| RRC ID |
52654
|
| 著者 |
Shinno N, Kimura H, Sada R, Takiguchi S, Mori M, Fumoto K, Doki Y, Kikuchi A.
|
| タイトル |
Activation of the Dickkopf1-CKAP4 pathway is associated with poor prognosis of esophageal cancer and anti-CKAP4 antibody may be a new therapeutic drug.
|
| ジャーナル |
Oncogene
|
| Abstract |
Aberrant expression of the secretory protein Dickkopf1 (DKK1) is associated with poor prognosis of esophageal squamous cell carcinoma (ESCC), but the underlying mechanism of how DKK1 is involved in aggressiveness of ESCC is not clear. In this study, we show that cytoskeleton-associated protein 4 (CKAP4) functions as a DKK1 receptor in ESCC cells. Immunohistochemical analyses of ESCC revealed that both DKK1 and CKAP4 are minimally expressed in associated normal esophageal squamous mucosa of non-tumor regions, but strongly expressed in tumor lesions. Forty-six of 119 cases (38.7%) were positive for both DKK1 and CKAP4. Those expressing both proteins showed poor prognosis and relapse-free survival. Multivariate analysis demonstrated that expression of both proteins was the poor prognostic factor. The Cancer Genome Atlas data set indicated that the mRNA levels of DKK1 and CKAP4 are significantly elevated in the tumor lesions compared to non-tumor regions. DKK1 bound to CKAP4 at endogenous levels. DKK1 induced the internalization of CKAP4 from and its recycling to the plasma membrane. AKT was activated in ESCC cells in which DKK1 was highly expressed and CKAP4 was localized to the plasma membrane. Knockdown of either DKK1 or CKAP4 inhibited AKT activity and cell proliferation in vitro and xenograft tumor formation. Wild-type CKAP4 or DKK1, but not a DKK1 mutant that was unable to bind to CKAP4, rescued phenotypes induced by CKAP4 or DKK1 knockdown, respectively. The anti-CKAP4 antibody also inhibited AKT activity and suppressed xenograft tumor formation. In contrast, in ESCC cells in which DKK1 was marginally expressed, knockdown of CKAP4 or anti-CKAP4 antibody affected neither AKT activity nor cell proliferation. These findings suggest that the DKK1-CKAP4 pathway promotes ESCC cell proliferation and that CKAP4 might represent a novel therapeutic target for ESCCs expressing both DKK1 and CKAP4.
|
| 巻・号 |
37(26)
|
| ページ |
3471-3484
|
| 公開日 |
2018-6-1
|
| DOI |
10.1038/s41388-018-0179-2
|
| PII |
10.1038/s41388-018-0179-2
|
| PMID |
29563607
|
| MeSH |
Adult
Aged
Aged, 80 and over
Animals
Cell Line, Tumor
Cell Membrane / metabolism
Cell Proliferation / genetics
Esophageal Neoplasms / genetics
Esophageal Neoplasms / mortality*
Esophageal Neoplasms / pathology
Esophageal Squamous Cell Carcinoma / genetics
Esophageal Squamous Cell Carcinoma / mortality
Esophageal Squamous Cell Carcinoma / pathology*
Female
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Male
Membrane Proteins / genetics
Membrane Proteins / immunology
Membrane Proteins / metabolism*
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Neoplasm Transplantation
Protein Binding / genetics
Proto-Oncogene Proteins c-akt / metabolism*
RNA Interference
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Transplantation, Heterologous
|
| IF |
7.971
|
| 引用数 |
11
|
| リソース情報 |
| ヒト・動物細胞 |
TE-1(RCB1894)
TE-4(RCB2097)
TE-5(RCB1949)
TE-6(RCB1950)
TE-8(RCB2098)
TE-9(RCB1988)
TE-10(RCB2099)
TE-11(RCB2100) |
