New Papers Identify a Micro RNA That Drives Both Cancer Onset and Metastasis

Findings show that miR-22 plays a key role in both breast cancer and blood cancer

Newswise BOSTON A mere 25 years ago, noncoding RNAs were considered nothing more than background noise in the overall genomic landscape. Now, two new studies reveal that one of these tiny noncoding molecules microRNA-22 plays an outsized role in two types of cancer.

Reported on-line July 3 in the journals Cell and Cell Stem Cell, the two papers demonstrate in mouse models that miR-22 drives both the onset and spread of breast cancer, as well as the onset of blood cancer. The findings, led by investigators at Beth Israel Deaconess Medical Center (BIDMC), further suggest that inhibition of miR-22 through a decoy method offers a novel therapeutic option for treating hematological malignancies.

This is the first time that a microRNA has been shown to drive both cancer initiation and metastasis in a mouse model, explains senior author Pier Paolo Pandolfi, MD, PhD, Scientific Director of the Cancer Center at BIDMC and the George Reisman Professor of Medicine at Harvard Medical School. Its amazing that, by itself, this one little microRNA can trigger cancer in two different organs, perhaps in many more, and in the case of breast cancer, can also promote metastasis.

Although many advances have been made in identifying the genetic causes of some cancers, it has become apparent that changes in the primary DNA sequence alone cannot explain the many steps that are necessary to turn a normal cell into a cancer cell. As these new papers confirm, epigenetic modifications which occur apart from changes in the underlying DNA sequences and include DNA methylation and histone modification have now been recognized as playing integral roles in cancer.

Our discovery is exciting for several reasons, says Pandolfi. Mechanistically, we have revealed one way in which microRNAs can fundamentally reconfigure the way that DNA is read. Our findings show that miR-22 triggers an epigenetic re-wiring, if you will, which represses the expression of certain genes as well as other selected microRNAs. Based on these studies, we now know that one miRNA can communicate and repress other miRNAs epigenetically. In this particular case, we have also learned that miR-22 does so by silencing a family of enzymes called TET proteins, which act as tumor suppressors.

In addition, the scientific team, led by first author Su Jung Song, PhD, a postdoctoral fellow in the Pandolfi laboratory, discovered that overexpression of miR-22 also triggers metastasis the spread of cancer from a primary site to other organs, in this case, from breast tissue to the lungs.

Metastasis remains one of the most complex and challenging problems of oncology. Recent studies have demonstrated that as tumors progress, genetic and epigenetic mechanisms may lead to the emergence of a self-renewing metastatic cancer stem cell or cancer-initiating cell, which can enter the blood stream and seed a secondary tumor in a distinct organ.

We showed that by promoting epithelial to mesenchymal transition [EMT], a process by which cancer cells gain properties that enable them to become both more motile and more invasive, miR-22 promotes aggressive metastatic disease in breast cancer, explains Song, who describes this course of events in the paper published in Cell. Specifically, she adds, miR-22 silences the anti-metastatic miR-200 through direct targeting of TET proteins, as shown in a mouse model.

But, notes Pandolfi, While these findings are extremely novel, what makes this work even more exciting is its therapeutic implications.

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New Papers Identify a Micro RNA That Drives Both Cancer Onset and Metastasis