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首页> 外文期刊>American Journal of Pathology: Official Publication of the American Association of Pathologists >Hypoxia-inducible factor-1 facilitates cervical cancer progression in human papillomavirus type 16 transgenic mice.
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Hypoxia-inducible factor-1 facilitates cervical cancer progression in human papillomavirus type 16 transgenic mice.

机译：低氧诱导因子1促进人乳头瘤病毒16型转基因小鼠的宫颈癌进展。

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摘要

Advanced cervical cancer remains a vexing clinical challenge despite screening programs. Many of these cancers are hypoxic, and expression of the alpha subunit of the major regulator of the hypoxic cellular response, the transcription factor hypoxia-inducible factor-1 (HIF-1), is correlated with poor prognosis. Here, we tested a functional role for HIF-1alpha in pathogenesis of cervical cancer in estrogen-treated transgenic mice. Double-transgenic (DTG) mice developed locally invasive cervical cancers 70 times larger than K14-HPV16 mice. In vivo bromodeoxyuridine incorporation was elevated in DTG cancers without a significant increase in apoptosis. HIF-1alpha gain of function did not up-regulate canonical HIF-1 targets in premalignant DTG cervices, in contrast to elevation of these targets in K14-HIF-1alpha transgenic cervices. The DTG transcriptional signature included up-regulation of mRNAs encoding cytokines and chemokines, immune signaling molecules, extracellular proteases, and cell motility factors, as well as reduced expression of cell adhesion and epithelial differentiation genes. Importantly, a set of gene markers derived from the DTG transcriptome predicted cervical cancer progression in patients. This study suggests a novel paradigm for HIF-1 function evident in multistage carcinogenesis as opposed to established malignancies, including interaction with viral oncogenes to induce multiple genomic networks in premalignancy that fosters the development of advanced cervical cancer.
机译：尽管有筛查程序，晚期宫颈癌仍是一项艰巨的临床挑战。这些癌症中许多都是低氧的，低氧细胞反应的主要调节因子，即转录因子低氧诱导因子-1（HIF-1）的α亚基的表达与不良预后相关。在这里，我们测试了HIF-1alpha在雌激素治疗的转基因小鼠宫颈癌发病中的功能作用。双转基因（DTG）小鼠发生的局部浸润性宫颈癌比K14-HPV16小鼠大70倍。体内溴脱氧尿苷的掺入在DTG癌症中升高，而凋亡却没有明显增加。与K14-HIF-1alpha转基因宫颈癌中的这些靶标升高相比，HIF-1alpha功能获得性并未在恶性前DTG宫颈癌中上调典型的HIF-1靶蛋白。 DTG的转录特征包括编码细胞因子和趋化因子，免疫信号分子，细胞外蛋白酶和细胞运动因子的mRNA的上调，以及细胞粘附和上皮分化基因表达的降低。重要的是，一组源自DTG转录组的基因标记可预测患者的宫颈癌进展。这项研究表明，与已确立的恶性肿瘤相反，HIF-1功能的新范式在多阶段癌变中显而易见，包括与病毒致癌基因的相互作用以诱导恶性前期的多种基因组网络，从而促进晚期宫颈癌的发展。

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