DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness,Cancer Science

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DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness
Cancer Science ( IF 4.5 ) Pub Date : 2023-01-31 , DOI: 10.1111/cas.15743
Kosuke Iguchi _{1,

2} , Ryota Sada _{1,

3} , Shinji Matsumoto _{1,

3} , Hirokazu Kimura _{1,

4} , Yoh Zen ₅ , Masayuki Akita ₂ , Hidetoshi Gon ₂ , Takumi Fukumoto ₂ , Akira Kikuchi _{1,

6}

Affiliation

Hepatocellular carcinoma (HCC) is the most prevalent malignant liver neoplasm. Despite the advances in diagnosis and treatment, the prognosis of HCC patients remains poor. Cytoskeleton-associated membrane protein 4 (CKAP4) is a receptor of the glycosylated secretory protein Dickkopf-1 (DKK1), and the DKK1-CKAP4 axis is activated in pancreatic, lung, and esophageal cancer cells. Expression of DKK1 and CKAP4 has been examined in HCC in independent studies that yielded contradictory results. In this study, the relationship between the DKK1-CKAP4 axis and HCC was comprehensively examined. In 412 HCC cases, patients whose tumors were positive for both DKK1 and CKAP4 had a poor prognosis compared to those who were positive for only one of these markers or negative for both. Deletion of either DKK1 or CKAP4 inhibited HCC cell growth. In contrast to WT DKK1, DKK1 lacking the CKAP4 binding region did not rescue the phenotypes caused by DKK1 depletion, suggesting that binding of DKK1 to CKAP4 is required for HCC cell proliferation. Anti-CKAP4 Ab inhibited HCC growth, and its antitumor effect was clearly enhanced when combined with lenvatinib, a multikinase inhibitor. These results indicate that simultaneous expression of DKK1 and CKAP4 is involved in the aggressiveness of HCC, and that the combination of anti-CKAP4 Ab and other therapeutics including lenvatinib could represent a promising strategy for treating advanced HCC.

中文翻译：

DKK1-CKAP4信号轴促进肝细胞癌侵袭性

肝细胞癌（HCC）是最常见的恶性肝脏肿瘤。尽管诊断和治疗取得了进步，HCC患者的预后仍然较差。细胞骨架相关膜蛋白 4 (CKAP4) 是糖基化分泌蛋白 Dickkopf-1 (DKK1) 的受体，DKK1-CKAP4 轴在胰腺癌细胞、肺癌细胞和食道癌细胞中被激活。独立研究在 HCC 中检测了 DKK1 和 CKAP4 的表达，但得出了相互矛盾的结果。本研究全面探讨了DKK1-CKAP4轴与HCC之间的关系。在 412 例 HCC 病例中，与仅其中一种标记物呈阳性或两种标记物均呈阴性的患者相比，肿瘤 DKK1 和 CKAP4 均呈阳性的患者预后较差。DKK1 或 CKAP4 的缺失会抑制 HCC 细胞的生长。与WT DKK1相比，缺乏CKAP4结合区的DKK1并不能挽救DKK1缺失引起的表型，这表明DKK1与CKAP4的结合是HCC细胞增殖所必需的。抗CKAP4抗体可抑制HCC生长，与多激酶抑制剂乐伐替尼联合使用时，其抗肿瘤作用明显增强。这些结果表明，DKK1 和 CKAP4 的同时表达与 HCC 的侵袭性有关，并且抗 CKAP4 Ab 与包括乐伐替尼在内的其他治疗药物的组合可能代表治疗晚期 HCC 的有前途的策略。

更新日期：2023-01-31

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