microRNA expression may be useful in determining prognosis in hepatocellular carcinoma

Men and women with hepatocellular carcinoma had differing expression patterns of microRNAs in liver tissue, and the expression status of one microRNA — miR-26 —may contribute to determining survival and response to adjuvant therapy in these patients.

Researchers evaluated data from three independent cohorts of patients with hepatocellular carcinoma. All patients underwent radical tumor resection from 1999 to 2003. The researchers performed microRNA-expression profiling in 241 patients to identify tumor-related microRNAs and evaluate their association with survival. To validate their findings, the researchers measured microRNAs with quantitative reverse-transcriptase polymerase-chain-reaction assays in 214 patients who were included in two independent, prospective, randomized, controlled trials of adjuvant interferon alfa therapy.

Women demonstrated higher expression of miR-26a and miR-26b in non-tumor liver tissue compared with men. The researchers found reduced levels of miR-26 expression in tumors compared with noncancerous tissue, which they said indicated miR-26 expression levels are associated with hepatocellular carcinoma.

Patients with tumors that demonstrated low miR-26 expression responded better to interferon therapy than patients who had tumors with high expressions of miR-26. However, patients with low expression levels also demonstrated shorter OS. The researchers wrote that, based on these results, miR-26 status in tumors may be a tool to estimate prognosis in patients with hepatocellular carcinoma and to select patients who would likely benefit from adjuvant therapy with interferon alfa.

“Our results suggest that miR-26 may be a tumor suppressor and that miR-26 silencing in hepatocytes may contribute to the development of a more aggressive form of hepatocellular carcinoma in men,” the researchers wrote.

In an accompanying editorial, Judy Lieberman, MD, PhD, of Children’s Hospital Boston and Harvard Medical School, wrote: “The major obstacle to therapies that are based on RNA interference is delivering these oligonucleotides inside cells. Because of its filtering role, the liver traps and internalizes both small RNA drugs and gene-therapy viruses, making it an ideal testing ground for this new approach to treating cancer.” – by Tina DiMarcantonio

Ji J. N Engl J Med. 2009;361:1437-1447.

This study provides evidence that low levels of expression of a particular microRNA identify a subset of resectable hepatocellular carcinomas that have a different molecular profile than those with high levels of expression. This subset has a particularly bad prognosis but a markedly higher benefit from adjuvant interferon. The study is unable to provide insight into whether the benefit of the interferon is related to anti-tumor effects, anti-viral effects, or some other effect on the underlying liver disease. More importantly, the population in the study was all Asian, and almost exclusively had hepatitis B as the primary underlying cause of disease — a very different population than we see in North America. Before these findings could alter our practice, it would be critical to replicate the findings in a different population, preferably in a prospective fashion.

– Edward Greeno, MD

Associate Professor of Medicine, Medical Director of the Hematology/Oncology Clinic
University of Minnesota