Barium Promotes Anchorage-Independent Growth and Invasion of Human HaCaT Keratinocytes via Activation of c-SRC Kinase

Explosive increases in skin cancers have been reported in more than 36 million patients with arsenicosis caused by drinking arsenic-polluted well water. This study and previous studies showed high levels of barium as well as arsenic in the well water. However, there have been no reports showing a correlation between barium and cancer. In this study, we examined whether barium (BaCl2) may independently have cancer-related effects on human precancerous keratinocytes (HaCaT). Barium (5–50 µM) biologically promoted anchorage-independent growth and invasion of HaCaT cells in vitro. Barium (5 µM) biochemically enhanced activities of c-SRC, FAK, ERK and MT1-MMP molecules, which regulate anchorage-independent growth and/or invasion. A SRC kinase specific inhibitor, protein phosphatase 2 (PP2), blocked barium-mediated promotion of anchorage-independent growth and invasion with decreased c-SRC kinase activity. Barium (2.5–5 µM) also promoted anchorage-independent growth and invasion of fibroblasts (NIH3T3) and immortalized nontumorigenic melanocytes (melan-a), but not transformed cutaneous squamous cell carcinoma (HSC5 and A431) and malignant melanoma (Mel-ret) cells, with activation of c-SRC kinase. Taken together, our biological and biochemical findings newly suggest that the levels of barium shown in drinking well water independently has the cancer-promoting effects on precancerous keratinocytes, fibroblast and melanocytes in vitro.已有研究报道，在因饮用砷污染井水而罹患砷中毒（arsenicosis）的超3600万患者中，皮肤癌发病率呈爆发式增长。本研究与既往研究均发现，此类污染井水中不仅含有高浓度砷，还存在高浓度钡（barium）。然而目前尚无研究证实钡与癌症存在关联。本研究旨在探究氯化钡（BaCl₂）是否可单独对人癌前角质形成细胞（HaCaT）产生与癌症相关的生物学效应。在体外实验中，5~50 μM浓度的钡可促进HaCaT细胞的非锚定依赖性生长与侵袭能力。5 μM浓度的钡可在生化层面增强c-SRC、FAK、ERK及MT1-MMP分子的活性，上述分子均参与调控非锚定依赖性生长与/或侵袭过程。SRC激酶特异性抑制剂蛋白磷酸酶2（PP2）可通过降低c-SRC激酶活性，阻断钡介导的非锚定依赖性生长与侵袭促进效应。2.5~5 μM浓度的钡还可通过激活c-SRC激酶，促进成纤维细胞（NIH3T3）与永生化非致瘤性黑素细胞（melan-a）的非锚定依赖性生长及侵袭能力，但对转化性皮肤鳞状细胞癌细胞（HSC5、A431）及恶性黑素瘤细胞（Mel-ret）无此效应。综上，本研究的生物学与生化实验结果首次表明，饮水中检出的钡浓度可单独在体外对癌前角质形成细胞、成纤维细胞及黑素细胞产生促癌效应。