p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4
p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4
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DOI：
10.1158/0008-5472.can-18-1749
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发表时间：
2018-11-01
期刊：
影响因子：
11.2
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
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作者：
Kajiwara, Chihiro;Fumoto, Katsumi;Kikuchi, Akira
Dickkopf 3（DKK 3）是属于DKK家族的分泌蛋白，但与其他家族成员表现出结构差异，其相应的受体仍有待鉴定。虽然DKK 3已被证明在某些癌症类型中具有致癌功能，但DKK 3促进肿瘤发生的潜在机制仍有待澄清。我们在这里显示，DKK 3刺激食管癌细胞增殖通过细胞因子相关蛋白4（CKAP 4），作为DKK 3的受体。DKK 3在大约50%的食管鳞状细胞癌（ESCC）病例的肿瘤病变中表达; DKK 3和CKAP 4同时表达与预后不良相关。抗CKAP 4抗体抑制DKK 3与CKAP 4的结合和ESCC细胞诱导的异种移植肿瘤形成。p63是一种p53相关的转录因子，在ESCC中频繁扩增，与DKK 3基因的上游区域结合。敲除p63降低了ESCC细胞中DKK 3的表达，并且DKK 3的再表达部分挽救了p63缺失的ESCC细胞中的细胞增殖。Delta Np 63 α和DKK 3的表达增加了肿瘤样食管类器官的大小，抗CKAP 4抗体抑制了食管类器官的生长。两者合计，这些结果表明，DKK 3-CKAP 4轴可能作为一个新的分子靶点ESCC.Significance：在食管癌，研究结果确定DKK 3作为一个不良预后指标，并证明CKAP 4抑制作为一种有效的治疗策略。(C)2018年AACR。
Dickkopf3 (DKK3) is a secretory protein that belongs to the DKK family, but exhibits structural divergence from other family members, and its corresponding receptors remain to be identified. Although DKK3 has been shown to have oncogenic functions in certain cancer types, the underlying mechanism by which DKK3 promotes tumorigenesis remains to be clarified. We show here that DKK3 stimulates esophageal cancer cell proliferation via cytoskeleton-associated protein 4 (CKAP4), which acts as a receptor for DKK3. DKK3 was expressed in approximately 50% of tumor lesions of esophageal squamous cell carcinoma(ESCC) cases; simultaneous expression of DKK3 and CKAP4 was associated with poor prognosis. Anti-CKAP4 antibody inhibited both binding of DKK3 to CKAP4 and xenograft tumor formation induced by ESCC cells. p63, a p53-related transcriptional factor frequently amplified in ESCC, bound to the upstream region of the DKK3 gene. Knockdown of p63 decreased DKK3 expression in ESCC cells, and reexpression of DKK3 partially rescued cell proliferation in p63-depleted ESCC cells. Expression of Delta Np63 alpha and DKK3 increased the size of tumor-like esophageal organoids, and anti-CKAP4 antibody inhibited growth of esophageal organoids. Taken together, these results suggest that the DKK3-CKAP4 axis might serve as a novel molecular target for ESCC.Significance: In esophageal cancer, findings identify DKK3 as a poor prognostic indicator and demonstrate CKAP4 inhibition as an effective therapeutic strategy. (C) 2018 AACR.