Levels of a small non-coding RNA molecule called let-7 appear to define different stages of cancer better than some of the "classical" markers for tumor progression, researchers from the University of Chicago report in the June 25, 2007, early online edition of the Proceedings of the National Academy of Sciences.
By suppressing genes that are active in the developing embryo, silenced just before birth, and re-activated years later in many advanced cancers, the let-7 family of "microRNAs" tiny snippets of RNA that can put the brakes on expression of selected genes appears to prevent human cancer cells from reasserting their prenatal capacity to divide rapidly, travel and spread.
Since they were first discovered in 1993, there had been growing interest in microRNAs and their role in gene regulation. Hundreds of these tiny molecules, about 20 nucleotides in length, have been discovered, scattered throughout the human genome. They act in most cases by attaching themselves to specific sites on messenger RNA, where they block ribosome access and thus prevent production of that protein.
"There may be no human cancer that is not regulated by microRNAs," said study author Marcus Peter, professor in the Ben May Department for Cancer Research at the University of Chicago, "and among microRNAs, let-7 appears to be a key player in preventing a cancer from becoming more aggressive."
"We found that expression levels of let-7 can discriminate more effectively between more and less advanced stages of cancers than any other microRNA," Peter said. "We suspect that loss of members of the let-7 family may be a major determinant of cancer progression."
Understanding how microRNAs such as let-7 keep cancers in check could also point toward a whole new class of anti-cancer therapies, he suggested.
Peter and colleagues focused their initial studies on a standard panel, known as NCI60, of 60 human tumor cell lines that can genetically be divided into two large groups, which they called superclusters 1 and 2. Supercluster 1 cells may represent less differentiated, more aggressive stages of cancer. In contrast, supercluster 2 cells express a gene signature that is consistent with more differentiated, less aggressive cancers.
They tracked down one of let-7's primary targets, a gene called HMGA2, which is overexpressed in a wide variety of cancers. Tumor cells with high levels of let-7, the researchers found, had low levels of HGMA2 and tumor cells with low expression of let-7 expressed high amounts of HMGA2.
Next, they turned to a colleague, gynecologic oncologist Ernst Lengyel, an assistant professor of obstetrics and gynecology at the University of Chicago, whose research group focuses on ovarian cancer. Their theory was first confirmed with ovarian cancer cell lines and then the Peter/Lengyel team tested HGMA2 protein levels in tumor samples from 100 patients with ovarian cancer.
Neither normal ovarian tissue nor benign ovarian tumors expressed HGMA2, they found. However full blown carcinoma expresses large quantities of HMGA2. They also found that a high level of HGMA2 was highly correlated with poor prognosis, and that high HGMA2 levels were closely tied to low let-7 expression.