Koukourakis M I, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter K C, Harris A L
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
Br J Cancer. 2003 Sep 1;89(5):877-85. doi: 10.1038/sj.bjc.6601205.
Lactate dehydrogenase-5 (LDH-5) catalyses the reversible transformation of pyruvate to lactate, having a principal position in the anaerobic cellular metabolism. Induction of LDH-5 occurs during hypoxia and LDH-5 transcription is directly regulated by the hypoxia-inducible factor 1 (HIF1). Serum LDH levels have been correlated with poor prognosis and resistance to chemotherapy and radiotherapy in various neoplastic diseases. The expression, however, of LDH in tumours has never been investigated in the past. In the present study, we established an immunohistochemical method to evaluate the LDH-5 overexpression in tumours, using two novel antibodies raised against the rat muscle LDH-5 and the human LDH-5 (Abcam, UK). The subcellular patterns of expression in cancer cells were mixed nuclear and cytoplasmic. In direct contrast to cancer cells, stromal fibroblasts were reactive for LDH-5 only in a minority of cases. Serum LDH, although positively correlated with, does not reliably reflect the intratumoral LDH-5 status. Lactate dehydrogenase-5 overexpression was directly related to HIF1alpha and 2alpha, but not with the carbonic anhydrase 9 expression. Patients with tumours bearing high LDH-5 expression had a poor prognosis. Tumours with simultaneous LDH-5 and HIF1alpha (or HIF2alpha) overexpression, indicative of a functional HIF pathway, had a particularly aggressive behaviour. It is concluded that overexpression of LDH-5 is a common event in non-small-cell lung cancer, can be easily assessed in paraffin-embedded material and provides important prognostic information, particularly when combined with other endogenous markers of hypoxia and acidity.
乳酸脱氢酶-5（LDH-5）催化丙酮酸与乳酸之间的可逆转化，在无氧细胞代谢中占据主要地位。LDH-5在缺氧时被诱导，其转录直接受缺氧诱导因子1（HIF1）调控。血清LDH水平与多种肿瘤性疾病的预后不良以及对化疗和放疗的耐药性相关。然而，过去从未对肿瘤中LDH的表达进行过研究。在本研究中，我们建立了一种免疫组织化学方法，使用两种针对大鼠肌肉LDH-5和人LDH-5制备的新型抗体（英国Abcam公司）来评估肿瘤中LDH-5的过表达情况。癌细胞中的亚细胞表达模式为核质混合。与癌细胞形成直接对比的是，基质成纤维细胞仅在少数情况下对LDH-5有反应。血清LDH虽然与之呈正相关，但并不能可靠地反映肿瘤内LDH-5的状态。乳酸脱氢酶-5过表达与HIF1α和2α直接相关，但与碳酸酐酶9的表达无关。LDH-5高表达的肿瘤患者预后较差。同时存在LDH-5和HIF1α（或HIF2α）过表达的肿瘤，表明HIF途径功能活跃，具有特别侵袭性的行为。结论是，LDH-5过表达在非小细胞肺癌中是常见现象，可在石蜡包埋材料中轻松评估，并提供重要的预后信息，尤其是与其他缺氧和酸性内源性标志物联合使用时。
