New research at MD Anderson Cancer Center has found that oxygen-deprived RNA molecules lead to tumor progression.
As tumors grow, they can outgrow their blood supply, leaving some areas of the tumor tissue oxygen starved, a condition known as tumor hypoxia. Conventional wisdom suggests the lack of oxygen would slow tumor growth. Surprisingly, the researchers found that cancer cells are able to adapt in order to keep growing. The study’s findings are published in the journal Nature Communications.
“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. “This process results in increased cancer progression when studied at the cellular level.”
Rajesha Rupaimoole, a graduate student 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).
With a better understanding of how hypoxia regulates critical enzymes, Sood and his colleagues believe 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 toward comprehending how miRNA can go awry during cancer progression.”