UK researchers switch off genes that trigger cervical cancerBMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7364.563 (Published 14 September 2002) Cite this as: BMJ 2002;325:563
UK researchers have reported that they have been able to switch off a human papillomavirus gene that triggers cervical cancer, using a new highly targeted technique—RNA interference.
A team at the University of York reported last week that RNA interference, which works by selectively “silencing” homologous genes, completely eliminated all human cervical cancer cells in vitro yet left healthy cells unharmed (Oncogene 2002;21: 6041-8)
This was the first evidence that RNA interference can turn off genes of infectious viruses in tumour cells, rendering them harmless.
The researchers chose human cervical cancer cells that are positive for human papillomavirus type 16 for the experimental model because the type is well understood and clinically important. Over 90% of human cervical cancers test positive for papillomavirus, and abnormal cell proliferation is driven by the effects of two viral genes—E6 and E7.
Professor Jo Milner, professor of cell biology at the University of York, and coworker Dr Ming Jiang tested whether RNA interference could silence E6 and E7 gene expression and restore normal cell functions. They designed short interfering RNA (siRNA) for each gene and used liposomes to introduce it into the cells.
The siRNA targeted homologous messenger RNA (mRNA—the intermediate messenger molecule that carries the code from DNA in cell nuclei to build proteins in the cell cytoplasm—resulting in its destruction. RNA interference degrades mRNA and so blocks the production of the protein it codes for.
Professor Milner reported: “Silencing E6 completely eliminated E6 mRNA in cervical cancer cells, but the cells continued to grow, although at a slower rate. We then thought perhaps we might need to silence both E6 and E7.”
Her research team tested siRNA for E7 alone to ensure that it worked. “To our surprise, silencing E7 completely stopped cell proliferation and caused massive apoptosis of the cells,” she said. Apoptosis is the process of cell suicide that enables controlled removal of cells without inducing an inflammatory response. It is disrupted in many cancers, resulting in uncontrolled cell growth.
Reassuringly, the study showed that siRNA for E7 had no effect on healthy cells, showing its highly selective anticancer effect.
“For the first time, we have demonstrated that siRNA can induce selective silencing of exogenous oncogenic viral genes in mammalian cells,” Professor Milner explained. “Secondly, we have shown that the process of RNA interferece does not interfere with the recovery of cellular regulatory systems previously inhibited by viral gene expression.”
She added: “The research indicated that E7 siRNA has major therapeutic potential for the treatment, and possibly the prevention, of human cervical cancer.”
The next step is to identify how E7 disrupts the normal apoptotic pathway. Many cancers involve an imbalance between processes that promote or inhibit cell death, so the proof that RNA interference can silence the genes leading to this loss of control could have wide applications.