Gene Summary

Gene:WNT1; Wnt family member 1
Aliases: INT1, OI15, BMND16
Summary:The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family. It is very conserved in evolution, and the protein encoded by this gene is known to be 98% identical to the mouse Wnt1 protein at the amino acid level. The studies in mouse indicate that the Wnt1 protein functions in the induction of the mesencephalon and cerebellum. This gene was originally considered as a candidate gene for Joubert syndrome, an autosomal recessive disorder with cerebellar hypoplasia as a leading feature. However, further studies suggested that the gene mutations might not have a significant role in Joubert syndrome. This gene is clustered with another family member, WNT10B, in the chromosome 12q13 region. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:proto-oncogene Wnt-1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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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.

  • Proto-Oncogene Proteins
  • Mammary Tumor Virus, Mouse
  • Cytoskeletal Proteins
  • Cell Movement
  • Chromosome 12
  • Cell Proliferation
  • Oligonucleotide Array Sequence Analysis
  • Repressor Proteins
  • Mammary Neoplasms, Experimental
  • Western Blotting
  • Neoplasm Invasiveness
  • Drosophila Proteins
  • Gene Expression Profiling
  • Down-Regulation
  • Signal Transduction
  • Transcription Factors
  • Transfection
  • Trans-Activators
  • Gene Expression
  • Breast Cancer
  • CCN Intercellular Signaling Proteins
  • Mice, Inbred BALB C
  • Phenotype
  • Spectral Karyotyping
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • Wnt1 Protein
  • Neoplastic Cell Transformation
  • Immunohistochemistry
  • Up-Regulation
  • Apoptosis
  • Validation Studies as Topic
  • Wnt Signaling Pathway
  • Mutation
  • Lung Cancer
  • Cancer Stem Cells
  • RNA-Binding Proteins
  • Mice, Transgenic
  • Disease Models, Animal
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: WNT1 (cancer-related)

Guo Q, Wang L, Zhu L, et al.
The clinical significance and biological function of lncRNA SOCAR in serous ovarian carcinoma.
Gene. 2019; 713:143969 [PubMed] Related Publications
BACKGROUND: Ovarian cancer (OvCa) is one of the most lethal gynecologic malignancies worldwide. Pelvic and abdominal metastasis is a leading cause for the poor prognosis of OvCa patients. The relationship between long non-coding RNAs (lncRNAs) and OvCa remains unclear. Identifying key lncRNAs related with OvCa metastasis is crucial for research on the mechanism of OvCa metastasis. This study was designed to investigate the role of a novel lncRNA, which we named SOCAR, in serous OvCa.
METHODS: LncRNA microarray and Real-time PCR were used to examine SOCAR expression in high grade serous ovarian cancer (HGSOC) and normal ovary tissues. The proliferation, migration and invasion of OvCa cell lines SKOV-3 and OVCAR-3 were analyzed by CCK-8, Transwell and Scratch wound healing assays. Western blotting was used to detect the expression of Wnt/β-catenin pathway-related proteins.
RESULTS: A novel serous OvCa-related lncRNA, SOCAR, was identified via microarray. SOCAR was overexpressed in primary HGSOC tumors compared with normal ovary tissues, and the expression of SOCAR correlated with progression in HGSOC patients. SOCAR also had higher expression in metastatic HGSOC tissues compared with primary cancer tissues. Moreover, upregulation of SOCAR promoted proliferation, migration and invasion in OvCa cells. Expression of Wnt1, β-catenin and MMP-9 were all increased by SOCAR overexpression.
CONCLUSION: SOCAR is related with HGSOC oncogenesis and progression. It may promote proliferation, migration and invasion in OvCa cells partially by upregulating MMP-9 through the Wnt/β-catenin pathway.

Zhang F, Li Y, Xu W, et al.
Long non-coding RNA ZFAS1 regulates the malignant progression of gastric cancer via the microRNA-200b-3p/Wnt1 axis.
Biosci Biotechnol Biochem. 2019; 83(7):1289-1299 [PubMed] Related Publications
Gastric cancer is a common malignant tumor. Studies from our laboratory or others have shown that long non-coding RNA (lncRNA) zinc finger antisense (ZFAS)1 often acts as an oncogene. However, the molecular underpinnings of how ZFAS1 regulates gastric cancer remain to be elucidated. Results showed that ZFAS1 expression was upregulated, and microRNA-200b-3p (miR-200b) expression was downregulated in gastric cancer tissues. MiR-200b overexpression suppressed the proliferation, cell cycle process, and Wnt/β-catenin signaling of gastric cancer cells. Subsequently, we identified miR-200b is a target of ZFAS1 and Wnt1 is a target of miR-200b. Furthermore, promotion of cancer malignant progression and activation of Wnt/β-catenin signaling induced by ZFAS1 was counteracted by increasing miR-200b expression.

Kerdidani D, Chouvardas P, Arjo AR, et al.
Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma.
Nat Commun. 2019; 10(1):1405 [PubMed] Free Access to Full Article Related Publications
Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

Liang X, Dong Z, Bin W, et al.
PAX3 Promotes Proliferation of Human Glioma Cells by WNT/β-Catenin Signaling Pathways.
J Mol Neurosci. 2019; 68(1):66-77 [PubMed] Related Publications
The PAX3 (paired box 3) gene plays an important role in embryonic development, diseases, and cancer formation. Our preliminary studies have shown that PAX3 gene is upregulated in glioma cells, which is associated with a worse prognosis. Moreover, PAX3, by facilitating cell proliferation and invasion and inhibiting cell apoptosis, plays an oncogenic role in glioma. However, the specific molecular mechanism of PAX3 acting as an oncogene in glioma remains unclarified. In the present study, we have found that PAX3 overexpression was observed in high grade glioma and predicted a worse prognosis. PAX3 overexpression did not correlate significantly to IDH1 mutation and MGMT methylation. Moreover, the expression of PAX3 was positively correlated with that of β-catenin. In U87 glioma cells, PAX3 interacted with β-catenin, as was confirmed by CO-IP. Besides, PAX3 overexpression promoted cell proliferation and cell cycle progression, while it inhibited cell apoptosis by altering the expressions of important molecules associated with the Wnt signaling pathway, including β-catenin, Myc, VEGF, cyclinD1, MMP7, and Wnt1. In the meantime, it was also proved that PAX3 correlated to β-catenin through a negative regulatory mechanism with respect to the promotion of U87 glioma cell proliferation and cell cycle progression and inhibition of the cell apoptosis. Our experiment demonstrated the role of PAX3 in promoting glioma growth and development, possibly by interacting directly with β-catenin and regulating the Wnt signaling pathway.

Gao H, Yin FF, Guan DX, et al.
Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of β-catenin/TCF/LEF signalling.
Cell Prolif. 2019; 52(3):e12583 [PubMed] Related Publications
OBJECTIVES: Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive.
MATERIALS AND METHODS: The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting.
RESULTS: The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of β-catenin to the nucleus by activating glycogen synthase kinase-3β (GSK3β). Moreover, constitutively active β-catenin blocked the suppressive effects of WISP3 on HCC.
CONCLUSIONS: Our study showed that WISP3 suppressed the progression of HCC by negative regulation of β-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.

Liang TS, Zheng YJ, Wang J, et al.
MicroRNA-506 inhibits tumor growth and metastasis in nasopharyngeal carcinoma through the inactivation of the Wnt/β-catenin signaling pathway by down-regulating LHX2.
J Exp Clin Cancer Res. 2019; 38(1):97 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT)-associated proteins play key roles in cancer progression and metastasis with the involvement of microRNAs (miRNAs). This study aims to assess the role of miR-506 working in tandem with LIM Homeobox 2 (LHX2) in EMT and metastasis through the Wnt/β-catenin signaling pathway in nasopharyngeal carcinoma (NPC).
METHODS: Differentially expressed genes associated with NPC were screened using microarray analyses, from which LHX2 was identified. Next, the potential relationship between miR-506 and LHX2 was analyzed. In order to explore the effect of miR-506 or LHX2 on NPC cell proliferation, migration, invasion and apoptosis, serials of mimics, inhibitors or siRNA against LHX2 were transfected into NPC cells. Then, the expression patterns of LHX2, Wnt1, β-catenin, E-cadherin, Vimentin, TCF4 and Twist were determined to assess the influence of miR-506 or LHX2 on EMT as well as the relationship between the Wnt/β-catenin signaling pathway and TCF4. The tumorigenicity and lymph node metastasis (LNM) in xenograft tumors of nude mice were observed.
RESULTS: The has-miR-506-3p was identified as the down-regulated gene in NPC based on the microarray data while LHX2 was negatively regulated by miR-506. Over-expression of miR-506 or silencing of LHK2 inhibited NPC cell proliferation, migration, invasion, tumorigenicity and LNM but promoted apoptosis indicated by decreased Wnt1, β-catenin, Vimentin, TCF4 and Twist expressions along with increased E-cadherin expressions.
CONCLUSIONS: miR-506 inhibits tumor growth and metastasis in NPC via inhibition of Wnt/β-catenin signaling by down-regulating LHX2, accompanied by decreased TCF4. Taken together, miR-506 targeted-inhibition LHX2 presents a promising therapeutic strategy for the treatment of NPC.
TRIAL REGISTRATION: ChiCTR1800018889 . Registered 15 October 2018.

Yu X, Wang M, Wu J, et al.
ZNF326 promotes malignant phenotype of glioma by up-regulating HDAC7 expression and activating Wnt pathway.
J Exp Clin Cancer Res. 2019; 38(1):40 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Zinc-finger protein-326 (ZNF326) was initially found in the NIH3T3 cell line to regulate cell growth, however, the expression and underlying role of ZNF326 in human tumours, especially in glioma, is not fully understood.
METHODS: Immunohistochemistry was applied to detect the expression of ZNF326 in glioma tissues, and statistical analysis was used to analyse the relationship between ZNF326 expression and clinicopathological factors. The effect of ZNF326 on glioma cells proliferation and invasion was conducted by functional experiments both in vivo and in vitro. Chromatin immunoprecipitation and dual-luciferase assays were performed to demonstrate that histone deacetylase enzyme-7 (HDAC7) is the target gene of ZNF326. Immunoblotting, real-time PCR, GST-pulldown and co-immunoprecipitation assays were used to clarify the underlying role of ZNF326 on Wnt pathway activation.
RESULTS: High nuclear expression of ZNF326 was observed in glioma cell lines and tissues, and closely related with advanced tumour grade in the patients. Moreover, ectopic ZNF326 expression promoted the proliferation and invasiveness of glioma cells. Mechanistically, ZNF326 could activate HDAC7 transcription by binding to a specific promoter region via its transcriptional activation domain and zinc-finger structures. The interaction of the up-regulated HDAC7 with β-catenin led to a decrease in β-catenin acetylation level at Lys-49, followed by a decrease in β-catenin phosphorylation level at Ser-45. These changes in β-catenin posttranscriptional modification levels promoted its redistribution and import into the nucleus. Additionally, ZNF326 directly associated with β-catenin in the nucleus, and enhanced the binding of β-catenin to TCF-4, serving as a co-activator in stimulating Wnt pathway.
CONCLUSIONS: Our findings elucidated ZNF326 promotes the malignant phenotype of human glioma via ZNF326-HDAC7-β-catenin signalling. This study reveals the vital role and mechanism of ZNF326 in the malignant progression of glioma, and provides the reference for finding biomarkers and therapeutic targets for glioma.

Zhou P, Liu P, Zhang J
Long noncoding RNA RUSC1‑AS‑N promotes cell proliferation and metastasis through Wnt/β‑catenin signaling in human breast cancer.
Mol Med Rep. 2019; 19(2):861-868 [PubMed] Free Access to Full Article Related Publications
Breast cancer is one of the most frequently diagnosed cancers among females worldwide. Long noncoding RNAs (lncRNAs) have been revealed to serve significant roles in diagnosis and treatment of breast cancer. In the present study, the novel lncRNA RUSC1‑AS‑N was demonstrated to promote cell viability and metastasis. A total of 100 patients with breast cancer were recruited for this study and it was revealed that RUSC1‑AS‑N was upregulated in tumor tissues compared with in adjacent non‑cancerous counterparts. In addition, using several breast cancer cell lines, it was demonstrated that the mRNA levels of RUSC1‑AS‑N were highest in the notably metastatic cell lines MDA‑MB‑231 and MDA‑MB‑468. Knockdown of RUSC1‑AS‑N in breast cancer cells inhibited cell proliferation in the colony formation and cell proliferation assays. Furthermore, depletion of RUSC1‑AS‑N suppressed cell metastasis, as revealed by wound‑healing and western blot assays. In addition, the protein levels of Wnt1 and β‑catenin were significantly decreased when RUSC1‑AS‑N was knocked down. However, Wnt signaling pathway activator Wnt agonist 1 reversed the effects of RUSC1‑AS‑N knockdown on cell proliferation and metastasis. The present study demonstrated that lncRNA RUSC1‑AS‑N promoted cell viability and metastasis via Wnt/β‑catenin signaling in human breast cancer, which may indicate novel targets for the treatment of breast cancer in clinic.

Cao F, Yin LX
miR-122 enhances sensitivity of hepatocellular carcinoma to oxaliplatin via inhibiting MDR1 by targeting Wnt/β-catenin pathway.
Exp Mol Pathol. 2019; 106:34-43 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the primary causes of cancer-related death and resistance to cytotoxic chemotherapy is the major cause of mortality in HCC patients. miR-122 is a liver specific miRNA and is found to be reduced in HCC, however, the function of miR-122 in HCC chemosensitivity remains elusive.
METHODS: We used qRT-PCR to measure expressions of miR-122, β-catenin and MDR1 in four HCC cell lines. And we assessed the effects of miR-122 or β-catenin on cell viability and apoptosis upon oxaliplatin (OXA) treatment by MTT assay and flow cytometry. In addition, we validated the interactions of miR-122/β-catenin and β-catenin/MDR1 by dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). Western blotting was used to determine the protein levels of β-catenin, Wnt1 and MDR1. In the end, we verified the anti-tumor effect of miR-122 in vivo by using mouse tumor xenograft model.
RESULTS: We found that miR-122 was down-regulated in HCC cells. Up-regulation of miR-122 or inhibition of Wnt/β-catenin signaling promoted HCC cells apoptosis and increased the sensitivity of HCC cells to OXA. On the molecular level, we showed that miR-122 directly targeted and suppressed Wnt/β-catenin pathway while β-catenin bound with MDR1 promoter and activated its transcription. Overexpression of miR-122 inhibited MDR1 expression via directly suppressing Wnt/β-catenin pathway.
CONCLUSION: Our study fully demonstrated that miR-122 inhibits MDR1 expression via suppression of Wnt/β-catenin pathway, thereby enhancing HCC sensitivity to OXA. Therefore, miR-122 could serve as a novel potential therapeutic target for HCC.

Su H, Wu Y, Fang Y, et al.
MicroRNA‑301a targets WNT1 to suppress cell proliferation and migration and enhance radiosensitivity in esophageal cancer cells.
Oncol Rep. 2019; 41(1):599-607 [PubMed] Related Publications
Esophageal cancer (EC) is one of the leading causes of death among malignancies. Radiotherapy for esophageal squamous cell carcinoma (ESCC) patients is limited by resistance to ionizing radiation (IR). An increasing body of evidence has demonstrated that aberrant expression of microRNA‑301a (miR‑301a) contributes to cancer progression and sensitivity to radiation. The aim of the present study was to investigate the exact functions and potential mechanisms of miR‑301a in ESCC radioresistance. Initially, the miR‑301a‑transfected radioresistant ESCC cells KYSE‑150R exhibited a decreased proliferation rate, and enhanced radiosensitivity and migration, whereas downregulation of miR‑301a in radiosensitive KYSE‑150 cells produced the opposite results. miR‑301a regulates WNT1 expression at both the mRNA and protein levels. Furthermore, dual‑luciferase reporter assays revealed that WNT1 was a target gene of miR‑301a. In addition, the expression of miR‑301a markedly affected the expression of Wnt/β‑catenin‑related proteins such as β‑catenin and cyclin D1. Finally, overexpression of miR‑301a inhibited epithelial‑mesenchymal transition (EMT) conversion by directly targeting Snail and vimentin in radioresistant‑ESCC cell lines; however, no inhibitory effects were exerted on Twist. Collectively, these results indicated that miR‑301a increased the radiosensitivity and inhibited the migration of radioresistant‑ESCC cells by targeting WNT1, thereby inactivating the Wnt/β‑catenin signaling pathway and EMT reversal. Thus, miR‑301a may be a potential therapeutic target for the treatment of EC radioresistance.

Wu Y, Chen W, Gong L, et al.
Elevated G-Protein Receptor 125 (GPR125) Expression Predicts Good Outcomes in Colorectal Cancer and Inhibits Wnt/β-Catenin Signaling Pathway.
Med Sci Monit. 2018; 24:6608-6616 [PubMed] Free Access to Full Article Related Publications
BACKGROUND G-protein receptor 125 (GPR125), as a transmembrane signal transducer, is involved in regulating cancer development. Although GPR125 is related with several cancers, its role in colorectal cancer (CRC) and the underlying mechanism are still unknown. Here, we investigated the clinical significance of GPR125 in CRC. MATERIAL AND METHODS We assessed the expression level of GPR125 in CRC tissues by analyzing 3 datasets in the Gene Expression Omnibus (GEO) database and in human samples. The correlation between GPR125 expression and clinicopathological features was further analyzed. Survival analysis was performed to assess the association between GPR125 expression and recurrence-free survival (RFS). Cox logistic regression analysis was used to analyze the role of GPR125 expression in overall survival (OS). Moreover, we activated the Wnt pathway in HCT116 cells to investigate their potential mechanism. RESULTS Analysis of the GEO database showed that the expression of GPR125 was down-regulated in CRC tissues, consistent with our human samples experiments, and patients with higher GPR125 expression had a longer RFS. Also, we found that high GPR125 expression was associated with better tumor outcomes in clinical stage, metastasis, and KRAS status. Cox logistic regression analysis demonstrated that GPR125 was an independent prognostic factor for favorable outcome. Mechanistically, GPR125 overexpression inhibited the β-catenin transcriptional activity, and down-regulated the expression levels of the Wnt downstream proteins-Axin2, c-Myc, cylinD1, and lef-1. CONCLUSIONS GPR125 may be a potential prognosis-related anti-oncogene and its effects on inactivating Wnt/β-catenin signaling pathway might be a key link to inhibiting CRC formation.

Zhao W, Yang S, Chen J, et al.
Forced overexpression of FBP1 inhibits proliferation and metastasis in cholangiocarcinoma cells via Wnt/β-catenin pathway.
Life Sci. 2018; 210:224-234 [PubMed] Related Publications
AIM: To investigate the effect of fructose-1,6-bisphosphatase 1 (FBP1) on the malignant phenotypes of cholangiocarcinoma (CCA) cells, and to explore the underlying mechanism.
MAIN METHODS: The expression of FBP1 in clinical CCA tissues was detected by real-time PCR, Western blot and immunohistochemistry staining. FBP1 was overexpressed by transfection of a forced expression plasmid. MTT, plate colony formation assay, Hoechst staining, flow cytometry, Western blot, wound healing, transwell assays and xenograft were performed to detect the growth, proliferation, cell cycle, apoptosis, migration, invasion and tumorigenesis in RBE and HCCC-9801 cells. In addition, the Wnt/β-catenin signaling was detected.
KEY FINDINGS: FBP1 was downregulated in clinical CCA specimens and cell lines, compared to paired para-carcinoma tissues or normal cholangetic epithelial cells. Gain-of-function experiments demonstrated that the forced expression of FBP1 inhibited the proliferation, colony formation, and blocked cell cycle of RBE and HCCC-9801 cells. Apoptosis of CCA cells was significantly enhanced by FBP1 overexpression, evidenced by upregulation of cleaved caspase-3, cleaved PARP and Bax levels, while downregulation of Bcl-2 level. Moreover, overexpression of FBP1 decreased the migratory and invasive ability in RBE and HCCC-9801 cells. However, FBP1-induced phenotypic changes were eliminated by overexpression of β-catenin. Finally, the forced overexpression of FBP1 inhibited tumorigenesis in vivo.
SIGNIFICANCE: Our findings demonstrate that FBP1 is downregulated in CCA tissues and cell lines, and the overexpression of FBP1 inhibits the proliferation, migration, invasion and tumorigenesis of CCA cells partly via inactivation of Wnt/β-catenin pathway. FBP1 may be a novel early diagnosis marker and therapeutic target for CCA.

Ren Y, Tao J, Jiang Z, et al.
Pimozide suppresses colorectal cancer via inhibition of Wnt/β-catenin signaling pathway.
Life Sci. 2018; 209:267-273 [PubMed] Related Publications
OBJECTIVE: Wnt/β‑catenin signaling pathway plays important role in colorectal cancer (CRC) and acts as a potential therapeutic target. Pimozide is a FDA-approved clinical drug used to treat psychotic diseases and it has shown anticancer effect in some tumors partially via inhibition of Wnt/β‑catenin signaling pathway. This study aimed to investigate whether pimozide exerts anticancer effect on CRC and explore underlying mechanism.
METHODS AND RESULTS: Pimozide was administrated to treat HCT116 and SW480 cells. Quantitative real-time polymerase chain reaction and western blot were used to detect the expression of epithelial-to-mesenchymal transition markers and Wnt/β‑catenin signaling pathway-related proteins. Cell proliferation and migration were measured by Cell Counting Kit-8 and Transwell assays respectively. HCT116 and SW480 cells were subcutaneously injected into nude mice and when the volume of tumor grown measureable (approximately 100 mm
CONCLUSION: Pimozide exerts anticancer effect in CRC via inhibition of wnt/β‑catenin signaling pathway, suggesting it as a potential therapeutic drug for CRC.

Kumaradevan S, Lee SY, Richards S, et al.
c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/β-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation.
Am J Pathol. 2018; 188(8):1921-1933 [PubMed] Free Access to Full Article Related Publications
The proto-oncogene β-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear β-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear β-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target β-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear β-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear β-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/β-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/β-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.

Knutti N, Huber O, Friedrich K
CD147 (EMMPRIN) controls malignant properties of breast cancer cells by interdependent signaling of Wnt and JAK/STAT pathways.
Mol Cell Biochem. 2019; 451(1-2):197-209 [PubMed] Related Publications
EMMPRIN (extracellular matrix metalloproteinase inducer, EMN, CD147) is a member of the immunoglobulin superfamily expressed in numerous cell types both as a soluble and a membrane-spanning glycoprotein. It is involved in many physiological processes, as well as in cancer. This study addresses mechanisms of crosstalk between EMN-driven cancer-related cellular responses and the canonical Wnt-pathway in MCF-7 breast carcinoma cells. Genetic knockdown of EMN in MCF-7 resulted in characteristic changes in cellular shape, organization of the actin cytoskeleton and malignancy profile, indicating that EMN expression represses cell motility, but, in contrast, exerts a stimulatory effect on cell proliferation and invasive properties. Increased invasiveness coincided with elevated expression of Wnt-target genes and established invasion driver matrix metalloproteinase MMP14. Activation of the downstream Wnt-pathway by means of heterologous β-catenin and/or TCF-4 expression, through inhibition of GSK-3β by LiCl treatment, or by cell stimulation with insulin-like growth factor-1 (IGF-1) resulted in increased EMN expression. EMN over-expression raised the ratio of the two opposing Wnt pathway-driven transcription factors Sp1 and Sp5, leading to stimulation of the EMN promoter. Furthermore, the EMN promoter was activated by a feed-forward circuit involving an EMN-dependent drop in expression of the repressive signal transducer and activator of transcription 1 (STAT1). Taken together, we show that the influence of EMMPRIN on malignancy-related properties of breast cancer cells is functionally connected to both Wnt- and JAK/STAT pathways.

Xu Y, Liu X, Zhang H, et al.
Overexpression of HES6 has prognostic value and promotes metastasis via the Wnt/β-catenin signaling pathway in colorectal cancer.
Oncol Rep. 2018; 40(3):1261-1274 [PubMed] Free Access to Full Article Related Publications
HES6 is a member of the hairy-enhancer of the split homolog family, which has been implicated in oncogenesis and cancer progression in a variety of human cancers, including prostate and breast cancer. However, its clinical significance and biological role in colorectal cancer (CRC) remain unclear. In the present study, the expression of HES6 was significantly upregulated in CRC cell lines and CRC tissues at both the mRNA and protein levels. The present study also reported high expression of HES6 in 138/213 (64.8%) paraffin-embedded archived CRC specimens. HES6 expression was significantly correlated with T classification (P<0.001), N classification (P=0.020), and distant metastasis (P<0.001). Patients with higher HES6 expression levels exhibited a reduced overall survival (P<0.001). In addition, a multivariate analysis revealed that the expression of HES6 may be a novel prognostic marker for the survival of patients with CRC. Furthermore, the present study demonstrated that ectopic expression of HES6 enhanced the migration and invasive abilities of CRC cells. These abilities were significantly inhibited upon knockdown of endogenous HES6 expression by specific short hairpin RNAs. Additionally, the present study reported that the effects of HES6 on metastasis may be associated with the activation of the Wnt/β-catenin signaling pathway. Collectively, the findings of the present study revealed that overexpression of HES6 played a key role in the progression of CRC, leading to a poor prognosis and clinical outcome.

Chen L, Wang X, Zhu Y, et al.
miR‑200b‑3p inhibits proliferation and induces apoptosis in colorectal cancer by targeting Wnt1.
Mol Med Rep. 2018; 18(3):2571-2580 [PubMed] Free Access to Full Article Related Publications
MicroRNA (miR)‑200b‑3p is downregulated in multiple human cancer types. Wnt signaling serves a role in human colorectal cancer (CRC). The present study aimed to examine the effect of miR‑200b‑3p on human CRC and its potential association with Wnt signaling. The Cell Counting Kit‑8 (CCK‑8) was employed to assess cell viability. A flow cytometric assay was conducted to examine cell proliferation and apoptosis. The regulation model of miR‑200b‑3p and Wnt1 was assessed by a luciferase reporter assay. A commercial kit was used to evaluate the activity of caspase‑3 following treatment of the cells by miR‑200b‑3p or Wnt1. The expression of target factors was determined by a quantitative real‑time polymerase chain reaction and western blot analysis. The expression of miR‑200b‑3p was decreased in human CRC tissues and in cell lines. The bioinformatics analysis and the luciferase reporter assay revealed that Wnt1 may be a direct target of miR‑200b‑3p. Moreover, the viability and proliferation of CRC cells was suppressed by miR‑200b‑3p. miR‑200b‑3p additionally induced apoptosis in CRC cells. Furthermore, the caspase‑3 activity was enhanced in the miR‑200b‑3p mimics group. The expression of antigen Ki‑67 (additionally termed KI‑67) and β‑catenin was decreased, while the expression of cleaved caspase‑3 was increased by miR‑200b‑3p. In conclusion, miR‑200b‑3p inhibited proliferation and induced apoptosis in CRC cells by inactivating Wnt/β‑catenin signaling. The present study provided potential biomarkers and candidate modalities for the management of CRC.

Chen CT, Lee HL, Chiou HL, et al.
Impacts of WNT1-inducible signaling pathway protein 1 polymorphism on hepatocellular carcinoma development.
PLoS One. 2018; 13(6):e0198967 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: WNT1-inducible signaling pathway protein 1 (WISP1) is a member of CCN protein family and a downstream target of β-catenin. Aberrant WISP1 expression is associated with carcinogenesis. In the current study, we focused on examining WISP1 single nucleotide polymorphisms (SNPs) to elucidate hepatocellular carcinoma (HCC) clinicopathologic characteristics.
METHODOLOGY/PRINCIPAL FINDINGS: The WISP1 SNPs rs2977530, rs2977537, rs2929973, rs2929970, rs62514004, and rs16893344 were analyzed by real-time polymerase chain reaction in 332 patients with HCC and 664 cancer-free controls.
RESULTS: The patients with higher frequencies of WISP1 rs62514004 (AG + GG) and rs16893344 (CT + TT) variants revealed a lower risk to reach a later clinical stage compared with their wild-type carriers. Furthermore, individuals who carried WISP1 rs62514004 and rs16893344 haplotype G-T showed a greater synergistic effect combined with alcohol drinking on HCC development (AOR = 26.590, 95% CI = 9.780-72.295).
CONCLUSIONS: Our results demonstrated that the HCC patients with WISP1 SNPs are associated with HCC development, and WISP1 SNPs may serve as markers or therapeutic targets for HCC.

Carreras J, Yukie Kikuti Y, Miyaoka M, et al.
Genomic Profile and Pathologic Features of Diffuse Large B-Cell Lymphoma Subtype of Methotrexate-associated Lymphoproliferative Disorder in Rheumatoid Arthritis Patients.
Am J Surg Pathol. 2018; 42(7):936-950 [PubMed] Related Publications
Rheumatoid arthritis patients often develop the diffuse large B-cell lymphoma subtype of methotrexate-associated lymphoproliferative disorder (DLBCL). We characterized the genomic profile and pathologic characteristics of 20 biopsies using an integrative approach. DLBCL was associated with extranodal involvement, a high/high-intermediate international prognostic index in 53% of cases, and responded to MTX withdrawal. The phenotype was nongerminal center B-cell in 85% of samples and Epstein-Barr encoding region positive (EBER) in 65%, with a high proliferation index and intermediate MYC expression levels. The immune microenvironment showed high numbers of CD8 cytotoxic T lymphocytes and CD163 M2 macrophages with an (CD163/CD68) M2 ratio of 3.6. Its genomic profile was characterized by 3p12.1-q25.31, 6p25.3, 8q23.1-q24.3, and 12p13.33-q24.33 gains, 6q22.31-q24.1 and 13q21.33-q34 losses, and 1p36.11-p35.3 copy neutral loss-of-heterozygosity. This profile was closer to nongerminal center B-cell DLBCL not-otherwise-specified, but with characteristic 3q, 12q, and 20p gains and lower 9p losses (P<0.05). We successfully verified array results using fluorescent DNA in situ hybridization on PLOD2, MYC, WNT1, and BCL2. Protein immunohistochemistry revealed that DLBCL expressed high IRF4 (6p25.3) and SELPLG (12q24.11) levels, intermediate TNFRSF14 (1p36.32; the exons 1 to 3 were unmutated), BTLA (3q13.2), PLOD2 (3q24), KLHL6 (3q27.1), and MYC (8q24.21) levels, and low AICDA (12p13.31) and EFNB2 (13q33.3) levels. The correlation between the DNA copy number and protein immunohistochemistry was confirmed for BTLA, PLOD2, and EFNB2. The characteristics of EBER versus EBER cases were similar, with the exception of specific changes: EBER cases had higher numbers of CD163 M2 macrophages and FOXP3 regulatory T lymphocytes, high programmed cell death 1 ligand 1 expression levels, slightly fewer genomic changes, and 3q and 4p focal gains. In conclusion, DLBCL has a characteristic genomic profile with 3q and 12 gains, 13q loss, different expression levels of relevant pathogenic biomarkers, and a microenvironment with high numbers of cytotoxic T lymphocytes and M2 macrophages.

Li Z, Luo J
Research on epigenetic mechanism of SFRP2 in advanced chronic myeloid leukemia.
Biochem Biophys Res Commun. 2018; 501(1):64-72 [PubMed] Related Publications
Secreted frizzled-related protein 2 (SFRP2) has been reported to act as a tumor suppressors. This study aims to detect the biological role of SFRP2 in advanced chronic myeloid leukemia (CML). In this study we examined bone marrow samples from 45 CML patients and 10 healthy donors. K562 and KCL22 cells were cultured and treated with demethylation drug and histone deacetylase inhibitor (HDACi). KCL22 and K562 cells were transfected with lentiviral vector (LV)-SFRP2, LV-control. The cells were then subjected to proliferation and apoptosis assays, real time polymerase chain reaction (PCR), Methylation-specific PCR (MSP), Western blotting, co-immunoprecipitation (CoIP) and Chromatin immunoprecipitation (ChIP), We found that SFRP2 was down-regulated in the accelerated and blast phase of CML, whereas, the levels of WNT1, WNT3 and WNT5A were up-regulated in the accelerated and blast phase of CML. Overexpression SFRP2 inhibited proliferation, promoted apoptosis and activated the WNT pathway. CoIP-MS results showed that SFRP2 interacted with WNT1 and WNT5A. ChIP-seq result indicated that the promoter of H3K4me3 and H3K27me3 were able to interact with SFRP2. In conclusion, our findings demonstrated the SFRP2 act as a potential therapeutic target for advanced CML. Furthermore, our results support the use of demethylation drugs and HDACi as a potential CML treatment strategy.

Sun N, Zhang G, Liu Y
Long non-coding RNA XIST sponges miR-34a to promotes colon cancer progression via Wnt/β-catenin signaling pathway.
Gene. 2018; 665:141-148 [PubMed] Related Publications
Little is known about the role of long non-coding RNA XIST in the development of colon cancer. The aim of the present study was to investigate the levels of XIST in colon cancer, and explore its underlying mechanism. In this study, we found XIST expression level was upregulated in colon cancer tissues and cell lines. In addition, the growth rate of cells transfected with si-XIST was significantly decreased compared to that with si-NC, which was reversed by miR-34a targeted with 3'-UTR. Moreover, miR-34a suppressed the expression of WNT1 by binding with the 3'-UTR, which interact with WNT1 to inhibit the proliferation of cells. Furthermore, miR-34a inhibitor rescued the dysregulation of WNT1, β-catenin, cyclinD1, c-Myc and MMP-7 by si-XIST. Besides, XIST knockdown inhibited tumor growth in vivo. In short, the current study suggests XIST plays as an important role in colon cancer progression targeted by miR-34a via Wnt/β-catenin signaling pathway, providing a novel insight for the pathogenesis and underlying therapeutic target for colon cancer.

Zhu J, Ren J, Tang L
Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression.
Mol Med Rep. 2018; 17(5):7265-7273 [PubMed] Related Publications
Colon cancer is characterized by invasion and migration. DNA methylation of CpG islands in tumor suppressor genes is considered to be an epigenetic mechanism underlying cancer development. Epigenetic silencing of a gene may be reversed by drugs, including genistein. The present study aimed to determine the effect of genistein on Wnt inhibitory factor 1 (WIF1) and invasion, and migration of colon cancer cells. The viability of HT29 colon cancer cells was suppressed by genistein in a dose dependent manner. Following 72 h of treatment with 10, 20 and 60 µmol/l genistein, increased demethylation of WIF1 was induced in a dose‑dependent manner. Additionally, the invasive/migratory abilities of cells treated with genistein decreased in a dose‑dependent manner. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were performed to identify the mRNA and protein expression levels of invasion/migration‑associated factors. Following treatment with genistein, matrix metalloproteinase (MMP) 2 and MMP9 expression levels decreased, whereas the expression of metalloproteinase inhibitor 1 and E‑cadherin increased significantly. In addition, the expression levels of proto‑oncogene Wnt‑1 (Wnt‑1)/β‑catenin pathway‑associated factors, β‑catenin, c‑Myc proto‑oncogene protein and cyclin D1 decreased in a dose‑dependent manner following treatment with genistein. The invasive/migratory abilities of cells transfected with WIF1‑small interfering (si) RNA, and those transfected with WIF1‑siRNA and treated with genistein, increased notably compared with the control group. The present study demonstrated that genistein was able to inhibit the cell invasion and migration of colon cancer cells by inducing demethylation, and recovering the activity of WIF1 by altering the expression of invasion‑associated factors, and components of the Wnt signaling pathway.

Zheng Y, Zeng Y, Qiu R, et al.
The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.
Theranostics. 2018; 8(4):972-989 [PubMed] Free Access to Full Article Related Publications
The homeodomain transcription factor SIX3 was recently reported to be a negative regulator of the Wnt pathway and has an emerging role in cancer. However, how SIX3 contributes to tumorigenesis and metastasis is poorly understood.
METHODS: We employed affinity purification and mass spectrometry (MS) to identify the proteins physically associated with SIX3. Genome-wide analysis of the SIX3/LSD1/NuRD(MTA3) complex using a chromatin immunoprecipitation-on-chip approach identified a cohort of target genes including
RESULTS: We demonstrate that the SIX3/LSD1/NuRD(MTA3) complex inhibits carcinogenesis in breast cancer cells and suppresses metastasis in breast cancer. SIX3 expression is downregulated in various human cancers and high SIX3 is correlated with improved prognosis.
CONCLUSION: Our study revealed an important mechanistic link between the loss of function of SIX3 and tumor progression, identified a molecular basis for the opposing actions of MTA1 and MTA3, and may provide new potential prognostic indicators and targets for cancer therapy.

Zhang W, Sun Z, Su L, et al.
miRNA-185 serves as a prognostic factor and suppresses migration and invasion through Wnt1 in colon cancer.
Eur J Pharmacol. 2018; 825:75-84 [PubMed] Related Publications
Colon cancer is one of the deadliest cancers worldwide; abnormal microRNA expression is common during colon cancer development. The aim of the present study was to elucidate the role played by miR-185 in this context. We used quantitative real-time PCR (qRT-PCR) to measure miR-185 expression levels in colon cancer cell lines. The effects of miR-185 on colon cancer cell proliferation and invasion were assessed using the MTT, colony-forming, wound-healing, and transwell assays. A luciferase activity assay was used to confirm the target of miR-185. Our data showed that miR-185 was significantly down-regulated in colon cancer cells and colonic cancer tissues compared with NCM460 normal colonic epithelial cells and adjacent normal tissues. A functional analysis revealed that ectopic expression of miR-185 significantly inhibited colon cancer cell proliferation, colony formation, migration, and invasion. In addition, western blot, qRT-PCR, and luciferase assays confirmed in colon cancer cells that Wnt1 was a downstream target of miR-185, in turn suppressing β-catenin-mediated signaling. In conclusion, we found that miR-185 inhibits colon cancer cell proliferation and invasion by targeting Wnt1, and that it serves as a tumor suppressor, indicating that the modulation of miR-185 levels may potentially be therapeutic in colon cancer patients.

Wen D, Liao T, Ma B, et al.
Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β-catenin signaling and sensitizes cancer cells to FH535 therapy.
Cancer Med. 2018; 7(2):285-296 [PubMed] Free Access to Full Article Related Publications
The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short-hairpin RNA-mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated β-catenin expression was also analyzed. CSN6 levels were determined by real-time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK-8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized β-catenin and facilitated the epidermal-to-mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated β-catenin expression in a β-Trcp-dependent manner and triggered expression of several EMT-related genes regulated by β-catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/β-catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/β-catenin signaling pathway.

Polovic M, Dittmar S, Hennemeier I, et al.
Identification of a novel lncRNA induced by the nephrotoxin ochratoxin A and expressed in human renal tumor tissue.
Cell Mol Life Sci. 2018; 75(12):2241-2256 [PubMed] Related Publications
Long non-coding RNAs represent a fraction of the transcriptome that is being increasingly recognized. For most of them no function has been allocated so far. Here, we describe the nature and function of a novel non-protein-coding transcript, named WISP1-AS1, discovered in human renal proximal tubule cells exposed to the carcinogenic nephrotoxin ochratoxin A. WISP1-AS1 overlaps parts of the fourth intron and fifth exon of the Wnt1-inducible signaling pathway protein 1 (WISP1) gene. The transcript is 2922 nucleotides long, transcribed in antisense direction and predominantly localized in the nucleus. WISP1-AS1 is expressed in all 20 samples of a human tissue RNA panel with the highest expression levels detected in uterus, kidney and adrenal gland. Its expression was confirmed in primary tissues of human kidneys. In addition, WISP1-AS1 is expressed at higher levels in renal cell carcinoma (RCC) cell lines compared to primary proximal tubule cells as well as in RCC lesions than in the adjacent healthy control tissue from the same patient. Using specific gapmer antisense oligonucleotides to prevent its upregulation, we show that WISP1-AS1 (1) does not influence the mRNA expression of WISP1, (2) affects transcriptional regulation by Egr-1 and E2F as revealed by RNA-sequencing, enrichment analysis and reporter assays, and (3) modulates the apoptosis-necrosis balance. In summary, WISP1-AS1 is a novel lncRNA with modulatory transcriptional function and the potential to alter the cellular phenotype in situations of stress or oncogenic transformation. However, its precise mode of action and impact on cellular functions require further investigations.

Wils LJ, Bijlsma MF
Epigenetic regulation of the Hedgehog and Wnt pathways in cancer.
Crit Rev Oncol Hematol. 2018; 121:23-44 [PubMed] Related Publications
The Hedgehog (Hh) and wingless-Int1 (Wnt) pathways are important for tissue patterning in the developing embryo. In adult tissue, both pathways are typically dormant but are activated under certain conditions such as tissue damage. Aberrant activation of these pathways by mutations in key pathway regulators contributes to the genesis and progression of several cancer types. In addition, the impact of epigenetic regulation of the Hh and Wnt pathways on cancer is becoming increasingly clear. In this review, current knowledge on the epigenetic control of Hh and Wnt and the impact on tumor formation will be discussed. First, the role of epigenetic control on ligand production will be discussed, followed by the epigenetic regulation of the extra- and intracellular pathway members. Furthermore, the epigenetic control of pathway target genes will be highlighted. Lastly, an overview of current therapeutic strategies to target aberrant epigenetic control of the Hh and Wnt pathways is provided.

Guo P, Wang Y, Dai C, et al.
Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/β-catenin-induced FGF18 expression in hepatocellular carcinoma.
Oncogene. 2018; 37(9):1220-1236 [PubMed] Related Publications
Ribosomal protein s15a (RPS15A) plays a promotive role in the mRNA/ribosome interactions during early translation. Our previous study has found that inhibiting RPS15A expression can decrease proliferation and induce cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism underlying the involvement of RPS15A in HCC pathogenesis and the clinical significance of RPS15A expression remain unclear. In this study, an evaluation of RPS15A expression in 110 surgically resected HCCs and matched tumor-adjacent normal tissues revealed an overexpression of RPS15A in HCC, which was correlated with worse survival. In addition, tumor tissue with higher RPS15A expression demonstrated a higher microvascular density (MVD). Subsequently, two HCC cell lines, Huh7 (low-level constitutive RPS15A expression) and HepG2 (high RPS15A expression) were used to further evaluate the role of RPS15A in angiogenesis. The co-culture experiment of HCC cells with endothelial cells revealed that the induced overexpression of RPS15A in Huh7 cells increased the angiogenic potential of HUVEC in a paracrine fashion; conversely, knockdown of RPS15A in HepG2 cells showed an opposite effect. Further analysis indicated that RPS15A modulated FGF signaling by enhancing Wnt/beta-catenin-mediated FGF18 expression in HCC cells. FGF18, in turn, through binding to its FGFR3 receptor on endothelial cells, can activate the AKT and ERK pathway and promotes angiogenesis in a tumor microenvironment. Our in vivo experiment further confirmed that inhibition of RPS15A expression in HCC xenografts dramatically hindered tumor growth and inhibited tumor angiogenesis. Together, our findings suggest that RPS15A promotes angiogenesis in HCCs by enhancing Wnt/beta-catenin induced FGF18 expression. The RPS15A/FGF18 pathway may be a rational target for anti-angiogenic therapy of HCC.

Jiang Z, Jiang J, Zhao B, et al.
CPNE1 silencing inhibits the proliferation, invasion and migration of human osteosarcoma cells.
Oncol Rep. 2018; 39(2):643-650 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary malignancy of the bone affecting children and adolescents. Copine 1 (CPNE1) is a highly conserved calcium-dependent phospholipid-binding protein and may function in regulating signal transduction and membrane trafficking. In the present study, we investigated CPNE1 expression in osteosarcoma tissues and cells, and studied the effects of small interfering RNA (siRNA)-targeting CPNE1 on proliferation, metastasis and chemosensitivity of the osteosarcoma cells. The results demonstrated that CPNE1 was highly expressed in the osteosarcoma tissues and cell lines. Moreover, functional investigations confirmed that CPNE1 knockdown significantly inhibited cell proliferation, colony formation, invasion and metastasis in Saos-2 and HOS cells. Western blot analysis indicated that CPNE1 silencing downregulated the expression of many proteins associated with tumorigenesis and development, including Ras, MEK-1/2, WNT1, β-catenin, cyclin A1, IRAK2 and cIAP2. In addition, CPNE1 downregulation enhanced the sensitivity of Saos-2 cells towards cisplatin and adriamycin. The present study provides deep insight into the clinical use of lentiviral-mediated CPNE1 silencing for osteosarcoma therapy.

Liang G, Fang X, Yang Y, Song Y
Silencing of CEMIP suppresses Wnt/β-catenin/Snail signaling transduction and inhibits EMT program of colorectal cancer cells.
Acta Histochem. 2018; 120(1):56-63 [PubMed] Related Publications
Cell migration inducing hyaluronan binding protein (CEMIP) is a hyaluronic acid binding protein, the abnormal elevation of which is suggested as a contributor in the carcinogenesis of colorectal cancer (CRC). Cancer cells lose their adhesive properties and acquire an enhanced mobility by undergoing epithelial-mesenchymal transition (EMT). This study is performed to investigate whether and how CEMIP orchestrates the EMT process of CRC cells. To avoid the unexpected off-target effects possibly caused by one single shRNA, two shRNAs targeting different mRNA regions of CEMIP gene were used to knock down the mRNA and protein expression of CEMIP. Our data showed that the proliferation, migration and invasion of two CRC cell lines, HCT116 and SW480 cells, were inhibited by CEMIP shRNA. We here defined EMT as the complete or partial loss of E-cadherin and zona occludens protein 1 (ZO-1) (epithelial markers) and the gain of Vimentin and N-cadherin (mesenchymal markers), and found that the EMT process was attenuated in CEMIP-silenced SW480 cells. Snail, a direct target of β-catenin/T cell factor complex, is known to activate the EMT program during cancer metastasis. CEMIP shRNA was further found to suppress the Wnt/β-catenin/Snail signaling transduction in CRC cells as manifested by the decreased nuclear β-catenin and Snail. Collectively, our work demonstrates that CEMIP contributes to metastatic phenotype of CRC cells in vitro.

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