Leo C, Horn L-C, Höckel M
Department of Gynecology, Leipzig University, Philipp-Rosenthal-Strasse 55, 04103 Leipzig, Germany.
Int J Gynecol Cancer. 2006 May-Jun;16(3):1314-20. doi: 10.1111/j.1525-1438.2006.00394.x.
Hypoxia plays a major role in the malignant progression of tumors. Here, we investigate the expression of Bcl-2/adenovirus E1B 19 kd-interacting protein 3 (BNIP3), a proapoptotic Bcl-2 family member, and its relationship to hypoxia in cervical cancer cell lines and clinical samples of cervical cancer. Cervical cancer cell lines were grown under hypoxia or normoxia, and BNIP3 mRNA expression was examined by Northern blot analysis. In 50 patients with cervical cancer, intratumoral oxygen measurement with the Eppendorf electrode and needle biopsies of the tumor were performed. The obtained tissue was subsequently analyzed by immunohistochemistry with an anti-BNIP3 antibody. Cervical cancer tissue collected upon surgery was used for Northern blot analysis of in vivo BNIP3 mRNA expression. BNIP3 mRNA is strongly induced under hypoxic conditions in all cervical cancer cell lines investigated. Furthermore, Northern blot analysis revealed that BNIP3 mRNA is expressed in cervical cancer tissue. Using immunohistochemistry, we demonstrated that BNIP3 protein is expressed in 82% of the investigated cervical cancers and that more advanced tumor stages showed significantly stronger BNIP3 expression. However, we observed no correlation between BNIP3 expression and intratumoral hypoxia. In conclusion, BNIP3 is expressed in different cervical cancer cell lines as well as in clinical samples of cervical cancer. Although BNIP3 is clearly hypoxia-inducible in vitro, our results suggest additional mechanisms of BNIP3 regulation in vivo. Our findings therefore highlight a discrepancy between in vitro models of tumor hypoxia and the complexity of human cancer.
缺氧在肿瘤的恶性进展中起主要作用。在此，我们研究促凋亡Bcl-2家族成员Bcl-2/腺病毒E1B 19kd相互作用蛋白3（BNIP3）的表达及其与子宫颈癌细胞系和子宫颈癌临床样本中缺氧的关系。子宫颈癌细胞系在缺氧或常氧条件下培养，通过Northern印迹分析检测BNIP3 mRNA表达。对50例子宫颈癌患者进行肿瘤内氧含量的Eppendorf电极测量及肿瘤组织穿刺活检。随后用抗BNIP3抗体进行免疫组织化学分析所获得的组织。手术时收集的子宫颈癌组织用于体内BNIP3 mRNA表达的Northern印迹分析。在所有研究的子宫颈癌细胞系中，缺氧条件下BNIP3 mRNA均被强烈诱导。此外，Northern印迹分析显示BNIP3 mRNA在子宫颈癌组织中表达。通过免疫组织化学，我们证实82%的被研究子宫颈癌中表达BNIP3蛋白，且肿瘤分期越晚，BNIP3表达越强。然而，我们未观察到BNIP3表达与肿瘤内缺氧之间存在相关性。总之，BNIP3在不同的子宫颈癌细胞系以及子宫颈癌临床样本中均有表达。虽然BNIP3在体外明显可被缺氧诱导，但我们的结果提示其在体内存在其他调控机制。因此，我们的研究结果凸显了肿瘤缺氧体外模型与人类癌症复杂性之间的差异。
