Dickkopf-related protein 3 (DKK3) (DKK3)

Dickkopf-related protein 3 (DKK3), also known as REIC (Reduced Expression in Immortalized Cells), is a secreted glycoprotein and a member of the Dickkopf family that primarily functions as a tumor suppressor [1, 3, 5]. It is frequently downregulated in various human cancers due to promoter hypermethylation, and its loss is associated with tumor progression and poor prognosis [1, 5, 18]. DKK3 modulates several signaling pathways, most notably the Wnt/beta-catenin and TGF-beta pathways, and plays a critical role in inducing cancer-specific apoptosis through the activation of endoplasmic reticulum (ER) stress and the c-Jun N-terminal kinase (JNK) pathway [1, 17, 21]. Beyond its direct pro-apoptotic effects, DKK3 acts as an immunomodulator by promoting the differentiation of monocytes into dendritic cells and stimulating the production of interleukin-7 (IL-7) to activate natural killer (NK) cells, effectively functioning as an endogenous cancer vaccine [1, 4, 7]. Therapeutic strategies targeting this pathway include adenovirus-mediated gene therapy (Ad-REIC), which has shown promise in clinical trials for prostate and liver cancers, as well as recombinant protein approaches and epigenetic reactivation [1, 4, 16, 20]. Additionally, DKK3 has been identified as an atheroprotective factor and a potential biomarker for kidney injury, highlighting its diverse roles in human physiology and disease [6, 13].

Other names

Reduced expression in immortalized cellsREICDickkopf-3Dkk-3Dickkopf homolog 3DKK-3

Induction of cancer-specific apoptosis via endoplasmic reticulum (ER) stress and JNK activation; stimulation of systemic anti-tumor immunity through monocyte-to-dendritic cell differentiation and IL-7-mediated NK cell activation; and promotion of PD-L1 degradation by competing with CMTM6.