Acs Geza, Zhang Paul J, McGrath Cindy M, Acs Peter, McBroom John, Mohyeldin Ahmed, Liu Suzhen, Lu Huasheng, Verma Ajay
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Am J Pathol. 2003 Jun;162(6):1789-806. doi: 10.1016/S0002-9440(10)64314-3.
Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.
组织缺氧是宫颈癌的一个特征性属性，它使肿瘤对化疗和放疗产生抗性。促红细胞生成素（Epo）是一种缺氧诱导的红细胞生成刺激因子。Epo通过其受体（EpoR）发挥作用，上调bcl-2并抑制红系细胞凋亡，使神经元免受缺氧损伤。除人乳头瘤病毒感染外，bcl-2表达增加和凋亡减少被认为在宫颈肿瘤形成过程中起作用。我们通过逆转录聚合酶链反应和蛋白质印迹法表明，HeLa和SiHa宫颈癌细胞以及人宫颈癌均表达EpoR，且缺氧可增强EpoR表达。外源性Epo刺激酪氨酸磷酸化并抑制顺铂对HeLa宫颈癌细胞的细胞毒性作用。我们采用免疫组织化学方法检测了促红细胞生成素（Epo）、促红细胞生成素受体（EpoR）、p16、缺氧诱导因子（HIF）-1α和bcl-2在良性和发育异常的宫颈鳞状上皮以及浸润性鳞状细胞癌（ISCC）中的表达。EpoR在良性上皮中的表达局限于基底细胞层，而在发育异常中，它越来越多地出现在更浅表的细胞层，并且与发育异常的严重程度显著相关。在所有浸润性鳞状细胞癌中均发现EpoR弥漫性表达。与良性上皮相比，发育异常中Epo和HIF-1α的表达增加。在浸润性鳞状细胞癌的坏死区域附近可见局灶性Epo和HIF-1α表达，且它们在空间分布上具有相关性。在良性和发育异常的鳞状上皮中，EpoR的表达与p16和bcl-2之间存在显著相关性。我们的结果表明，Epo和EpoR表达增加可能在宫颈癌发生和肿瘤进展中起重要作用。缺氧诱导的Epo信号传导可能在缺氧性宫颈癌的侵袭性行为和治疗抗性中起重要作用。
