Function of carbonic anhydrase IX in glioblastoma multiforme
Function of carbonic anhydrase IX in glioblastoma multiforme
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DOI：
10.1093/neuonc/nos216
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发表时间：
2012-11-01
期刊：
影响因子：
15.9
通讯作者：
Brawanski, Alexander
中科院分区：
文献类型：
--
作者：
Proescholdt, Martin A.;Merrill, Marsha J.;Brawanski, Alexander
碳酸酐酶(CA)IX在胶质母细胞瘤中过度表达；然而，其在这方面的功能尚不清楚。在代谢方面，胶质母细胞瘤是高度糖酵解的，导致显著的乳酸负荷。矛盾的是，细胞内的pH值是碱性的。我们假设CAIX有助于将氢离子挤出到细胞外空间，从而调节细胞内外的pH，并创造有利于增强侵袭的环境。我们研究了CAIX作为胶质母细胞瘤患者预后标志物的作用及其体外生物学功能。应用免疫组织化学方法检测59例胶质母细胞瘤组织中CAIX的表达。表达水平与总生存期相关。体外低氧培养U251和Ln-18胶质母细胞瘤细胞，诱导CAIX表达，RNA干扰(RNAi)检测CAIX在细胞黏附、侵袭、细胞内能量传递和辅助治疗敏感性等方面的作用。CAIX的高表达被认为是胶质母细胞瘤患者生存不良的独立因素。在体外，CAIX基因被敲除后，细胞的黏附和侵袭能力显著降低。最后，CAIX干扰后放疗和化疗的作用明显增强，并伴随着更高的细胞凋亡率。CAIX是胶质母细胞瘤患者预后不良的独立预后因素。CAIX的高表达显著影响辅助治疗过程中细胞的黏附、侵袭和存活。这些结果表明，抑制CAIX是治疗胶质母细胞瘤的潜在代谢靶点。
Carbonic anhydrase (CA) IX is over-expressed in glioblastoma; however, its functions in this context are unknown. Metabolically, glioblastomas are highly glycolytic, leading to a significant lactic acid load. Paradoxically, the intracellular pH is alkaline. We hypothesized that CAIX contributes to the extrusion of hydrogen ions into the extracellular space, thereby moderating intra- and extracellular pH and creating an environment conductive to enhanced invasion. We investigated the role of CAIX as a prognostic marker in patients with glioblastoma and its biological function in vitro. CAIX expression was analyzed in 59 patients with glioblastoma by immunohistochemistry. The expression levels were correlated to overall survival. In vitro, U251 and Ln 18 glioblastoma cells were incubated under hypoxia to induce CAIX expression, and RNA interference (RNAi) was used to examine the function of CAIX on cell attachment, invasion, intracellular energy transfer, and susceptibility to adjuvant treatment. High CAIX expression was identified as an independent factor for poor survival in patients with glioblastoma. In vitro, cell attachment and invasion were strongly reduced after knockdown of CAIX. Finally, the effects of radiation and chemotherapy were strongly augmented after CAIX interference and were accompanied by a higher rate of apoptotic cell death. CAIX is an independent prognostic factor for poor outcome in patients with glioblastoma. Cell attachment, invasion, and survival during adjuvant treatment are significantly influenced by high CAIX expression. These results indicate that inhibition of CAIX is a potential metabolic target for the treatment of patients with glioblastoma.