Gene Summary

Gene:DKK3; dickkopf WNT signaling pathway inhibitor 3
Aliases: RIG, REIC
Summary:This gene encodes a protein that is a member of the dickkopf family. The secreted protein contains two cysteine rich regions and is involved in embryonic development through its interactions with the Wnt signaling pathway. The expression of this gene is decreased in a variety of cancer cell lines and it may function as a tumor suppressor gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:dickkopf-related protein 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Gene Silencing
  • Cancer Gene Expression Regulation
  • Seoul
  • Cell Proliferation
  • Paraffin Embedding
  • Signal Transduction
  • Intercellular Signaling Peptides and Proteins
  • Breast Cancer
  • alpha-Fetoproteins
  • Wnt Signaling Pathway
  • Stomach Cancer
  • Cervical Cancer
  • Transfection
  • Genetic Therapy
  • Western Blotting
  • Proteins
  • Apoptosis
  • Lung Cancer
  • Staging
  • Promoter Regions
  • Prostate Cancer
  • Young Adult
  • Tissue Distribution
  • Umbilical Veins
  • Adenocarcinoma
  • Gene Expression Profiling
  • Adenoviridae
  • DNA Methylation
  • Tissue Array Analysis
  • Epigenetics
  • Cancer RNA
  • CpG Islands
  • Transcription Factors
  • Tumor Burden
  • Biomarkers, Tumor
  • Repressor Proteins
  • Neoplasm Invasiveness
  • Chromosome 11
  • Wnt1 Protein
  • Membrane Proteins
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DKK3 (cancer-related)

Pećina-Šlaus N, Kafka A, Gotovac Jerčić K, et al.
Comparable Genomic Copy Number Aberrations Differ across Astrocytoma Malignancy Grades.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
A collection of intracranial astrocytomas of different malignancy grades was analyzed for copy number aberrations (CNA) in order to identify regions that are driving cancer pathogenesis. Astrocytomas were analyzed by Array Comparative Genomic Hybridization (aCGH) and bioinformatics utilizing a Bioconductor package, Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0.23 and DAVID software. Altogether, 1438 CNA were found of which losses prevailed. On our total sample, significant deletions affected 14 chromosomal regions, out of which deletions at 17p13.2, 9p21.3, 13q12.11, 22q12.3 remained significant even at 0.05

van Andel H, Kocemba KA, Spaargaren M, Pals ST
Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options.
Leukemia. 2019; 33(5):1063-1075 [PubMed] Related Publications
Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.

Ferrari N, Ranftl R, Chicherova I, et al.
Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts.
Nat Commun. 2019; 10(1):130 [PubMed] Free Access to Full Article Related Publications
Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs.

Katase N, Nishimatsu SI, Yamauchi A, et al.
DKK3 knockdown confers negative effects on the malignant potency of head and neck squamous cell carcinoma cells via the PI3K/Akt and MAPK signaling pathways.
Int J Oncol. 2019; 54(3):1021-1032 [PubMed] Related Publications
Dickkopf‑related protein 3 (DKK3), which is a member of the Dickkopf WNT signaling pathway inhibitor family, is considered to be a tumor suppressor, due to its reduced expression in cancer cells and its ability to induce apoptosis when overexpressed by adenovirus. However, our previous study demonstrated alternative functions for DKK3 in head and neck squamous cell carcinoma (HNSCC). Our study reported that DKK3 expression was predominantly upregulated in HNSCC cell lines and tissue samples, and its expression was significantly correlated with poor prognosis. Furthermore, DKK3 overexpression in HNSCC cells significantly increased cancer cell proliferation, migration, invasion and in vivo tumor growth. These data have led to the hypothesis that DKK3 may exert oncogenic functions and may increase the malignant properties of HNSCC. The present study established a stable DKK3 knockdown cell line (HSC‑3 shDKK3) using lentivirus‑mediated short hairpin RNA, and assessed its effects on cancer cell behavior using MTT, migration and invasion assays. In addition, its effects on in vivo tumor growth were assessed using a xenograft model. Furthermore, the molecular mechanisms underlying the effects of DKK3 knockdown were investigated by microarray analysis, pathway analysis and western blotting. Compared with control cells, HSC‑3 shDKK3 cells exhibited significantly reduced proliferation, migration and invasion, and formed significantly smaller tumor masses when subcutaneously transplanted into nude mice. In addition, in HSC‑3 shDKK3 cells, the expression levels of phosphorylated (p)‑protein kinase B (Akt) (Ser473), p‑phosphoinositide 3‑kinase (PI3K) p85 (Tyr467), p‑PI3K p55 (Try199), p‑3‑phosphoinositide‑dependent protein kinase‑1 (PDK1) (Ser241) and total p38 mitogen‑activated protein kinase (MAPK) were reduced. Furthermore, phosphorylation of mechanistic target of rapamycin (mTOR) (Ser2448) was slightly decreased in HSC‑3 shDKK3 cells, which may be due to the increased expression of DEP domain‑containing mTOR‑interacting protein. Conversely, DKK3 overexpression in HSC‑3 shDKK3 cells rescued cellular proliferation, migration and invasion. With regards to expression levels, p‑PI3K and p‑PDK1 expression was not altered, whereas mTOR and p‑p38 MAPK expression was elevated. These data supported the hypothesis and indicated that DKK3 may contribute to the malignant phenotype of HNSCC cells via the PI3K/Akt/mTOR and MAPK signaling pathways.

Jacobson ME, Wang-Bishop L, Becker KW, Wilson JT
Delivery of 5'-triphosphate RNA with endosomolytic nanoparticles potently activates RIG-I to improve cancer immunotherapy.
Biomater Sci. 2019; 7(2):547-559 [PubMed] Related Publications
RNA agonists of the retinoic acid gene I (RIG-I) pathway have recently emerged as a promising class of cancer immunotherapeutics, but their efficacy is hindered by drug delivery barriers, including nuclease degradation, poor intracellular uptake, and minimal access to the cytosol where RIG-I is localized. Here, we explore the application of pH-responsive, endosomolytic polymer nanoparticles (NPs) to enhance the cytosolic delivery and immunostimulatory activity of synthetic 5' triphosphate, short, double-stranded RNA (3pRNA), a ligand for RIG-I. Delivery of 3pRNA with pH-responsive NPs with an active endosomal escape mechanism, but not control carriers lacking endosomolytic activity, significantly increased the activity of 3pRNA in dendritic cells, macrophages, and cancer cell lines. In a CT26 colon cancer model, activation of RIG-I via NP delivery of 3pRNA induced immunogenic cell death, triggered expression of type I interferon and pro-inflammatory cytokines, and increased CD8+ T cell infiltration into the tumor microenvironment. Consequently, intratumoral (IT) delivery of NPs loaded with 3pRNA inhibited CT26 tumor growth and enhanced the therapeutic efficacy of anti-PD-1 immune checkpoint blockade, resulting in a 30% complete response rate and generation of immunological memory that protected against tumor rechallenge. Collectively, these studies demonstrate that pH-responsive NPs can be harnessed to strongly enhance the immunostimulatory activity and therapeutic efficacy of 3pRNA and establish endosomal escape as a critical parameter in the design of carriers for immunotherapeutic targeting of the RIG-I pathway.

Tang XD, Zhang DD, Jia L, et al.
lncRNA AFAP1-AS1 Promotes Migration and Invasion of Non-Small Cell Lung Cancer via Up-Regulating IRF7 and the RIG-I-Like Receptor Signaling Pathway.
Cell Physiol Biochem. 2018; 50(1):179-195 [PubMed] Related Publications
BACKGROUND/AIMS: Accumulating evidence has highlighted the importance of long non-coding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) in tumor biology. Among others, actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) has been associated with non-small cell lung cancer (NSCLC). However, it remains unclear how AFAP1-AS1 participates in the development and progression of NSCLC.
METHODS: The peripheral blood samples were collected from patients with NSCLC. White blood cell subsets were classified and levels of interleukin (IL)-10, IL-12 and IFN-γ in serum were measured. We then identified its target gene of AFAP1-AS1 via bioinformatics methods. NSCLC cell line with the highest expression of AFAP1-AS1, i.e. H1975 was selected for in vitro experiments. A series of inhibitor, vector and siRNA were employed to validate the regulatory mechanisms of AFAP1-AS1 in the development and progression of NSCLC. Cell proliferation was detected by MTT assay and EdU staining. Cell migration and invasion, and cell cycle and apoptosis were measured by transwell assay and flow cytometry, respectively.
RESULTS: A high expression of AFAP1-AS1 was identified in NSCLC, alongside with a reduced level of IL-12 and increased levels of IL-10 and interferon (IFN)-γ. Aberrant expressions of AFAP1-AS1 were associated with pathological grade, TNM staging and metastatic potential of NSCLC. AFAP1-AS1 could activate interferon regulatory factor (IRF)7, the retinoid-inducible protein (RIG)-I-like receptor signaling pathway and Bcl-2 in vitro. Over-expression of AFAP1-AS1 promoted NSCLC cell proliferation, invasion and migration while inhibiting cell apoptosis.
CONCLUSION: lncRNA AFAP1-AS1 promotes migration and invasion of non-small cell lung cancer via up-regulating IRF7 and the RIG-I-like receptor signaling pathway.

Daßler-Plenker J, Paschen A, Putschli B, et al.
Direct RIG-I activation in human NK cells induces TRAIL-dependent cytotoxicity toward autologous melanoma cells.
Int J Cancer. 2019; 144(7):1645-1656 [PubMed] Related Publications
Activation of the innate immune receptor retinoic acid-inducible gene I (RIG-I) by its specific ligand 5'-triphosphate RNA (3pRNA) triggers anti-tumor immunity, which is dependent on natural killer (NK) cell activation and cytokine induction. However, to date, RIG-I expression and the functional consequences of RIG-I activation in NK cells have not been examined. Here, we show for the first time the expression of RIG-I in human NK cells and their activation upon RIG-I ligand (3pRNA) transfection. 3pRNA-activated NK cells killed melanoma cells more efficiently than NK cells activated by type I interferon. Stimulation of RIG-I in NK cells specifically increased the surface expression of membrane-bound TNF-related apoptosis-inducing ligand (TRAIL) on NK cells, while activated NK cell receptors were not affected. RIG-I-induced membrane-bound TRAIL initiated death-receptor-pathway-mediated apoptosis not only in allogeneic but also in autologous human leukocyte antigen (HLA) class I-positive and HLA class I-negative melanoma cells. These results identify the direct activation of RIG-I in NK cells as a novel mechanism for how RIG-I can trigger enhanced NK cell killing of tumor cells, underscoring the potential of RIG-I activation for tumor immunotherapy.

Lin LL, Huang CC, Wu MT, et al.
Innate immune sensor laboratory of genetics and physiology 2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma.
Cancer Sci. 2018; 109(11):3494-3502 [PubMed] Free Access to Full Article Related Publications
The innate immune receptors, such as toll-like receptor 3 (TLR3), melanoma differentiation-associated 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I), have been shown to be differentially expressed in neuroblastoma (NB) and promote dsRNA poly (I:C)-induced NB suppression in vitro and in vivo. However, the role of another important innate immune cytosolic sensor, laboratory of genetics and physiology 2 (LGP2), in the cancer behavior of NB remains unclear. Here, we demonstrated that the expression levels of LGP2 were either low or undetectable in all NB cell lines tested with or without MYCN amplification. LGP2 expression levels were significantly increased only in NB cells without MYCN amplification, including SK-N-AS and SK-N-FI after poly (I:C) treatment in vitro and in mouse xenograft models. Ectopic expression of LGP2 in NB cells significantly enhanced poly (I:C)-induced NB cell death associated with downregulation of MDA5, RIG-I, MAVS and Bcl-2, as well as upregulation of Noxa and tBid. By immunofluorescence analyses, LGP2 localized mainly in the cytoplasm of NB cells after poly (I:C) treatment. In human NB tissue samples, cytoplasmic LGP2 expression was positively correlated with histological differentiation and inversely correlated with MYCN amplification. Positive cytoplasmic LGP2 expression in tumor tissues could predict a favorable outcome in NB patients independent of other prognostic factors. In short, LGP2 was effective in promoting poly (I:C)-induced NB suppression and cytoplasmic LGP2 can serve as an independent favorable prognostic factor in NB patients.

Le AV, Szaumkessel M, Tan TZ, et al.
DNA Methylation Profiling of Breast Cancer Cell Lines along the Epithelial Mesenchymal Spectrum-Implications for the Choice of Circulating Tumour DNA Methylation Markers.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
(1) Background: Epithelial⁻mesenchymal plasticity (EMP) is a dynamic process whereby epithelial carcinoma cells reversibly acquire morphological and invasive characteristics typical of mesenchymal cells. Identifying the methylation differences between epithelial and mesenchymal states may assist in the identification of optimal DNA methylation biomarkers for the blood-based monitoring of cancer. (2) Methods: Methylation-sensitive high-resolution melting (MS-HRM) was used to examine the promoter methylation status of a panel of established and novel markers in a range of breast cancer cell lines spanning the epithelial⁻mesenchymal spectrum. Pyrosequencing was used to validate the MS-HRM results. (3) Results:

Chen E, Li Q, Wang H, et al.
MiR-92a promotes tumorigenesis of colorectal cancer, a transcriptomic and functional based study.
Biomed Pharmacother. 2018; 106:1370-1377 [PubMed] Related Publications
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Accumulation of varieties of epigenetic changes, including miRNA regulation, is one of the fundamental processes driving CRC initiation and progression. Mir-92a has been reported in several studies as an oncogene, and particularly in colorectal cancer, it has become a useful biomarker for early detection of CRC in both serum or stool. The Cancer Genome Atlas (TCGA) is a powerful database to analyze cancer-related genes and their correlation with patients' pathological information. However, miR-92a expression and its regulating target genes has yet to be investigated in TCGA system. In this study, we found miR-92a expression is associated with CRC pathological process. Notably, high expression of miR-92a mainly occurs in microsatellite-stable (MSS) cases. Further experiments showed exogenous introduction of miR-92a into LoVo and SW480 cells could enhance cell proliferation, migration, and invasion, whereas inhibition of miR-92a showed the opposite effects. A system analysis based on binding capacity and expression correlation analysis confirmed DKK3 and KLF4 are the top target genes of miR-92a, and novel target SMAD7 highlights the role of miR-92a in BMPs/SMAD pathway. In conclusion, miR-92a acts as an oncomir and directly targets Wnt/β-catenin, PTEN/Akt/FoxO, and BMP/Smads related genes, thus participates in CRC progression.

Makjaroen J, Somparn P, Hodge K, et al.
Comprehensive Proteomics Identification of IFN-λ3-regulated Antiviral Proteins in HBV-transfected Cells.
Mol Cell Proteomics. 2018; 17(11):2197-2215 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Interferon lambda (IFN-λ) is a relatively unexplored, yet promising antiviral agent. IFN-λ has recently been tested in clinical trials of chronic hepatitis B virus infection (CHB), with the advantage that side effects may be limited compared with IFN-α, as IFN-λ receptors are found only in epithelial cells. To date, IFN-λ's downstream signaling pathway remains largely unelucidated, particularly via proteomics methods. Here, we report that IFN-λ3 inhibits HBV replication in HepG2.2.15 cells, reducing levels of both HBV transcripts and intracellular HBV DNA. Quantitative proteomic analysis of HBV-transfected cells was performed following 24-hour IFN-λ3 treatment, with parallel IFN-α2a and PBS treatments for comparison using a dimethyl labeling method. The depth of the study allowed us to map the induction of antiviral proteins to multiple points of the viral life cycle, as well as facilitating the identification of antiviral proteins not previously known to be elicited upon HBV infection (

Ding C, He J, Zhao J, et al.
β-catenin regulates IRF3-mediated innate immune signalling in colorectal cancer.
Cell Prolif. 2018; 51(5):e12464 [PubMed] Related Publications
OBJECTIVE: β-catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage-associated molecular patterns (DAMPs) and primes the anti-tumour adaptive responses. While the function of β-catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of β-catenin in inhibiting RIG-I-like receptor (RLR)-mediated IFN-β signalling in colorectal cancer.
MATERIALS AND METHODS: Immunohistochemical staining and western blotting were conducted to study the expression of β-catenin, IRF3 and phospho-IRF3 (p-IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of β-catenin on IFN-β signalling. The inhibition of β-catenin on RLR-mediated IFN-β signalling was further studied by real-time analyses and reporter assays in the context of lentiviral-mediated β-catenin stably knocking down. Lastly, co-immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between β-catenin and IRF3.
RESULTS: We found that high expression of β-catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of β-catenin increased the viral replication. Conversely knocking down of β-catenin inhibited viral replication. Furthermore, our data demonstrated that β-catenin could inhibit the expression of IFN-β and interferon-stimulated gene 56 (ISG56). Mechanistically, we found that β-catenin interacted with IRF3 and blocked its nuclear translocation.
CONCLUSION: Our study reveals an unprecedented role of β-catenin in enabling innate immune evasion in CRC.

Kim SH, Park KH, Shin SJ, et al.
CpG Island Methylator Phenotype and Methylation of Wnt Pathway Genes Together Predict Survival in Patients with Colorectal Cancer.
Yonsei Med J. 2018; 59(5):588-594 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
PURPOSE: Dysregulation of the Wnt pathway is a crucial step in the tumorigenesis of colorectal cancer (CRC). This study aimed to determine whether DNA methylation of Wnt pathway genes helps predict treatment response and survival in patients with metastatic or recurrent CRC.
MATERIALS AND METHODS: We retrospectively collected primary tumor tissues from 194 patients with metastatic or recurrent CRC. Pyrosequencing was used to examine the methylation of 10 CpG island loci in DNA extracted from formalin-fixed paraffin-embedded specimens. To elucidate the predictive role of DNA methylation markers, Kaplan-Meier survival estimation and Cox regression were performed for progression-free survival and overall survival (OS).
RESULTS: The methylation frequencies of the 10 genes analyzed (p16, p14, MINT1, MINT2, MINT31, hMLH1, DKK3, WNT5A, AXIN2, and TFAP2E) were 47.9%, 10.8%, 21.1%, 16.0%, 20.6%, 0.5%, 53.1%, 32.0%, 2.6%, and 2.1%, respectively. We divided patients into three groups based on the number of methylated genes (group 1, no methylation n=38; group 2, 1-2 methylations n=92; group 3, 3 or more methylations n=64). Among patients treated with palliative chemotherapy (n=167), median OSs of groups 1, 2, and 3 were 39.1, 39.7, and 29.1 months, respectively (log rank p=0.013). After adjustment, number of methylations was identified as an independent poor prognostic factor (0-2 methylated vs. ≥3 methylated: hazard ratio, 1.72; 95% confidence interval, 1.16-2.56, p=0.007).
CONCLUSION: This study suggests that methylation of Wnt pathway genes, in addition to known CpG island methylator phenotype markers, may help predict treatment outcome and survival in patients with CRC.

Chen GY, Zheng HC
The clinicopathological and prognostic significances of Dkk3 expression in cancers: A bioinformatics analysis.
Cancer Biomark. 2018; 23(3):323-331 [PubMed] Related Publications
BACKGROUND: Dkk3 protein attenuates the expression of Wnt3a, Wnt5a and LRP6, and their interaction, and interacts with βTrCP to suppress wnt/β-catenin pathway.
METHODS: We performed a bioinformatics analysis of Dkk3 mRNA expression through Oncomine, TCGA and Kaplan-Meier plotter databases up to July 10, 2017.
RESULTS: Up-regulated Dkk3 expression was higher in gastric, breast, and ovarian cancers than normal tissues (p< 0.05). Bitter's database showed a higher Dkk3 expression in ovarian cytoadenocarcinoma than clear cell adenocarcinoma (p< 0.05). Dkk3 was more expressed in ductal breast cancer in situ than invasive ductal breast cancer (p< 0.05), in mixed lobular and ductal cancer, and lobular cancer than ductal breast cancer (p< 0.05). In TCGA data, Dkk3 expression was lower in gastric cancers with than without Barret's esophagus (p< 0.05), in intestinal-type than diffuse-type cancers (p< 0.05), and in the cancers of elder than younger patients (p< 0.05). Dkk3 expression was higher in squamous cell carcinoma than adenocarcinoma (p< 0.05). Dkk3 expression was higher in ductal than lobular breast cancer, or in younger than elder patients with breast cancer (p< 0.05). According to Kaplan-Meier plotter, Dkk3 expression was negatively correlated with overall, progression-free, relapse-free or distant-metastasis-free survival rate of gastric, breast or ovarian cancer patients, but versa for lung cancer patients (p< 0.05).
CONCLUSION: Dkk3 expression might be employed as a potential marker to indicate carcinogenesis and histogenesis, even prognosis.

Fujihara T, Mizobuchi Y, Nakajima K, et al.
Down-regulation of MDR1 by Ad-DKK3 via Akt/NFκB pathways augments the anti-tumor effect of temozolomide in glioblastoma cells and a murine xenograft model.
J Neurooncol. 2018; 139(2):323-332 [PubMed] Related Publications
BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant of brain tumors. Acquired drug resistance is a major obstacle for successful treatment. Earlier studies reported that expression of the multiple drug resistance gene (MDR1) is regulated by YB-1 or NFκB via the JNK/c-Jun or Akt pathway. Over-expression of the Dickkopf (DKK) family member DKK3 by an adenovirus vector carrying DKK3 (Ad-DKK3) exerted anti-tumor effects and led to the activation of the JNK/c-Jun pathway. We investigated whether Ad-DKK3 augments the anti-tumor effect of temozolomide (TMZ) via the regulation of MDR1.
METHODS: GBM cells (U87MG and U251MG), primary TGB105 cells, and mice xenografted with U87MG cells were treated with Ad-DKK3 or TMZ alone or in combination.
RESULTS: Ad-DKK3 augmentation of the anti-tumor effects of TMZ was associated with reduced MDR1 expression in both in vivo and in vitro studies. The survival of Ad-DKK3-treated U87MG cells was inhibited and the expression of MDR1 was reduced. This was associated with the inhibition of Akt/NFκB but not of YB-1 via the JNK/c-Jun- or Akt pathway.
CONCLUSIONS: Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells.

Bahl C, Singh N, Behera D, Sharma S
High-order gene interactions between the genetic polymorphisms in Wnt and AhR pathway in modulating lung cancer susceptibility.
Per Med. 2017; 14(6):487-502 [PubMed] Related Publications
AIM: Genetic variations present within Wnt and AhR pathway might be related to the lung cancer susceptibility.
METHODS: A total of 555 subjects were genotyped using PCR-RFLP technique for polymorphic sites in DKK4, DKK3, DKK2, sFRP3, sFRP4, Axin2 and AhR. Multifactor dimensionality reduction method and classification and regression tree analysis was used.
RESULTS: Overall sFRP4
CONCLUSION: Both DKK2 and sFRP4 polymorphisms are found to play a crucial role; especially for smokers towards modulating risk for lung cancer. AhR variants are contributing maximally toward lung cancer risk.

Uribe D, Cardona A, Esposti DD, et al.
Antiproliferative Effects of Epigenetic Modifier Drugs Through E-cadherin Up-regulation in Liver Cancer Cell Lines.
Ann Hepatol. 2018 May-June; 17(3):444-460 [PubMed] Related Publications
INTRODUCTION AND AIM: Epigenetic alterations play an essential role in cancer onset and progression, thus studies of drugs targeting the epigenetic machinery are a principal concern for cancer treatment. Here, we evaluated the potential of the combination of the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5aza-dC) and the pan-deacetylase inhibitor Trichostatin A (TSA), at low cytotoxic concentrations, to modulate the canonical Wnt/β-catenin pathway in liver cancer cells.
MATERIAL AND METHODS: Pyrosequencing was used for DNA methylation analyses of LINE-1 sequences and the Wnt/β-catenin pathway antagonist DKK3, SFRP1, WIF1 and CDH1. qRT-PCR was employed to verify the expression of the antagonist. Pathway regulation were evaluated looking at the expression of β-catenin and E-cadherin by confocal microscopy and the antitumoral effects of the drugs was studied by wound healing and clonogenic assays.
RESULTS: Our result suggest that 5aza-dC and TSA treatments were enough to induce a significant expression of the pathway antagonists, decrease of β-catenin protein levels, re-localization of the protein to the plasma membrane, and pathway transcriptional activity reduction. These important effects exerted an antitumoral outcome shown by the reduction of the migration and clonogenic capabilities of the cells.
CONCLUSION: We were able to demonstrate Wnt/ β-catenin pathway modulation through E-cadherin up-regulation induced by 5aza-dC and TSA treatments, under an activation-pathway background, like CTNNB1 and TP53 mutations. These findings provide evidences of the potential effect of epigenetic modifier drugs for liver cancer treatment. However, further research needs to be conducted, to determine the in vivo potential of this treatment regimen for the management of liver cancer.

Yoshida A, Fujiwara T, Uotani K, et al.
Clinical and Functional Significance of Intracellular and Extracellular microRNA-25-3p in Osteosarcoma.
Acta Med Okayama. 2018; 72(2):165-174 [PubMed] Related Publications
Although there is considerable evidence indicating that the dysregulation of microRNAs (miRNAs) in malignant tumors plays a role in tumor development, the overall function of miRNAs and their clinicopathological significance are not well understood. In this retrospective analysis of 45 biopsy specimens from osteosarcoma (OS) patients, we investigated the functional and clinical significance of miR-25-3p in OS, which we previously identified as a highly expressed miRNA in OS patients' serum. We observed that miR-25-3p dysregulation in human OS tissues was negatively correlated with the clinical prognosis, whereas the expression level of its target gene, Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3), was positively correlated with the clinical prognosis. Endogenous miR-25-3p upregulation promoted tumor growth, invasion, and drug resistance, which was consistent with DKK3 silencing in OS cells. In addition, secretory miR-25-3p was embedded in tumor-derived exosomes, where it promoted capillary formation and the invasion of vascular endothelial cells. Overall, our results show that miR-25-3p has intracellular and extracellular oncogenic functions as well as clinicopathological relevance in OS, indicating its potential as a novel diagnostic and therapeutic tool for the clinical management of this disease.

Jucá CEB, Colli LM, Martins CS, et al.
Impact of the Canonical Wnt Pathway Activation on the Pathogenesis and Prognosis of Adamantinomatous Craniopharyngiomas.
Horm Metab Res. 2018; 50(7):575-581 [PubMed] Related Publications

Ghosh R, Roy S, Franco S
PARP1 depletion induces RIG-I-dependent signaling in human cancer cells.
PLoS One. 2018; 13(3):e0194611 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
DNA Damage Response (DDR) and DNA repair pathways are emerging as potent, ubiquitous suppressors of innate immune signaling in human cells. Here, we show that human cells surviving depletion of the Single Strand Break (SSB) repair protein PARP1 undergo p21-dependent senescence or cell cycle checkpoint activation in the context of activation of innate immune signaling, or viral mimicry. Specifically, we observe induction of a large number of interferon-stimulated genes (ISGs) and multiple pattern recognition receptors (PRRs; including RIG-I, MDA-5, MAVS, TLR3 and STING) and increased nuclear IRF3 staining. Mechanistically, depletion of the double-stranded RNA (dsRNA) helicase RIG-I or its downstream effector MAVS specifically rescues ISG induction in PARP1-depleted cells, suggesting that the RIG-I/MAVS pathway is required for sustained ISG expression in this context. Experiments with conditioned media or a neutralizing antibody to the α/β-IFN receptor revealed that persistent ISG expression additionally requires an autocrine/paracrine loop. Finally, loss of PARP1 and radiation-induced DNA damage strongly synergize in the induction of p21 and ISGs. Overall, these findings increase our understanding of how PARP1 may suppress deleterious phenotypes associated to aging, inflammation and cancer in humans.

Liu Y, Liu Y, Wu J, et al.
Innate responses to gene knockouts impact overlapping gene networks and vary with respect to resistance to viral infection.
Proc Natl Acad Sci U S A. 2018; 115(14):E3230-E3237 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Analyses of the levels of mRNAs encoding IFIT1, IFI16, RIG-1, MDA5, CXCL10, LGP2, PUM1, LSD1, STING, and IFNβ in cell lines from which the gene encoding LGP2, LSD1, PML, HDAC4, IFI16, PUM1, STING, MDA5, IRF3, or HDAC 1 had been knocked out, as well as the ability of these cell lines to support the replication of HSV-1, revealed the following: (

Matsumura T, Hida S, Kitazawa M, et al.
Fascin1 suppresses RIG-I-like receptor signaling and interferon-β production by associating with IκB kinase ϵ (IKKϵ) in colon cancer.
J Biol Chem. 2018; 293(17):6326-6336 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Fascin1 is an actin-bundling protein involved in cancer cell migration and has recently been shown also to have roles in virus-mediated immune cell responses. Because viral infection has been shown to activate immune cells and to induce interferon-β expression in human cancer cells, we evaluated the effects of fascin1 on virus-dependent signaling via the membrane- and actin-associated protein RIG-I (retinoic acid-inducible gene I) in colon cancer cells. We knocked down fascin1 expression with shRNA retrovirally transduced into a DLD-1 colon cancer and L929 fibroblast-like cell lines and used luciferase reporter assays and co-immunoprecipitation to identify fascin1 targets. We found that intracellular poly(I·C) transfection to mimic viral infection enhances the RIG-I/MDA5 (melanoma differentiation-associated gene 5)-mediated dimerization of interferon regulatory factor 3 (IRF-3). The transfection also significantly increased the expression levels of IRF-7, interferon-β, and interferon-inducible cytokine IP-10 in fascin1-deleted cells compared with controls while significantly suppressing cell growth, migration, and invasion. We also found that fascin1 constitutively interacts with IκB kinase ϵ (IKKϵ) in the RIG-I signaling pathway. In summary, we have identified fascin1 as a suppressor of the RIG-I signaling pathway associating with IκB kinase ϵ in DLD-1 colon cancer cells to suppress immune responses to viral infection.

Konno H, Yamauchi S, Berglund A, et al.
Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production.
Oncogene. 2018; 37(15):2037-2051 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The production of cytokines in response to DNA-damage events may be an important host defense response to help prevent the escape of pre-cancerous cells. The innate immune pathways involved in these events are known to be regulated by cellular molecules such as stimulator of interferon genes (STING), which controls type I interferon and pro-inflammatory cytokine production in response to the presence of microbial DNA or cytosolic DNA that has escaped from the nucleus. STING signaling has been shown to be defective in a variety of cancers, such as colon cancer and melanoma, actions that may enable damaged cells to escape the immunosurveillance system. Here, we report through examination of databases that STING signaling may be commonly suppressed in a greater variety of tumors due to loss-of-function mutation or epigenetic silencing of the STING/cGAS promoter regions. In comparison, RNA activated innate immune pathways controlled by RIG-I/MDA5 were significantly less affected. Examination of reported missense STING variants confirmed that many exhibited a loss-of-function phenotype and could not activate cytokine production following exposure to cytosolic DNA or DNA-damage events. Our data imply that the STING signaling pathway may be recurrently suppressed by a number of mechanisms in a considerable variety of malignant disease and be a requirement for cellular transformation.

Ma H, Jin S, Yang W, et al.
Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma.
Br J Cancer. 2018; 118(4):509-521 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: The epidermal growth factor receptor (EGFR)-targeted therapies have been tested in the clinic as treatments for head and neck squamous cell carcinoma (HNSCC). Owing to intrinsic or acquired resistance, EGFR-targeted therapies often lead to a low response rate and treatment failure. Interferon-alpha (IFNα) is a chemosensitising agent and multi-functional cytokine with a tumour inhibitory effect. However, the synergic effect of IFNα and EGFR-targeted therapies (erlotinib and nimotuzumab) and their mechanisms in HNSCC remain unclear.
METHODS: The interactions between IFNα, erlotinib, and nimotuzumab were evaluated in vitro in HNSCC cells. The synergistic effect of IFNα (20 000 IU per day, s.c.), erlotinib (50 mg kg
RESULTS: IFNα enhances the antitumour effects of erlotinib and nimotuzumab on HNSCC cells both in vitro and in vivo. Importantly, both IFNα and EGFR-targeted therapies promote the expression of RIG-I by activating signal transducers and activators of transcription 1 (STAT1) in HNSCC cells. RIG-I knockdown reduced the sensitivity of HN4 and HN30 cells to IFNα, erlotinib, and nimotuzumab. Moreover, IFNα transcriptionally induced RIG-I expression in HNSCC cells through STAT1.
CONCLUSIONS: IFNα enhances the effect of EGFR-targeted therapies by upregulating RIG-I, and its expression may represent a predictor of the effectiveness of a combination treatment including IFNα in HNSCC.

Yang L, Zhao S, Xia P, Zheng HC
Down-regulated REIC expression in lung carcinogenesis: a molecular target for gene therapy.
Histol Histopathol. 2018; 33(7):691-704 [PubMed] Related Publications
REIC (Reduced Expression in Immortalized Cells) gene is down-regulated in immortalized cells, compared with the normal parental counterparts. Its encoding protein could inhibit colony formation, tumor growth, and induce apoptosis. To investigate the roles of REIC expression in lung cancer, we examined REIC expression in lung cancer cells and tissues by RT-PCR or Western blot, and observed the effects of both recombinant REIC exposure and REIC overexpression on the aggressive phenotypes of lung cancer cells. It was found that the demethylation of REIC promoter by 5-Aza-dC could reserve its mRNA expression in lung cancer cells (P<0.05). There was a lower REIC mRNA expression in lung cancer than that in matched normal tissue (P<0.05). Recombinant REIC treatment enhanced the proliferation of lung cancer cells (P<0.05), but versa for REIC overexpression (P<0.05). Both recombinant REIC treatment and REIC overexpression induced apoptosis, and inhibited the migration and invasion of SQ-5 and KJ cells (P<0.05). Immunohistochemically, there was a positive correlation between REIC and Caspase-3 expression in lung cancer (P<0.05). According to Kaplan-Meier plotter, REIC mRNA overexpression was found to positively correlate with overall, progression-free and post- progression survival rates of lung cancer patients (P<0.05), even stratified by sex, histological subtyping, grading, TNM staging, chemotherapy, radiotherapy, or smoking. These findings suggested that the down-regulated REIC expression might be involved in lung carcinogenesis due to its promoter methylation. Both recombinant REIC exposure and REIC overexpression might reverse the aggressive phenotypes of lung cancer cells. REIC may be employed as a potential target of gene therapy for lung cancer.

Hamzehzadeh L, Caraglia M, Atkin SL, Sahebkar A
Dickkopf homolog 3 (DKK3): A candidate for detection and treatment of cancers?
J Cell Physiol. 2018; 233(6):4595-4605 [PubMed] Related Publications
Wnt signaling is an evolutionary highly conserved pathway that is modulated by several inhibitors and activators, and plays a key role in numerous physiological processes. One of the extracellular Wnt inhibitors is the DKK (Dickkopf Homolog) family which has four members (Dkk1-4) and a unique Dkk3-related gene, Dkkl1 (soggy). DKK3 is a divergent member of the DKK protein family. Evidence suggests that DKK3 may serve as a potential therapeutic target in several types of human cancers. We review here the biological role of DKK3 as a tumor suppressor gene (TSG) or oncogene, and its correlation with various miRNAs. In addition, we discuss the role of polymorphisms and promoter methylation of the DKK3 gene, and of its expression in regulating cancer cell proliferation. Finally, we propose that DKK3 may be considered as both a biomarker and a therapeutic target in different cancers.

Guo L, Zhang K, Bing Z
Application of a co‑expression network for the analysis of aggressive and non‑aggressive breast cancer cell lines to predict the clinical outcome of patients.
Mol Med Rep. 2017; 16(6):7967-7978 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Breast cancer metastasis is a demanding problem in clinical treatment of patients with breast cancer. It is necessary to examine the mechanisms of metastasis for developing therapies. Classification of the aggressiveness of breast cancer is an important issue in biological study and for clinical decisions. Although aggressive and non‑aggressive breast cancer cells can be easily distinguished among different cell lines, it is very difficult to distinguish in clinical practice. The aim of the current study was to use the gene expression analysis from breast cancer cell lines to predict clinical outcomes of patients with breast cancer. Weighted gene co‑expression network analysis (WGCNA) is a powerful method to account for correlations between genes and extract co‑expressed modules of genes from large expression datasets. Therefore, WGCNA was applied to explore the differences in sub‑networks between aggressive and non‑aggressive breast cancer cell lines. The greatest difference topological overlap networks in both groups include potential information to understand the mechanisms of aggressiveness. The results show that the blue and red modules were significantly associated with the biological processes of aggressiveness. The sub‑network, which consisted of TMEM47, GJC1, ANXA3, TWIST1 and C19orf33 in the blue module, was associated with an aggressive phenotype. The sub‑network of LOC100653217, CXCL12, SULF1, DOK5 and DKK3 in the red module was associated with a non‑aggressive phenotype. In order to validate the hazard ratio of these genes, the prognostic index was constructed to integrate them and examined using data from the Cancer Genomic Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Patients with breast cancer from TCGA in the high‑risk group had a significantly shorter overall survival time compared with patients in the low‑risk group (hazard ratio=1.231, 95% confidence interval=1.058‑1.433, P=0.0071, by the Wald test). A similar result was produced from the GEO database. The findings may provide a novel strategy for measuring cancer aggressiveness in patients with breast cancer.

Shu XS, Zhao Y, Sun Y, et al.
The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer.
J Pathol. 2018; 244(1):36-48 [PubMed] Related Publications
It has long been known that patients suffering from inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). The innate immune system of host cells provides a first-line defence against pathogenic infection, whereas an uncontrolled inflammatory response under homeostatic conditions usually leads to pathological consequences, as exemplified by the chronic inflammation of IBD. The key molecules and pathways keeping innate immunity in check are still poorly defined. Here, we report that the chromatin remodeller polybromo-1 (PBRM1) is a repressor of innate immune signalling mediated by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). Knockdown of PBRM1 in colon cancer cells increased the expression of two receptor genes (RIG-I and MDA5) and upregulated interferon (IFN)-related and inflammation-related gene signatures. The innate immune signal stimulated by a double-stranded RNA viral mimic was exaggerated by PBRM1 suppression. PBRM1 cooperated with polycomb protein EZH2 to directly bind the cis-regulatory elements of RIG-I and MDA5, thereby suppressing their transcription. Moreover, upregulation of RIG-I and MDA5 is required for IFN response activation induced by PBRM1 silencing. TRIM25, a protein stimulated by the RLR pathway and IFN production, physically interacted with PBRM1 and induced PBRM1 protein destabilization by promoting its ubiquitination. These findings reveal a PBRM1-RLR regulatory circuit that can keep innate immune activity at a minimal level in resting cells, and also ensure a robust inflammatory response in the case of pathogen invasion. PBRM1 was found to be downregulated in primary tissues from patients with CRC or IBD, and its expression correlated negatively with that of RLR genes and interferon-stimulated genes in CRC samples. Lower PBRM1 expression was associated with advanced pathological grade and poorer survival of CRC patients, indicating that PBRM1 could serve as a potential prognostic biomarker for CRC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Wu Y, Wu X, Wu L, et al.
The anticancer functions of RIG-I-like receptors, RIG-I and MDA5, and their applications in cancer therapy.
Transl Res. 2017; 190:51-60 [PubMed] Related Publications
Cancer is a major cause of death worldwide, and its incidence and mortality continuously increase in China. Nowadays, cancer heavily influences our health and constitutes enormous burden on society and families. Although there are many tools for cancer treatment, but the overall therapeutic effect is poor. In addition, cancer cells often develop resistance to therapy due to defective cell death or immune escape mechanisms. Therefore, it is a promising way for cancer treatment to effectively activate apoptosis and conquer immunosuppression. RIG-I-like receptors (RLRs) belong to RNA-sensing pattern recognition receptors (PRRs), one of the major subsets of PRRs, and play a critical role in sensing RNA viruses and initiate host antiviral responses such as the production of type I interferons (IFNs), proinflammatory cytokines, and other immune response molecules. Recent studies have demonstrated that tumor cells could mimic viral infection to activate viral recognition of immune system and the activation of interferon response pathway. RIG-I and MDA5, two members of RLRs family, could induce growth inhibition or apoptosis of multiple types of cancer cells on the activation by RNA ligands in IFN-dependent or IFN-independent approach. Previous studies have reviewed PRRs as promising immunotherapy targets for colorectal cancer and pancreatic cancer. However, until now, a comprehensive review on the role of RLRs in the development and treatment of various cancers is still lacking. In this article, we reviewed the latest studies on the roles as well as the mechanisms of RIG-I and MDA5 in the development of various cancers and therapeutic potentials of targeting RIG-I and MDA5 for cancer treatment.

Nakao T, Sasagawa Y, Nobusawa S, et al.
Radiation-induced gliomas: a report of four cases and analysis of molecular biomarkers.
Brain Tumor Pathol. 2017; 34(4):149-154 [PubMed] Related Publications
Radiation-induced glioma (RIG) is a rare secondary glioma. The tumors morphologically resemble their sporadically arising counterparts. Recently, the WHO classification of tumors of the central nervous system was revised to incorporate molecular biomarkers together with classic histological features. The status of molecular biomarkers in RIG, however, remains unclear. The objective of this study was to investigate if commonly accepted glioma-specific biomarkers are relevant in RIGs. Among 269 gliomas diagnosed as WHO grade 2, 3 and 4 in our institution, four were diagnosed as RIGs. Immunohistochemical (IHC) staining for isocitrate dehydrogenase 1 (IDH1), p53, alpha thalassemia/mental retardation syndrome X-linked (ATRX), and H3K27M, and direct DNA sequencing of IDH1/2, telomerase reverse transcriptase (TERT) promoter, Histone H3.3 (H3F3A) and B-Raf (BRAF) genes was performed. All tumor specimens were IDH1-, p53- and H3K27M-negative. The nuclei of tumor cells in all cases exhibited positive staining for ATRX. In direct DNA sequencing analysis, no IDH1, IDH2, TERT promoter, H3F3A or BRAF mutations were found in any of the cases. Our findings suggest that these characteristic glioma-associated molecular mutations may be rare events in RIGs. More RIGs need to be tested for analysis of molecular biomarkers to clarify the clinical and histopathological spectra of this tumor.

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