Hsa_circ_0001944 promotes colorectal cancer progression through the miR- 665/IGF2BP1/PKM2 axis-mediated glycolysis
This study demonstrates that hsa_circ_0001944 promotes colorectal cancer progression by acting as a molecular sponge for miR-665 to upregulate IGF2BP1, which subsequently enhances PKM2-mediated glycolysis and tumor growth.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Colorectal cancer is a formidable disease that often hides in its early stages, making it difficult to catch before it spreads. To understand how this cancer grows and spreads, scientists look beyond the DNA that makes up our genes and examine the complex chemical messages that cells use to communicate. Among these messengers are circular RNAs, which are tiny loops of genetic material that do not code for proteins but instead act as regulators, turning other genes on or off. Another group of messengers, known as microRNAs, are small strands that can silence specific genes. When these communication systems go wrong, cells can lose control, growing too fast and invading healthy tissue. Understanding how these molecules interact offers a way to see the inner workings of cancer and potentially find new ways to stop it.
Researchers at several hospitals in Anhui, China, focused their attention on a specific circular RNA called hsa_circ_0001944. They wanted to know if this molecule played a role in the progression of colorectal cancer. By examining tissue samples from patients and growing cancer cells in the lab, they discovered that this circular RNA is present in much higher amounts in cancerous tissue than in healthy tissue. It is found floating in the main part of the cell, the cytoplasm, rather than in the nucleus where DNA is stored. When the scientists reduced the amount of this RNA in cancer cells, the cells stopped growing as quickly and lost their ability to move and spread. In experiments where they injected these modified cells into mice, the tumors that formed were significantly smaller than those formed by cells with normal levels of the RNA. This suggested that hsa_circ_0001944 acts as a driver, pushing the cancer forward.
To understand how this molecule works, the team traced the path of its influence. They found that hsa_circ_0001944 acts like a sponge, soaking up a specific microRNA called miR-665. Under normal circumstances, miR-665 helps keep cancer growth in check by targeting a protein called IGF2BP1. However, when hsa_circ_0001944 is abundant, it soaks up so much miR-665 that there is not enough left to control IGF2BP1. This leads to a buildup of IGF2BP1, which in turn boosts the levels of another protein called PKM2. PKM2 is a key enzyme that helps cells burn sugar for energy in a specific way known as aerobic glycolysis. This metabolic process is a favorite fuel source for rapidly dividing cancer cells. The researchers confirmed this chain of events by showing that when they blocked the sponge effect of hsa_circ_0001944, the levels of miR-665 rose, IGF2BP1 dropped, and the cancer cells' ability to consume sugar and grow slowed down. Conversely, if they forced the cells to produce more IGF2BP1, the cancer cells regained their aggressive behavior even when the sponge was removed.
The study also looked at the energy consumption of these cells using specialized equipment that measures how much acid the cells release and how much oxygen they use. Cells with high levels of hsa_circ_0001944 released more acid, indicating they were burning sugar rapidly, while using less oxygen. When the researchers reduced the RNA, this pattern flipped: the cells burned less sugar and relied more on oxygen, a sign of slower, more normal metabolism. By connecting these dots, the researchers concluded that hsa_circ_0001944 promotes colorectal cancer by hijacking a specific signaling pathway that controls how cells generate energy. While the study was conducted in the lab and in mice, and the team noted that larger studies are needed to confirm these findings in humans, the work provides a clear map of how this specific molecule fuels cancer growth. It suggests that targeting this circular RNA or the proteins it influences could offer a new strategy for treating the disease.
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