p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4
| Autor: | Akira Kikuchi, Eiichi Morii, Makoto Yamasaki, Satoshi Nojima, Kazuki Odagiri, Yuichiro Doki, Keita Asano, Chihiro Kajiwara, Tetsuo Takehara, Katsumi Fumoto, Hirokazu Kimura, Hayato Hikita |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research Esophageal Neoplasms Carcinogenesis medicine.disease_cause Madin Darby Canine Kidney Cells Mice 0302 clinical medicine Genes Reporter Regulation of gene expression Aged 80 and over Mice Knockout Gene knockdown Mice Inbred BALB C Hep G2 Cells Esophageal cancer Middle Aged Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Intercellular Signaling Peptides and Proteins Female Esophageal Squamous Cell Carcinoma Chemokines Adult Biology 03 medical and health sciences Dogs Cell Line Tumor medicine Animals Humans Adaptor Proteins Signal Transducing Aged Cell Proliferation A549 cell Cell growth Tumor Suppressor Proteins HEK 293 cells Cancer Membrane Proteins medicine.disease HCT116 Cells 030104 developmental biology HEK293 Cells A549 Cells Cancer research Caco-2 Cells Neoplasm Transplantation Transcription Factors |
| Zdroj: | Cancer research. 78(21) |
| ISSN: | 1538-7445 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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