A commensal microbe protects the skin from UV-induced neoplasia. Staphylococcus epidermidis strain:MO34

In this study, we report discovery of strains of S. epidermidis that produce 6-N-hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity by competing for adenosine incorporation. In culture, 6-HAP selectively inhibited proliferation of tumor lines but not primary keratinocytes. Resistance to 6-HAP was associated with expression of mitochondrial amidoxime reducing components (mARCs), enzymes that reduce N-hydroxyl group and were not observed in cells sensitive to 6-HAP. IV injection of 6-HAP in mice suppressed growth of locally inoculated B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with a S. epidermidis strain producing 6-HAP reduced the incidence of UV-induced tumors while mice colonized by a control strain of S. epidermidis that did not produce 6-HAP had significantly more tumors. S. epidermidis strains producing 6-HAP were found in the metagenome from multiple healthy human subjects. These findings show a potential role for skin commensal bacteria to protect against skin cancer.

本研究报道了产6-N-羟氨基嘌呤（6-N-hydroxyaminopurine，6-HAP）的表皮葡萄球菌（Staphylococcus epidermidis，S. epidermidis）菌株的发现，该分子可通过竞争腺苷掺入通路抑制DNA聚合酶（DNA polymerase）活性。体外培养实验中，6-HAP可选择性抑制肿瘤细胞系的增殖，却对原代角质形成细胞（primary keratinocytes）无此效应。对6-HAP的耐药性与线粒体酰胺肟还原组分（mitochondrial amidoxime reducing components，mARCs）的表达相关，这类酶可还原N-羟基基团，而在对6-HAP敏感的细胞中未检测到此类酶的表达。向小鼠静脉注射（intravenous injection，IV）6-HAP，可抑制原位接种的B16F10黑色素瘤的生长，且未观察到全身毒性反应。用产6-HAP的表皮葡萄球菌菌株定植小鼠，可降低紫外线诱导的皮肤肿瘤发生率；而定植不产6-HAP的表皮葡萄球菌对照菌株的小鼠，肿瘤发生率显著更高。在多名健康人类受试者的宏基因组（metagenome）中，均检测到了产6-HAP的表皮葡萄球菌菌株。上述研究结果表明，皮肤共生菌在抵御皮肤癌方面具有潜在的保护作用。