Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer.
Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer.
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DOI：
10.1186/s12885-018-3988-3
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发表时间：
2018-01-31
期刊：
影响因子：
3.8
通讯作者：
Oya M
中科院分区：
文献类型：
--
作者：
Hagiwara M;Kikuchi E;Tanaka N;Kosaka T;Mikami S;Saya H;Oya M
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，这些治疗的有效性受到严重限制。癌症干细胞已被证明是参与化疗耐药性的关键假设之一。CD 44 v8 -10已被鉴定为新的癌症干细胞标志物之一，并且最近显示通过与xCT（调节细胞内谷胱甘肽合成的胱氨酸转运蛋白的亚基）相互作用来增强抗氧化系统。本研究旨在探讨CD 44 v8 -10在尿路上皮癌中的临床作用以及通过CD 44 v8 -10获得顺铂耐药的分子机制。我们分析了免疫组化CD 44 v9表达的临床意义，检测人CD 44 v8 -10的免疫原，在77例尿路上皮癌患者接受顺铂为基础的全身化疗复发和/或转移。然后，我们使用尿路上皮癌细胞系T24和T24 PR评估了CD 44 v8 -10在获得顺铂耐药性中的生物学作用，所述尿路上皮癌细胞系是为了获得对顺铂的耐药性而产生的。CD 44 v9阳性组的5年癌症特异性生存率显著低于CD 44 v9阴性组（P = 0.008）。多变量分析显示，CD 44 v9阳性是复发和/或转移并接受顺铂化疗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）。CD 44 v8 -10和xCT在T24 PR细胞中的表达强于T24细胞。T24 PR细胞内谷胱甘肽的量显著高于T24细胞（p < 0.001），顺铂引起的T24 PR细胞内活性氧产生低于T24细胞。此外，通过siRNA敲低CD 44 v8 -10导致T24 PR细胞中顺铂敏感性的恢复。肿瘤标本中的CD 44 v9有可能作为一种新的指标，用于识别尿路上皮癌患者中的顺铂化疗耐药人群。CD 44 v8 -10通过促进xCT的功能（其调节谷胱甘肽的合成）而有助于参与化学抗性的活性氧防御。
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.
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影响因子：
8.8
作者：
Hirata K;Suzuki H;Imaeda H;Matsuzaki J;Tsugawa H;Nagano O;Asakura K;Saya H;Hibi T
通讯作者：
Hibi T
影响因子：
11.2
作者：
Adorno-Cruz V;Kibria G;Liu X;Doherty M;Junk DJ;Guan D;Hubert C;Venere M;Mulkearns-Hubert E;Sinyuk M;Alvarado A;Caplan AI;Rich J;Gerson SL;Lathia J;Liu H
通讯作者：
Liu H
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
11.2
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
通讯作者：
Simeone, Diane M.