In cancer research, one person's junk is increasingly becoming another person's treasure. Scientists have now uncovered new evidence showing how recently evolved "junk DNA" genetic elements can become integrated into ancient cellular pathways that regulate cancer. These findings may provide fresh insights into how evolutionary forces shape disease and reveal potential new targets for cancer research.
In a new study published today in the journal Science Advances (10.1126/sciadv.aeb5510), researchers from Arizona State University and an international team led by Tianjin Medical University, examined the evolutionary history of "junk DNA" molecules that were first identified a generation ago from the human genome project.
The phrase "junk DNA" often refers to DNA elements that do not produce proteins and possibly do not contribute to organism performance. Numerous classes of such elements make up much of the human genome. Scientists questioned why they were there. But further research proved this was a misnomer when they were found to play an important role in helping regulate how genes function, including emerging insights into how they may be associated with diseases like cancer.
Now referred to as long noncoding RNAs (lncRNAs), many are unique to primates and humans, and so scientists have increasingly recognized them as important players in cancer.
Lurking in the oldest branches of life
By performing a comparative genomic study, the researchers found that many cancer-associated lncRNAs first emerged on the scene as smaller, non-functional RNA fragments, or microRNA elements, through increased transcription. These gradually expanded in length to become lncRNAs by incorporating additional genetic material, and eventually became integrated into deeply conserved, vital cellular pathways that evolved hundreds of millions of years ago.
Our findings suggest that cancer-associated long noncoding RNAs are not simply recent evolutionary additions. Instead, they can gradually become integrated into regulatory systems that have existed for hundreds of millions of years, illustrating how evolution continually reshapes the architecture of cellular networks in ways that become relevant to diseases like cancer."
Michael Lynch, Professor, Biodesign Center for Mechanisms of Evolution at Arizona State University and co-author of the study
Using genomic sequence analyses of 18,000 lncRNAs across 17 animal species, the researchers reconstructed how lncRNAs first emerged and retraced their biological roles over almost 500 million years of evolutionary time. Overall, ~5000 lncRNAs were identified and found to be associated with at least one cancer type. These were retained for further investigation. During the evolutionary trajectory of primates, the studied lncRNAs showed significant expansion of their genomic segments, alongside a notable increase in their overall expression abundance.
The team explored the role of one particular lncRNA, MIR497HG, as a striking example of this process.
The molecule appears to have originated in a common human and primate ancestor as a microRNA some 29 million years ago, before a time when humans and macaques diverged.
Around that time, a single DNA mutation, changing the DNA code from A-to-T, created a new green "go" light to sputter out short bursts of RNA expression, and thus, MIR497HG was born.
After humans and macaques diverged 29 million years ago, a long form of MIR497HG first emerged, entirely unique to humans. As it grew and expanded, the molecule became interconnected to ancient regulatory networks (473 million years ago) ---important pathways necessary for multicellular life, including metabolism, stress responses and programmed cell death. Once expanded, they could repurpose these pathways for a brand-new role, where misexpression could be cancer-causing.
Lab experiments reenforce findings
Next, the team performed a series of experiments in human stem cells and multiple cancer cell lines to further demonstrate the role of MIR497HG. First, they found that reducing MIR497HG expression promoted cancer cell growth. They also showed that doing the opposite--- restoring its expression--- suppressed cancer proliferation across multiple cancer cell types.
"By combining evolutionary biology with cancer biology, we were able to trace how a young RNA molecule acquired regulatory functions within one of the cell's most ancient signaling networks," said Wen Wei, corresponding author of the study and researcher in the Biodesign Center for Mechanisms of Evolution at Arizona State University. "Understanding how these regulatory RNAs evolved gives us a new framework for identifying biomarkers and potential therapeutic targets across multiple cancer types."
The future impact of the results could point the way of using MIR497HG as a predictive cancer biomarker, because high levels are expressed in normal tissues while reduced levels are associated with the progression of cancer and poor clinical outcomes.
The work also identified a precise evolutionary connection between MIR497HG and the AMPK-ferroptosis regulatory axis, suggesting that disruption of this network may contribute to tumor development, and lead to a new avenue of cancer therapeutics research.
"We focused on how sequence expansion and alternative splicing allow a young lncRNA to plug into established regulatory machinery," said Yongmei Li, professor at Tianjin Medical University and co-author of the study. "Functionally, we demonstrate that the long, unspliced MIR497HG exerts its tumor-associated role by engaging the deeply conserved AMPK signaling pathway and ferroptosis to promote cancer cell proliferation. This finding uncovers a previously unrecognized evolutionary mechanism, in which a recently emerged RNA can functionally integrate into and repurpose cancer regulatory machinery rapidly."
In a silent way
The study greatly increased the number of lncRNAs found within the human genome, and a smaller subset specifically associated with cancer.
The findings suggest that many human-specific regulatory RNAs may have emerged through similar evolutionary processes, gradually becoming incorporated into conserved biological pathways while simultaneously increasing the complexity, and vulnerability of gene regulatory networks to disease.
The study supports an evolutionary model known as neutral evolution, in which initially genetic innovations can persist almost silently, located in a permissive environment for long enough to spread out and connect to the wiring of existing biological networks.
Beyond providing new insights into the origins of cancer-associated genes, the research highlights the value of evolutionary biology for understanding human disease and identifying new avenues for future cancer therapies as their database of lncRNAs is increasingly explored.
The study was conducted by researchers from Arizona State University, Tianjin Medical University, the University of Chicago, Zhejiang A&F University, Chengdu Neusoft University and other collaborating institutions.
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Journal reference:
Sun, L., et al. (2026). Rapid evolution of lncRNAs introduces novel regulatory inputs into ancestral cancer pathways. Science Advances. DOI: 10.1126/sciadv.aeb5510. https://www.science.org/doi/10.1126/sciadv.aeb5510