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Function of carbonic anhydrase IX in glioblastoma multiforme

机译：碳酸酐酶IX在胶质母细胞瘤中的作用

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摘要

Carbonic anhydrase (CA) IX is over-expressed in glioblastoma; however, its functions in this context are unknown. Metabolically, glioblastomas are highly gly-colytic, 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.
机译：碳酸酐酶（CA）IX在胶质母细胞瘤中过表达；但是，在此情况下其功能未知。在代谢上，胶质母细胞瘤具有高度的糖酵解作用，导致大量的乳酸负荷。矛盾的是，细胞内的pH是碱性的。我们假设CAIX有助于将氢离子挤出到细胞外空间，从而调节细胞内和细胞外的pH值，并创造有利于入侵增强的环境。我们调查了胶质母细胞瘤患者CAIX作为预后标志物的作用及其体外生物学功能。通过免疫组织化学分析了59例胶质母细胞瘤患者的CAIX表达。表达水平与总体存活率相关。在体外，在缺氧条件下孵育U251和Ln 18胶质母细胞瘤细胞以诱导CAIX表达，并使用RNA干扰（RNAi）来检查CAIX在细胞附着，侵袭，细胞内能量转移以及对辅助治疗的敏感性方面的功能。 CAIX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，敲低CAIX后细胞附着和侵袭被大大降低。最后，在CAIX干扰后，放疗和化疗的效果大大增强，并伴随着更高的凋亡率。 CAIX是胶质母细胞瘤患者预后不良的独立预后因素。辅助治疗过程中的细胞附着，侵袭和存活受到CAIX高表达的显着影响。这些结果表明，抑制CAIX是治疗胶质母细胞瘤患者的潜在代谢靶标。

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  • 来源
    《Neuro-Oncology》 |2012年第11期|1357-1366|共10页
  • 作者

    Martin A. Proescholdt; Marsha J. Merrill; Eva-Maria Stoerr; Annette Lohmeier; Fabian Pohl; Alexander Brawanski;

  • 作者单位

    Department of Neurosurgery, University Regensburg Medical Center, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany;

    Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland;

    Department of Neurosurgery, University of Regensburg Medical Center, Regensburg, Germany;

    Department of Neurosurgery, University of Regensburg Medical Center, Regensburg, Germany;

    Department of Radiation Oncology, University of;

    Department of Neurosurgery, University of Regensburg Medical Center, Regensburg, Germany;

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  • 正文语种 eng
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  • 关键词

    apoptosis; CAIX; hypoxia; invasion; pH;

    机译：细胞凋亡CAIX;缺氧侵入;pH值;

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