Contrary to conventional logic, if cancer’s oxygen supply is taken away, cancer will respond by growing even more. University of Texas MD Anderson Cancer Center’s Anil Sood, MD, discovered this phenomenon with members of his laboratory and published the results “Hypoxia-mediated Downregulation of miRNA Biogenesis Promotes Tumour Progression,” in 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),” Dr. Sood said in an MD Anderson news release. “MiRNAs are molecules naturally expressed by the cell that regulate a variety of genes. At a functional level, this process results in increased cancer progression when studied at the cellular level.”
Stated otherwise, when tumors are starved of oxygen, a condition known as tumor hypoxia results. Hypoxia alters protein-encoding miRNAs by modifying Drosha and Dicer enzyme activity. Dr. Sood published another study with the Ontario Cancer Institute in Toronto in the same issue of Nature Communications that detailed the role of Dicer and hypoxia in breast cancer.
“Although global miRNA downregulation in cancer has been reported, the mechanism behind it has not been fully understood,” said Dr. Sood. “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.”
MiRNA regulates approximately one-third of the body’s genes, which strongly suggests a role of miRNA in cancer progression. Through a set of experiments, many of which conducted by first-author Rajesha Rupaimoole, Dr. Sood’s laboratory found that miRNAs play a major role in cancer progression.
|Anil Sood, M.D.|
The results showed that hypoxia reduces the levels of Drosha and Dicer. The mechanism behind this decrease centered around the transcription factors ETS1 and ELK1, which downregulated Drosha in hypoxic conditions. Silencing these transcription factors using small interfering RNA (siRNA) allowed recovery of Drosha. “The rescue of Drosha by siRNAs targeting ETS1 and ELK1 led to significant tumor regression,” Dr.Rupaimoole explained .
At the end of the day, Dr. Sood, Rupaimoole, and colleagues believe these results can lead to new approaches for 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.”