Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.
Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.
J Pathol. 2018 Feb;244(2):151-163. doi: 10.1002/path.4991. Epub 2017 Dec 19.
Accumulating evidence indicates that the human papillomavirus (HPV) E6 protein plays a crucial role in the development of cervical cancer. Subpopulations of cells that reside within tumours are responsible for tumour resistance to cancer therapy and recurrence. However, the identity of such cells residing in cervical cancer and their relationship with the HPV-E6 protein have not been identified. Here, we isolated sphere-forming cells, which showed self-renewal ability, from primary cervical tumours. Gene expression profiling revealed that cluster of differentiation (CD) 55 was upregulated in primary cervical cancer sphere cells. Flow-cytometric analysis detected abundant CD55(+) populations among a panel of HPV-positive cervical cancer cell lines, whereas few CD55(+) cells were found in HPV-negative cervical cancer and normal cervical epithelial cell lines. The CD55(+) subpopulation isolated from the C33A cell line showed significant sphere-forming ability and enhanced tumourigenicity, cell migration, and radioresistance. In contrast, the suppression of CD55 in HPV-positive CaSki cells inhibited tumourigenicity both in vitro and in vivo, and sensitized cells to radiation treatment. In addition, ectopic expression of the HPV-E6 protein in HPV-negative cervical cancer cells dramatically enriched the CD55(+) subpopulation. CRISPR/Cas9 knockout of CD55 in an HPV-E6-overexpressing stable clone abolished the tumourigenic effects of the HPV-E6 protein. Taken together, our data suggest that HPV-E6 protein expression enriches the CD55(+) population, which contributes to tumourigenicity and radioresistance in cervical cancer cells. Targeting CD55 via CRISPR/Cas9 may represent a novel avenue for developing new strategies and effective therapies for the treatment of cervical cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
越来越多的证据表明，人乳头瘤病毒（HPV）E6 蛋白在宫颈癌的发展中起着至关重要的作用。存在于肿瘤中的细胞亚群负责肿瘤对癌症治疗和复发的抵抗。然而，这些存在于宫颈癌中的细胞的特性及其与 HPV-E6 蛋白的关系尚未确定。在这里，我们从原发性宫颈癌肿瘤中分离出具有自我更新能力的球体形成细胞。基因表达谱分析显示，CD55 在原发性宫颈癌球体细胞中上调。流式细胞术分析检测到 HPV 阳性宫颈癌细胞系中存在丰富的 CD55(+)群体，而 HPV 阴性宫颈癌和正常宫颈上皮细胞系中则很少有 CD55(+)细胞。从 C33A 细胞系中分离的 CD55(+)亚群表现出显著的球体形成能力和增强的致瘤性、细胞迁移和放射抗性。相比之下，在 HPV 阳性 CaSki 细胞中抑制 CD55 的表达，无论是在体外还是体内，均抑制了肿瘤的发生，并使细胞对放射治疗敏感。此外，HPV 阴性宫颈癌细胞中 HPV-E6 蛋白的异位表达显著富集了 CD55(+)亚群。在 HPV-E6 过表达的稳定克隆中，CRISPR/Cas9 敲除 CD55 消除了 HPV-E6 蛋白的致瘤作用。综上所述，我们的数据表明，HPV-E6 蛋白的表达丰富了 CD55(+)群体，这有助于宫颈癌细胞的致瘤性和放射抗性。通过 CRISPR/Cas9 靶向 CD55 可能为开发治疗宫颈癌的新策略和有效疗法提供新途径。版权所有 © 2017 英国和爱尔兰病理学学会。由 John Wiley & Sons，Ltd. 出版。
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