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MicroRNA Methylation Linked to Cancer Metastasis

NEW YORK (GenomeWeb News) – Methylating and silencing tumor suppressing microRNAs can hasten cancer metastasis, according to new research.
Using miRNA microarrays and demethylation experiments, an international team of researchers identified a handful of miRNAs — miR-148a, miR-34b/c, and miR-9 — that are methylated in conjunction with metastasis. In both cell culture and in mouse models, restoring the function of some of these miRNAs hindered cancer cell migration. The paper is scheduled to appear online this week in the Proceedings of the National Academy of Sciences.
“Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of human cancer metastasis,” senior author Manel Esteller, a researcher affiliated with the Spanish National Cancer Research Center and Barcelona’s Catalan Institute of Oncology, and his co-workers wrote.
Metastasis is implicated in the vast majority — some 90 percent — of cancer deaths for those with solid tumors. During metastasis, cells from a primary tumor acquire the ability to move into neighboring tissues, enter the bloodstream, and travel to others sites, where they produce secondary tumors.
To date, at least three miRNAs, short, non-coding RNAs that silence gene expression by binding to messenger RNA, have been implicated in cancer metastasis. Other miRNAs, meanwhile, seem to suppress metastasis by silencing cancer-causing oncogenes.
Based on previous findings suggesting that some miRNAs are silenced during CpG island methylation, the researchers speculated that looking at overall miRNA methylation patterns in metastatic cells might provide valuable clues about metastasis. To do this they treated lymph node cancer cells that had metastasized from colon, melanoma, and head and neck cancers with a demethylating agent. They then hybridized the RNA to a miRNA microarray before and after demethylation.
Using this approach, the team identified 57 miRNAs that were expressed at twice or more the original level after demethylation. Nearly half of these were found within CpG islands, regions of the genome that can be epigenetically methylated (for instance, in certain cancers).
By bisulfite genomic sequencing metastatic cells to assess the state of the 27 up-regulated miRNAs, the researchers confirmed that some 59 percent of the miRNAs were hypermethylated in CpG islands. After narrowing their search down to a group of miRNAs that were methylated in metastatic cancer cells but not in normal tissues, the team was left with a handful of potentially tumor-suppressing miRNAs: miR-148a, miR-34b/c, miR-9-1, miR-9-2, and miR-9-3.
After demonstrating that methylation did, indeed, decrease the expression of these miRNAs the team went on to show that they could curb the migration of metastatic carcinoma cells in vitro as well as the overall tumor growth and metastasis in nude mice injected with these cancer cells by adding back miR148a or miR-34b/c.
By sifting through the predicted targets of these miRNAs, the researchers also began developing hypotheses about how the miRNA influence metastasis. For instance, they found evidence suggesting that miR148a and miR-34b/c silence oncogenes coding for proteins such as C-MYC, CDK6, E2F3 and TGIF2. In the absence of this silencing, the proteins apparently help to drive metastasis.
Interestingly though, the miRNAs were not silenced exclusively in metastatic cells but also in some primary colon, lung, breast, melanoma, and head and neck tumors. Even so, the group’s work suggests that primary tumors containing the methylation signature were more likely to be found in individuals who also had secondary, metastatic tumors.
“The presence of miR-35b/c, miR-148, and miR-9-3 CpG island hypermethylation in the primary tumor was significantly associated with those tumors that were positive for metastatic cancer cells in the corresponding lymph nodes,” the authors wrote.
Overall, the results provide new insights into the process of metastasis — extending what is known about links between CpG island methylation, miRNA, and cancer. And, the researchers noted, the findings may eventually have prognostic or treatment implications.
“One application could be the use of miRNA methylation markers to predict tumor prognosis and metastatic behavior,” Esteller and co-workers wrote. “Most importantly of all, it might provide a mechanistic and molecular basis for a new therapeutic use for pharmacological compounds with DNA demethylating activity in the treatment of cancer patients with metastatic disease.”

At press time the paper had not yet been made available on PNAS' website.

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