The Dickkopf1‐cytoskeleton‐associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy

Kikuchi, Akira; Fumoto, Katsumi; Kimura, Hiroyuki

doi:10.1111/bph.13863

Cited by 55 publications

(53 citation statements)

References 108 publications

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“…In our preceding study, we found that CKAP4 is a DKK1 receptor (28,29,40); our current study suggests that CKAP4 also functions as a receptor for other DKK family proteins including DKK2, DKK3, and DKK4. This finding is especially important for DKK3, because its receptor has been unknown to date.…”

Section: Ckap4 Is a Receptor For Dkk3supporting

confidence: 62%

p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4

et al. 2018

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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 gene. Knockdown of decreased DKK3 expression in ESCC cells, and reexpression of DKK3 partially rescued cell proliferation in -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. In esophageal cancer, findings identify DKK3 as a poor prognostic indicator and demonstrate CKAP4 inhibition as an effective therapeutic strategy. .

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Section: Ckap4 Is a Receptor For Dkk3supporting

confidence: 62%

p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4

et al. 2018

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“…SENCR Maintains Adherens Junction Integrity by Binding CKAP4. Although CKAP4 has been shown to interact with several proteins, no studies have defined CKAP4-protein interactions in EC (25). We therefore performed an unbiased IP/mass spectrometry experiment in HUVEC to define CKAP4 interacting proteins.…”

Section: Resultsmentioning

confidence: 99%

SENCRstabilizes vascular endothelial cell adherens junctions through interaction with CKAP4

Lyu

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SENCR is a human-specific, vascular cell-enriched long-noncoding RNA (lncRNA) that regulates vascular smooth muscle cell and endothelial cell (EC) phenotypes. The underlying mechanisms of action of SENCR in these and other cell types is unknown. Here, levels of SENCR RNA are shown to be elevated in several differentiated human EC lineages subjected to laminar shear stress. Increases in SENCR RNA are also observed in the laminar shear stress region of the adult aorta of humanized SENCR-expressing mice, but not in disturbed shear stress regions. SENCR loss-of-function studies disclose perturbations in EC membrane integrity resulting in increased EC permeability. Biotinylated RNA pull-down and mass spectrometry establish an abundant SENCR-binding protein, cytoskeletal-associated protein 4 (CKAP4); this ribonucleoprotein complex was further confirmed in an RNA immunoprecipitation experiment using an antibody to CKAP4. Structure–function studies demonstrate a noncanonical RNA-binding domain in CKAP4 that binds SENCR. Upon SENCR knockdown, increasing levels of CKAP4 protein are detected in the EC surface fraction. Furthermore, an interaction between CKAP4 and CDH5 is enhanced in SENCR-depleted EC. This heightened association appears to destabilize the CDH5/CTNND1 complex and augment CDH5 internalization, resulting in impaired adherens junctions. These findings support SENCR as a flow-responsive lncRNA that promotes EC adherens junction integrity through physical association with CKAP4, thereby stabilizing cell membrane-bound CDH5.

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“…cell surface receptor for surfactant protein A, antiproliferative factor and Dickkopf 1 (DKK1) (11)(12)(13)(14), which are associated with tumor growth in cervical and bladder cancer (12,13). As a novel DKK1 receptor that stimulates tumor cell proliferation, CKAP4 is frequently upregulated in pancreatic cancer, lung cancer and esophageal squamous cell carcinoma (ESCC), and blocking CKAP4 activity via knockdown or anti-CKAP4 antibodies can prevent xenograft tumor formation (14)(15)(16). CKAP4 has also been demonstrated to be upregulated in chronic lymphocytic leukemia (CLL) (17).…”

Section: Cytoskeleton-associated Membrane Protein 4 Is Upregulated Inmentioning

confidence: 99%

Cytoskeleton-associated membrane protein�4 is upregulated in tumor tissues and is associated with clinicopathological characteristics and prognosis in hepatocellular carcinoma

et al. 2020

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The role of cytoskeleton-associated membrane protein 4 (CKAP4) in hepatocellular carcinoma (HCC) is controversial. The present study aimed to investigate the association between tumor CKAP4 mRNA expression and clinicopathological characteristics and prognosis in patients with HCC. Data relating to CKAP4 mRNA expression in HCC tumor and normal adjacent liver tissues, and clinicopathological characteristics, were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The CKAP4 mRNA levels in tumor tissues were compared with those in normal adjacent liver tissues, their association with clinicopathological parameters was analyzed, and diagnostic and prognostic values were evaluated in patients with HCC. In all 4 datasets (total samples, n=693), CKAP4 mRNA levels were significantly higher in tumor tissues compared with adjacent tissues (all P<0.001), with the area under the receiver operating characteristic curve ranging from 0.799-0.898 for HCC diagnosis. In patients with HCC with available clinical data (n=361), the low-level CKAP4 mRNA group exhibited a lower body mass index (P=0.005), higher α-fetoprotein level (P<0.001), more frequent adjacent liver tissue inflammation (P<0.001), poorer tumor histological grade (P<0.001), higher Ishak fibrosis score (P= 0.035) and a more advanced tumor node metastasis (TNM) stage (P=0.014) compared with the high-level CKAP4 mRNA group. Patients stratified by all the above parameters, except for TNM stage, exhibited significantly different expression of tissue CKAP4 mRNA (P<0.05-0.001). Furthermore, higher CKAP4 mRNA levels were observed in patients who died within one year following diagnosis compared with those who survived >3 years (P=0.003). The high-level CKAP4 mRNA group also exhibited lower overall survival (OS) and disease-free survival (DFS) rates compared with the low-level group [hazard ratio (HR)=1.494; 95% confidence interval (CI), 1.044-2.138; P=0.028] for OS and (HR=1.616; 95% CI, 1.022-2.555; P=0.040) for DFS. The results of the present study suggest that CKAP4 mRNA is upregulated in HCC tumor tissues compared with normal adjacent tissues, and is associated with poor clinical prognosis, pathological features and survival in patients with HCC. Thus, CKAP4 is a potential biomarker for HCC diagnosis and prognosis.

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The Dickkopf1‐cytoskeleton‐associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy

Cited by 55 publications

References 108 publications

p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4

p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4

SENCRstabilizes vascular endothelial cell adherens junctions through interaction with CKAP4

Cytoskeleton-associated membrane protein�4 is upregulated in tumor tissues and is associated with clinicopathological characteristics and prognosis in hepatocellular carcinoma

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