Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan.
BMC Cancer. 2018 Jan 31;18(1):113. doi: 10.1186/s12885-018-3988-3.
Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer.
We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin.
The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells.
CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione.
顺铂是治疗转移性和/或复发性尿路上皮癌患者最常用的化疗药物。然而，由于顺铂耐药性的发展，这些治疗的效果受到严重限制。癌症干细胞已被证明是参与化疗耐药的关键假说之一。CD44v8-10 已被确定为新的癌症干细胞标志物之一，最近的研究表明，它通过与胱氨酸转运体的亚基 xCT 相互作用来增强抗氧化系统，从而调节细胞内谷胱甘肽的合成。本研究旨在探讨 CD44v8-10 在尿路上皮癌中的临床作用及其通过 CD44v8-10 获得顺铂耐药的分子机制。
我们分析了 77 例接受顺铂为基础的系统化疗治疗复发和/或转移的尿路上皮癌患者的免疫组化 CD44v9 表达的临床意义，该表达检测人类 CD44v8-10 的免疫原。然后，我们使用 T24 和 T24PR 尿路上皮癌细胞系评估了 CD44v8-10 在获得顺铂耐药中的生物学作用，这两种细胞系是为获得顺铂耐药而产生的。
CD44v9 阳性组的 5 年癌症特异性生存率明显低于 CD44v9 阴性组（P=0.008）。多变量分析显示，CD44v9 阳性是接受顺铂为基础化疗的复发和/或转移的尿路上皮癌患者癌症特异性生存的独立危险因素（P=0.024，风险比=5.16）。T24PR 细胞中 CD44v8-10 和 xCT 的表达强于 T24 细胞。T24PR 细胞内谷胱甘肽的含量明显高于 T24 细胞（p<0.001），T24PR 细胞内由顺铂产生的活性氧生成量低于 T24 细胞。此外，siRNA 敲低 CD44v8-10 导致 T24PR 细胞对顺铂的敏感性恢复。
肿瘤标本中的 CD44v9 有可能成为识别尿路上皮癌患者中顺铂化疗耐药人群的新型指标。CD44v8-10 通过促进调节谷胱甘肽合成的 xCT 的功能，有助于活性氧防御，从而参与化疗耐药。
