the Ontario Cancer Institute (Toronto, Canada), which reported in the same issue on hypoxia and regulation of DICER in breast cancer.

The investigators discovered that hypoxia-altered miRNA’s ability to mature in cells. Given that about one-third of the body’s genes are controlled by miRNA, Dr. Sood noted that it was not surprising that cancer cells have modified 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 delayed 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 accordingly fuels continued tumor growth. Transcription factors are proteins that switch genetic instructions on and off.

Dr. 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 Mr. Rupaimoole.

With a better determination how hypoxia regulates critical enzymes, Dr. 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 Mr. 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.”

Related Links:
University of Texas MD Anderson Cancer Center