Overexpression of heme oxygenase-1 in murine melanoma - Increased proliferation and viability of tumor cells, decreased survival of mice
Overexpression of heme oxygenase-1 in murine melanoma - Increased proliferation and viability of tumor cells, decreased survival of mice
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DOI：
10.2353/ajpath.2006.051365
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发表时间：
2006-12-01
影响因子：
6
通讯作者：
Jozkowicz, Alicja
中科院分区：
文献类型：
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作者：
Was, Halina;Cichon, Tomasz;Jozkowicz, Alicja
血红素氧合酶-1（HO-1）是一种细胞保护酶，可在肿瘤中被诱导以响应抗癌治疗。我们研究了HO-1在B16（F10）、S91和Sk-mel 188黑色素瘤细胞中的作用。用腺病毒载体转导后，HO-1的过表达增加了细胞增殖，对H2 O2产生的氧化应激的抗性，以及通过诱导内皮细胞分裂确定的血管生成潜力。同样，稳定转染HO-1 cDNA的细胞（B16-HO-1）比野生型细胞系（B16-WT）表现出更高的增殖、应激抗性和血管生成活性。肿瘤中HO-1过表达显著缩短了皮下注射癌细胞后小鼠的生存期（B16-WT和B16-HO-1分别为38天和22天; P = 0.017）。这也导致了更多的肿瘤的发展，更多的黑色素瘤细胞，减少炎症水肿。注射B16-HO-1的小鼠肿瘤坏死因子水平较低，其可溶性受体肿瘤坏死因子-RI的血清浓度较高，而过表达HO-1的肿瘤显示血管化增强和血管内皮生长因子的产生更强。最后，静脉注射B16-HO-1细胞在肺中形成更多的转移。因此，HO-1过表达增加了黑色素瘤细胞的活力、增殖和血管生成潜力，增强了转移，并降低了荷瘤小鼠的存活率，这表明HO-1的诱导可能在黑色素瘤的抗癌治疗中是有害的。
Heme oxygenase-1 (HO-1), a cytoprotective enzyme, can be induced in tumors in response to anti-cancer therapies. We investigated the role of HO-1 in B16(F10), S91, and Sk-mel188 melanoma cells. Overexpression of HO-1 after transduction with adenoviral vectors increased cell proliferation, resistance to oxidative stress generated by H2O2, and angiogenic potential as determined by induction of endothelial cell divisions. Likewise, cells stably transfected with HO-1 cDNA (B16-HO-1) showed higher proliferation, stress resistance, and angiogenic activity than the wild-type line (B16-WT). HO-1 overexpression in tumors significantly shortened survival of mice after subcutaneous injection of cancer cells (38 and 22 days for B16-WT and B16-HO-1, respectively; P = 0.017). This also resulted in development of more packed tumors, with more melanoma cells, and reduced inflammatory edemas. Mice injected with B16-HO-1 had lower levels of tumor necrosis factor and higher serum concentrations of its soluble receptor tumor necrosis factor-RI, whereas tumors overexpressing HO-1 displayed augmented vascularization and stronger production of vascular endothelial growth factor. Finally, B16-HO-1 cells injected intravenously formed more metastases in lungs. Thus, HO-1 overexpression increased viability, proliferation, and angiogenic potential of melanoma cells, augmented metastasis, and decreased survival of tumor-bearing mice, suggesting that induction of HO-1 may be detrimental in anti-cancer therapy of melanoma.