Tumor cells with low levels of let-7 had high levels of HGMA2 signalling an aggressive form of the disease.

Levels of the let-7 family of miRNAs define different stages of cancer better than some of the classical markers for tumor progression, according to researchers from the University of Chicago.

“We found that expression levels of let-7 can discriminate more effectively between more and less advanced stages of cancers than any other microRNA,” says Marcus Peter, Ph.D., professor in the Ben May Department for Cancer Research at the University of Chicago.

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 miRNAs appears to prevent human cancer cells from reasserting their prenatal capacity to divide rapidly, travel, and spread.

Dr. Peter and colleagues focused their initial studies on a standard panel, called 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 vice-versa.

The team confirmed their theory by testing HGMA2 protein levels in tumor samples from 100 patients with ovarian cancer. Neither normal ovarian tissue nor benign ovarian tumors expressed HGMA2, they found. Full blown carcinoma, however, expresses large quantities of HMGA2. They also found that a high level of HGMA2 was highly correlated with poor prognosis and low let-7 expression.

By combining the two measures, high HGMA2 and low let-7, the team separated patients into two groups, and predicted an outcome. For patients with high let-7 and low HGMA2, the five-year progression-free survival was nearly 40%. For patients with low let-7 and high HGMA2, it fell to less than 10%.

“Our data suggests that human tumors can be divided into two major subtypes, the let-7hi- and let-7lo-expressing tumor cells,” the authors write. This separation may not be restricted to ovarian cancer, or to the NCI60 panel of tumor cells, they suggest, but could apply to a multitude of tumor types.

In May, Ohio State University investigators reported that the expression pattern of miRNA may be useful in differentiating between chronic pancreatitis and pancreatic cancer.

The loss of let-7, the authors argue, could be seen as one crucial step in this process of tumor progression. One of its functions, they argue, is to maintain differentiated states by preventing the expression of embryonic genes such as HMGA2.

No rapid test of let-7 level is available for clinical use. “The levels are difficult to quantify in clinical samples,” Dr. Peter notes.

The study was published in the June 25 issue of PNAS.

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