Dickkopf-4 gene expression is associated with differentiation and lymph node metastasis in colorectal cancer

Background and Aim Although high expression of Dickkopf-4 (DKK-4) in colorectal cancer has been reported in previous studies, its impact on clinicopathological features, including the prognosis and mechanism of expression, has not been well clarified to date. Methods (i) DKK-4 protein expression was analyzed by immunohistochemical staining with anti-DKK-4 antibody using archived formalin-fixed paraffin-embedded specimens obtained at surgery from 122 patients with colorectal cancer, and its association with clinicopathological findings was also investigated. (ii) The association between intratumoral DKK-4 protein expression and somatic hotspot mutations in cancer-associated genes in 40 patients was investigated using a next-generation sequencer. Results In cross-section, DKK-4 protein expression in colorectal tissue was related to an adenocarcinoma of a histologically differentiated type (tub1/tub2, P = 0.032) and distant metastasis (P = 0.012). Longitudinally, however, DKK-4 was not an independent prognostic factor determining overall survival (OS). On the other hand, in patients with metastasis, high DKK-4 protein was independently associated with short OS (P = 0.013). In addition, colorectal cancer tissue with high DKK-4 protein expression was associated with hotspot mutations in Wnt/beta catenin-signaling molecules (APC, CTNNB1, and FBXW7, P = 0.03). Conclusion Intratumoral DKK-4 expression, by partly reflecting the Wnt/beta catenin pathway, is strongly associated with the advancement of colorectal cancer and OS in colorectal cancer patients with metastasis, although further studies are needed.