Targeting claudin‐4 enhances chemosensitivity of pancreatic ductal carcinomas
Targeting claudin‐4 enhances chemosensitivity of pancreatic ductal carcinomas
复制标题
靶向claudin-4增强胰腺导管癌的化疗敏感性
DOI：
10.1002/cam4.2547
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发表时间：
2019
期刊：
影响因子：
4
通讯作者：
Kuniyasu Hiroki
中科院分区：
文献类型：
--
作者：
Sasaki Takamitsu;Fujiwara‐Tani Rina;Kishi Shingo;Mori Shiori;Luo Yi;Ohmori Hitoshi;Kawahara Isao;Goto Kei;Nishiguchi Yukiko;Mori Takuya;Sho Masayuki;Kondo Masuo;Kuniyasu Hiroki
Claudin(CLDN)家族由形成紧密连接的蛋白质组成，参与调节细胞的极性和分化。在此，我们旨在研究抑制CLDN4在胰腺癌中的作用。我们首先用免疫组织化学方法检测了91例人PDC，发现CLDN4的表达与肿瘤的侵袭、淋巴结转移和远处转移有关。抗CLDN4胞外区抗体(4D3)可抑制MIA-PACA-2 PDC细胞的增殖，增加细胞内5-氟尿嘧啶(5-FU)浓度，降低跨上皮电阻。联合应用5-FU和4D3可协同抑制裸鼠MIA-PACA-2细胞的生长。此外，全剂量FFX治疗的MIA-Paca-2细胞肿瘤使肿瘤直径缩小到50%；然而，60%的小鼠死于不良反应。相比之下，半量FFX联合4D3治疗可减少相当于全量FFX的肿瘤，但没有不良反应。这些发现表明，靶向CLDN4可能会增加PDC抗癌药物治疗的有效性和安全性。
Claudin (CLDN) family comprises of protein that form a tight junction, and is involved in regulating polarity and differentiation of cells. Here, we aimed to investigate the effects of inhibiting CLDN4 in pancreatic ductal carcinomas (PDC). We first examined 91 cases of human PDC by immunohistochemistry and found that CLDN4 expression was correlated with tumor invasion, nodal metastasis, and distant metastasis. Anti‐CLDN4 extracellular domain antibody, previously established by us (4D3), inhibited the proliferation of MIA‐PaCa‐2 PDC cells and increased intracellular 5‐fluorouracil (5‐FU) concentration with lowering transepithelial electrical resistance. Concurrent treatment of 5‐FU and 4D3 resulted in synergistic inhibition of growth of MIA‐PaCa‐2 cells in nude mice. In addition, MIA‐PaCa‐2 cell tumors treated with full‐dose folfirinox (FFX) decreased tumor diameters to 50%; however, 60% of mice were dead from adverse effects. In contrast, half‐dose FFX concomitant with 4D3 treatment decreased tumors equivalent to full‐dose FFX, but without the adverse effects. These findings suggest that targeting CLDN4 might increase the effectiveness and safety of anticancer drug therapy in PDC.