Centre Hospitalier Universitaire de Nice, Louis Pasteur Hospital, Laboratory of Clinical and Experimental Pathology, Nice, France; Institute of Research on Cancer and Ageing in Nice IRCAN, INSERM U1081-CNRS UMR 7284, Team 3, Nice, France; University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
Lung Cancer. 2013 Oct;82(1):16-23. doi: 10.1016/j.lungcan.2013.07.005. Epub 2013 Jul 30.
The disorganized neo-vasculature in tumours causes fluctuations in the concentration of oxygen, which contributes to tumour development and metastatic potential. Although hypoxic regulation of the expression of the carbonic anhydrases CAIX and CAXII is well established, the effect of re-oxygenation on these proteins remains to be elucidated. A549 and H1975 human lung cancer cell lines were exposed to hypoxia for 24 h and then re-oxygenated. CAIX or CAXII expression and cell cycle progression at different time-points were monitored. A549-shCA9 cells were analyzed for cell cycle progression in the same conditions. We demonstrate for the first time an association between the stability of CAIX and restoration of the S/G2 phase of hypoxia-arrested cells subjected to re-oxygenation. In exchange, we have found that the loss of CA9 did not cause a decreased progression into S/G2 phase during re-oxygenation, but rather affected the hypoxic growth arrest. We previously demonstrated that CAIX expression is a poor prognostic factor and that CAXII expression is a good prognostic factor in non-small cell lung cancer (NSCLC) patients. We further detail the relevance of the combined expression of these proteins for predicting outcome in a large population of NSCLC patients after long-term follow-up. The high CAIX/low CAXII expression sub-group was associated with a high cumulative incidence of relapse and with poor overall survival of NSCLC patients (P < 0.0001). Our results demonstrate a critical role for re-oxygenation on CAIX and CAXII levels that may select for an aggressive lung cancer phenotype. These findings suggest that CAIX and CAXII play dual roles in tumour progression and emphasize their significant prognostic and potential therapeutic value.
肿瘤中组织紊乱的新生血管导致氧浓度波动，从而促进肿瘤发展和转移潜能。虽然缺氧对碳酸酐酶 CAIX 和 CAXII 的表达调控已得到充分证实，但再氧合对这些蛋白的影响仍有待阐明。将 A549 和 H1975 人肺癌细胞系暴露于缺氧 24 小时，然后再氧合。监测不同时间点 CAIX 或 CAXII 的表达和细胞周期进程。在相同条件下分析 A549-shCA9 细胞的细胞周期进程。我们首次证明，在经历再氧合的缺氧细胞中，CAIX 的稳定性与 S/G2 期的恢复之间存在关联。相反，我们发现 CA9 的缺失不会导致再氧合期间 S/G2 期的进展减少，而是影响缺氧生长停滞。我们之前证明，CAIX 的表达是 NSCLC 患者预后不良的因素，而 CAXII 的表达是预后良好的因素。我们进一步详细说明了在对大量 NSCLC 患者进行长期随访后，这些蛋白质联合表达对预测结果的相关性。高 CAIX/低 CAXII 表达亚组与 NSCLC 患者复发的累积发生率高和总生存差相关（P<0.0001）。我们的结果表明，再氧合对 CAIX 和 CAXII 水平具有关键作用，可能选择侵袭性肺癌表型。这些发现表明 CAIX 和 CAXII 在肿瘤进展中起双重作用，并强调它们具有重要的预后和潜在的治疗价值。
