A recent study examined how microRNA regulation could affect prostate cancer aggressiveness in hypoxic conditions. Researchers found that cancer cells in prostate tumors adapted their gene expression differently depending on the severity of oxygen deprivation, or hypoxia, in the tumor microenvironment. The findings may pave the way for novel approaches to combat aggressive prostate cancer by targeting microRNA pathways.

Tumor hypoxia—when cancer cells are deprived of oxygen—is known to drive more aggressive forms of prostate cancer, increasing the risk of recurrence following treatments such as radiotherapy and surgery. However, little has been known about the specific molecular mechanisms through which hypoxia impacts cancer cell behavior. The new study shed light on these mechanisms by showing how different levels of hypoxia regulate gene expression through microRNAs (miRNA).

MiRNAs are short, noncoding RNA molecules that regulate gene expression by degrading messenger RNA (mRNA) or inhibiting its translation into proteins. Each miRNA can target multiple genes, orchestrating large regulatory networks, especially under stress conditions like hypoxia. By examining tissue samples from 95 prostate cancer patients, the researchers were able to map miRNA activity at different hypoxia levels within tumors and predict their target genes.

In the study, published in the Journal of Pathology, the researchers identified several miRNAs associated with either moderate or severe hypoxia. These miRNAs regulated critical pathways involved in cancer progression, including cell proliferation and survival. Genes associated with the MYC oncoprotein were activated at all hypoxia levels, while the tumor suppressor gene PTEN was frequently inactivated in regions of severe hypoxia. These findings were confirmed by laboratory techniques such as quantitative PCR and immunohistochemistry.

The researchers developed a spatial analysis showing that cancer cells in severely hypoxic areas were more likely to exhibit aggressive traits such as higher rates of cell proliferation compared with those in moderately hypoxic regions. The study also confirmed that miRNA expression was colocalized with markers of cell proliferation and hypoxia, demonstrating the presence of miRNA regulation within these tumor regions.

In addition, the researchers found that the activity of certain miRNAs—along with the expression of their target genes—had significant prognostic value. In particular, high expression of MYC and the loss of PTEN in severely hypoxic regions were strongly linked to poor outcomes in patients with prostate cancer. The presence of proliferating cancer cells within these hypoxic regions was also associated with a higher risk of disease progression and recurrence.

These findings underscored the importance of miRNA regulation in shaping the aggressiveness of hypoxic prostate tumors. While previous studies have shown that hypoxia is a binary factor—either present or absent¹—the current study revealed a more nuanced picture. The level of hypoxia played a crucial role in determining how miRNAs influenced tumor behavior, making these molecules promising therapeutic targets.

The study’s findings indicated that the development of new therapies targeting the specific miRNAs involved in hypoxia-related tumor progression may offer a novel approach in combating aggressive prostate cancer. Based on the results of their study, the researchers noted that inhibiting upregulated miRNAs or restoring the function of downregulated ones could potentially slow down tumor growth and reduce the risk of recurrence.

The authors declared having no competing interests.

Reference

1. Hompland T, Fjeldbo CS, Lyng H. Tumor hypoxia as a barrier in cancer therapy: why levels matter. Cancers (Basel) 2021; 13: 499.