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Mar 30, 2009

Gene Previously Thought to Be an Oncogene Turns Out to Be a Tumor Suppressor in Melanoma

  • MMP-8, which was believed to be an oncogene, is actually a tumor suppressor in melanoma, according to researchers at the National Human Genome Research Institute (NHGRI). They also validated that mutations in other genes belonging to the MMP (matrix metalloproteinase) family were seen in melanoma tumors.

    MMP enzymes help the body break down and recycle proteins, playing a crucial role in the process of remodeling skin after sunburns, cuts, or other injuries. The MMP gene family has been associated with tumor growth in a variety of cancers including breast, colon, and melanoma. Yet, investigations into MMP-blocking drugs have failed, and the NHGRI team says that it’s because this gene family was mistakenly believed to consist of oncogenes.

    In the study, which appears on March 30 in Nature Genetics, the investigators studied a bank of tumor and blood samples collected by the NCI from 79 patients with aggressive melanoma. They compared the sequence of MMP genes in tumors and normal DNA from the same patients, looking for mutations in all 23 members of the MMP gene family.

    The researchers identified 28 different mutations in eight MMP genes in the melanoma tumors studied. These mutations were found to be distributed in different frequencies and patterns among the tumor samples.

    Nearly one-quarter of the tumors analyzed had at least one MMP gene mutation.  Some mutations were found in as few as 3% of tumors, while more than 6% of tumors had mutations in MMP-8 and more than 7% had mutations in MMP-27, which codes for an enzyme very similar to MMP-8.

    The team followed up the DNA sequencing work with cell and animal studies to see whether MMP-8 mutations affect enzyme function. Results showed that five of the mutations reduced activity of the MMP-8 enzyme.

    The researchers next studied whether MMP-8 mutations promote activities related to cancer. Cells with MMP-8 mutations showed increased ability to multiply outside the constraints of normal cells, just like anchorage-independent cancer growth. Likewise, cells with MMP-8 mutations had a greater ability to migrate than normal cells—a key aspect of cancer metastasis.

    Additionally, the investigators found that mice injected with cells expressing normal MMP-8 did not develop skin ulcers, which are one of the most important measures of cancer aggression in melanoma. In contrast, mice injected with cells expressing mutated MMP-8 went on to develop ulcerations and metastases in their lungs. So in the estimated 6% of melanoma patients whose tumors harbor a mutated MMP-8 gene or related tumor suppressor(s), it may not be wise to block all MMPs.



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