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.

Background: Recent studies have reported that the occurrence of postoperative complications after esophagectomy for esophageal cancer has a negative impact on long-term survival. Although salvage esophagectomy is associated with higher rates of morbidity and mortality, the impact of postoperative complications on long-term survival following salvage esophagectomy has not been fully investigated. Methods: We retrospectively analyzed 73 patients with thoracic esophageal cancer who underwent salvage esophagectomy between January 1997 and December 2017 after definitive chemoradiotherapy. We investigated the clinical impact of postoperative complications on long-term survival after salvage esophagectomy. Results: Postoperative complications, pulmonary complications, and anastomotic leakage occurred in 34 (47%), 14 (13%), and 14 (19%) of the patients, respectively. Patients with complications had significantly poorer survival than patients who did not have complications (HR [hazard ratio], 2.06; p = 0.017), but there were no significant differences in overall survival between patients with and those without pulmonary complications or anastomotic leakage (HR, 1.48, p = 0.318, and HR, 1.37, p = 0.377, respectively). Multivariate analysis revealed that pathological T3-4 disease (HR, 4.63; p = 0.001), residual disease (HR, 5.09; p = 0.001), and postoperative complications (HR, 3.85; p = 0.001) were significant independent prognostic factors. In particular, the frequency of death from other diseases among patients with postoperative complications was nonsignificantly higher than among patients without postoperative complications (26 vs. 10%; p = 0.071). Conclusion: The occurrence of complications leads to a poor prognosis for patients with esophageal cancer after salvage esophagectomy. Prevention of postoperative complications and long-term postoperative general supportive care might be important for improving patients' prognosis.

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