Abstract
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 ΔNp63α 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. Cancer Res; 78(21); 6107-20. ©2018 AACR.
Highlights
There are four Dickkopf (DKK) family members in vertebrates, including DKK1, DKK2, DKK3, and DKK4, all of which are secretory proteins and contain two cysteine-rich domains (CRD1 and CRD2; ref. 1)
DKK (s)-induced cellular proliferation was inhibited in cytoskeleton-associated protein 4 (CKAP4) knockout (KO) Madin-Darby canine kidney (MDCK) cells, which were generated by using CRISPR/ Cas9-based genome editing (Fig. 1E and F)
These results suggest that all DKK family proteins promote MDCK cell proliferation through CKAP4, suggesting that CKAP4 is a common receptor of DKK family proteins
Summary
There are four Dickkopf (DKK) family members in vertebrates, including DKK1, DKK2, DKK3, and DKK4, all of which are secretory proteins and contain two cysteine-rich domains (CRD1 and CRD2; ref. 1). There are four Dickkopf (DKK) family members in vertebrates, including DKK1, DKK2, DKK3, and DKK4, all of which are secretory proteins and contain two cysteine-rich domains DKK1 was originally identified as a head inducer in Xenopus embryos and the most extensively studied among DKK family proteins. DKK1 antagonizes b-catenin– dependent Wnt signaling by binding to and internalizing lowdensity lipoprotein receptor–related protein (LRP) 5 or 6, which are Wnt coreceptors [1,2,3,4]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
