Gene Summary

Gene:CTNNB1; catenin beta 1
Aliases: EVR7, CTNNB, MRD19, NEDSDV, armadillo
Summary:The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:catenin beta-1
Source:NCBIAccessed: 01 September, 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 01 September 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.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (13)

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

Entity Topic PubMed Papers
Colorectal CancerCTNNB1 and Colorectal Cancer View Publications567
-CTNNB1 and Hepatocellular Carcinoma View Publications387
Liver CancerCTNNB1 and Liver Cancer View Publications309
Stomach CancerCTNNB1 mutations in Gastric Cancer View Publications222
Ovarian CancerCTNNB1 and Ovarian Cancer View Publications181
Breast CancerCTNNB1 and Breast Cancer View Publications130
Prostate CancerCTNNB1 and Prostate Cancer View Publications116
Lung CancerCTNNB1 and Lung Cancer View Publications112
MelanomaCTNNB1 and Melanoma View Publications96
MedulloblastomaCTNNB1 and Medullobalastoma
In an ICGC deep sequencing study of 125 medulloblastoma tumour-normal pairs, (Jones DTW et al, 2012) reported CTNNB1 mutations in 15 (12%) of cases. In an exome sequencing study of medulloblastoma (Pugh et al, 2012) reported CTNNB1 as one of 12 genes mutated at significant levels: with CTNNB1 mutations in 6/92 patients (7%); all missense mutations.
View Publications75
Thyroid CancerCTNNB1 and Thyroid Cancer View Publications73
HepatoblastomaCTNNB1 and Hepatoblastoma View Publications44
Adrenocortical CancerCTNNB1 and Adrenocortical Carcinoma
Assié, et al (2014) identified recurrent alterations in CTNNB1 in a GWAS study of 45 Adrenocortical carcinomas, with results verified in a further independent set of 77 samples.
View Publications28

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

Latest Publications: CTNNB1 (cancer-related)

Fasihi A, Soltani BM, Ranjbaran ZS, et al.
Hsa-miR-942 fingerprint in colorectal cancer through Wnt signaling pathway.
Gene. 2019; 712:143958 [PubMed] Related Publications
The Wnt signaling pathway has been identified for its function in carcinogenesis and embryonic development. It is known to play a vital role in the initiation and development of colorectal cancer (CRC). Therefore, it is of great importance for CRC research to illuminate the mechanisms which regulate Wnt pathway activity. Here, we intended to examine the effect of hsa-miR-942 (miR-942) on the Wnt signaling activity, cell cycle progression, and its expression in CRC tissues. RT-qPCR results indicated that miR-942 is significantly upregulated in colorectal cancer. Then, overexpression of miR-942 promoted, whereas its inhibition decreased the Wnt signaling activity, detected by RT-qPCR and Top/Fop flash assay. Inhibition of Wnt signaling by using PNU-74654 or IWP-2 small molecules indicated that miR-942 applies its effect to the β-catenin degradation complex level. Then, RT-qPCR and dual luciferase assay showed that miR-942 upregulated Wnt signaling through direct targeting of APC, which is a tumor suppressor in Wnt signaling pathway. Furthermore, the western blotting analysis indicated that β.catenin, as a main member of Wnt signaling pathway is upregulated following the overexpression of miR-942. Finally, miR-942 overexpression resulted in cell cycle progression in SW480 cells. Taken together, our findings established an oncogenic role for miR-942 in CRC and indicated that this miRNA might be a crucial target for CRC therapy.

Kishore C, Sundaram S, Karunagaran D
Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.

Zhou X, Yan L, Bu XL, et al.
Arotinoid trometamol inhibits arsenic trioxide-stimulated keratinocyte proliferation via the Wnt, Shh, and bone morphogenetic protein signaling pathways.
J Biol Regul Homeost Agents. 2019 May-Jun; 33(3):731-743 [PubMed] Related Publications
Arsenic acts as a human carcinogen and contributes to skin cancer via mechanisms that remain largely unknown. Recent evidence implicates the perturbation of Wnt, Shh and BMP signals as a potential mechanism. We initiated studies to examine gene expression changes in these signaling pathways. Meanwhile, the antagonistic effect of retinoic acid was explored. In this study, HaCaT and NHEK cells were treated with arsenic trioxide (As2O3) alone or in combination with arotinoid trometamol (retinoic acid receptor agonist). Flow cytometric analysis, PCR array and Western blot were used to determine the potential mechanism and signaling pathways associated with arsenic carcinogenesis. The results showed that low concentration As2O3 could stimulate keratinocyte proliferation, and arotinoid trometamol inhibited the process via regulating the expression of about 20 genes. These genes included components of Wnt signaling (CSNK1A1L, CTNNB1, SFRP1, Wnt10B, Wnt11, Wnt16, Wnt5A, Wnt8A), Shh signaling (C6orf138, HHIP, PTCHD1) and BMP signaling pathway (BMP2, BMP7). The changes of some differentially expressed genes of these signaling pathways in As2O3 treatment group were counteracted by the subsequent arotinoid trometamol treatment. Our data suggest that dysregulation and cross-talk of Wnt, Shh and BMP signals play great roles in the process of arsenic-induced carcinogenesis, which could be antagonized by arotinoid trometamol.

Qin CJ, Bu PL, Zhang Q, et al.
ZNF281 Regulates Cell Proliferation, Migration and Invasion in Colorectal Cancer through Wnt/β-Catenin Signaling.
Cell Physiol Biochem. 2019; 52(6):1503-1516 [PubMed] Related Publications
BACKGROUND/AIMS: Zinc Finger Protein 281 (ZNF281) was recently identified as a novel oncogene in several human carcinomas. However, the clinical significance of ZNF281 in colorectal cancer (CRC) and the molecular mechanisms by which ZNF281 promotes the growth and metastasis of CRC remain unknown.
METHODS: ZNF281 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of ZNF281 expression. Cell Transwell assays and a wound healing assay were performed to assess the effects of ZNF281 on CRC cell migration and invasion in vitro. Western blotting was applied to analyze the potential mechanisms.
RESULTS: ZNF281 mRNA and protein levels were significantly increased in CRC tissues compared with normal colon tissues, and high ZNF281 expression was associated with advanced T stage, N stage, TNM stage and differentiation. Therefore, ZNF281 expression might be an independent prognostic indicator in CRC patients. Moreover, knockdown of ZNF281 expression suppressed cell proliferation, migration and invasion by inhibiting the Wnt/β-catenin pathway.
CONCLUSION: Our study indicates that ZNF281 plays a critical role in the progression and metastasis of CRC and could represent a potential therapeutic target for CRC.

Kim E, Lisby A, Ma C, et al.
Promotion of growth factor signaling as a critical function of β-catenin during HCC progression.
Nat Commun. 2019; 10(1):1909 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.

Hu C, Li M, Guo T, et al.
Anti-metastasis activity of curcumin against breast cancer via the inhibition of stem cell-like properties and EMT.
Phytomedicine. 2019; 58:152740 [PubMed] Related Publications
BACKGROUND: Curcumin is a polyphenolic compound with potent chemopreventive and anti-cancer efficacy.
PURPOSE: To explore the potential anti-metastasis efficacy of curcumin in breast cancer stem-like cells (BCSCs), which are increasingly considered to be the origin of the recurrence and metastasis of breast cancer.
METHODS: A CCK8 assay was performed to evaluate cell viability, and a colony formation assay was conducted to determine cell proliferation in MCF-7 and MDA-MB-231 adherent cells. Transwell and wound healing assays were used to detect the effect of curcumin on cell migration and invasion in MDA-MB-231 cells. Mammospheres were cultured with serum free medium (SFM) for three generations and the BCSC surface marker CD44
RESULTS: Curcumin exhibited anti-proliferative and colony formation inhibiting activities in both the MCF-7 and MDA-MB-231 cell lines. It also suppressed the migration and invasion of MDA-MB-231 cells. The CD44
CONCLUSION: The results of the present study suggest that the inhibitor effects of curcumin on breast cancer cells may be related to resistance to cancer stem-like characters and the EMT process. These data indicate that curcumin could function as a type of anti-metastasis agent for breast cancer.

Jiang J, Li Y, Jiang Z
Effects of LDOC1 on colorectal cancer cells via downregulation of the Wnt/β-catenin signaling pathway.
Oncol Rep. 2019; 41(6):3281-3291 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the most common tumor types of the digestive tract. Its incidence and mortality rates are among the highest of all gastrointestinal tumor types. The expression of leucine zipper downregulated in cancer 1 (LDOC1) is decreased in numerous cancer types. In the present study, the aim was to investigate the role of LDOC1 and determine the potential molecular mechanisms of its action in CRC. The expression of LDOC1 in CRC tissues and adjacent normal tissues was detected by reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. LDOC1 expression in four CRC cell lines, compared with normal colorectal tissue, was determined by reverse transcription‑ polymerase chain reaction (RT‑PCR), and two cell lines with relatively low expression were screened. Human LDOC1 cDNA was inserted into a lentiviral vector, and transfected into HCT‑116 and Caco2 cell lines. The transfection efficiency was identified by RT‑PCR and western blot analysis. Cell proliferation was detected by Cell Counting Kit‑8 and colony formation assays. Cell cycle and apoptosis were detected by flow cytometry assay. Migration and invasion were assessed using Transwell and Matrigel assays, respectively. Additionally, whether LDOC1 regulates the Wnt/β‑catenin pathway was investigated by western blot analysis, and the expression and localization of β‑catenin in CRC cells were demonstrated by cellular immunofluorescence. LDOC1 expression was downregulated in CRC tissues and cells. LDOC1 overexpression inhibited cell proliferation, migration and invasion, but promoted cells apoptosis. Furthermore, LDOC1 downregulated the Wnt/β‑catenin pathway in CRC. In conclusion, LDOC1 is a tumor suppressor in CRC and it inhibits cell proliferation and promotes cell apoptosis. Additionally, it inhibits CRC cell metastasis by downregulating the Wnt/β‑catenin signaling pathway.

Mu X, Li H, Zhou L, Xu W
TRIM52 regulates the proliferation and invasiveness of lung cancer cells via the Wnt/β‑catenin pathway.
Oncol Rep. 2019; 41(6):3325-3334 [PubMed] Related Publications
As a major cause of cancer‑associated mortalities, lung cancer is frequently diagnosed in males and females with an incidence ratio of 2.1:1. Tripartite motif 52 (TRIM52), an E3 ubiquitin ligase, has been reported to be involved in various biological functions, including cell proliferation and invasiveness. In the present study, an elevated TRIM52 level was observed in tumor tissues of patients with lung cancer and in lung cancer cell lines. The downregulation of TRIM52 in lung cancer cells significantly suppressed the proliferation of lung cancer cells, arrested the cell cycle at the G1 phase and was accompanied by a decrease in the levels of β‑catenin, proliferating cell nuclear antigen, c‑Myc and Cyclin D1 proteins. Additionally, TRIM52‑induced cell proliferation and invasiveness, as well as the levels of cell cycle‑associated proteins, were completely counteracted by the Wnt/β‑catenin inhibitor XAV939. Based on these data, it was speculated that TRIM52 is critical for lung cancer progression and that downregulation of TRIM52 could inhibit cell proliferation by blocking cell cycle progression. It was also speculated that TRIM52 upregulation promotes proliferation and invasiveness through activation of the Wnt/β‑catenin pathway. Thus, TRIM52 has the potential to be a therapeutic target for lung cancer.

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.

Li J, He M, Xu W, Huang S
LINC01354 interacting with hnRNP-D contributes to the proliferation and metastasis in colorectal cancer through activating Wnt/β-catenin signaling pathway.
J Exp Clin Cancer Res. 2019; 38(1):161 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long non-coding RNAs (lncRNAs) have been identified to play an important role in the development and progression of various tumors, including colorectal cancer (CRC). However, the regulatory molecular mechanism by lncRNA in CRC initiation and progression has not been fully clarified.
METHODS: TCGA database was used to identify the involvement of LINC01354 in CRC. qRT-PCR and western blot were used to determine RNA and protein expression. The gain- and loss-of-function assays were conducted to explore the function of LINC01354 in the progression of CRC. In order to investigate the LINC01354-mediated mRNA in CRC tumorigenesis, we applied the profiling analysis as well as GO and KEGG analysis. Pulldown and RIP assays were applied to detect the interaction of hnRNP-D with LINC01354 and β-catenin.
RESULTS: The upregulation of LINC01354 in CRC and its prognostic significance were identified by TCGA database and confirmed in CRC tissues. Functionally, forced expression of LINC01354 promoted, while knockdown of LINC01354 inhibited cell proliferation, migration and EMT phenotype formation of CRC cells. A significant enrichment of the Wnt/β-catenin signaling pathway genes under LINC01354 overexpression. In addition, LINC01354 modulated the mRNA stability of β-catenin through interacting with hnRNP-D, thereby activating Wnt/β-catenin signaling pathway.
CONCLUSIONS: Our investigations proposed novel regulatory axis of LINC01354/hnRNP-D/Wnt/β-catenin, which might be in favor of exploring novel therapeutic regimens for the clinical treatment of CRC.

Luo W, Yan D, Song Z, et al.
miR-126-3p sensitizes glioblastoma cells to temozolomide by inactivating Wnt/β-catenin signaling via targeting SOX2.
Life Sci. 2019; 226:98-106 [PubMed] Related Publications
AIMS: The acquired drug resistance has been regarded as a main barrier for the effective treatment of temozolomide (TMZ) in glioblastoma (GBM). MiR-126-3p is commonly down-regulated and exerts tumor-suppressive roles in kinds of human cancers, including GBM. This study was designed to investigate the functions and mechanisms of miR-126-3p in regulating TMZ resistance in GBM.
MATERIALS AND METHODS: qRT-PCR analysis was used to measure the expressions of miR-126-3p and SOX2 mRNA in GBM tissues and cells. Cell viability, colony forming ability and apoptosis were detected to evaluate the effect of miR-126-3p or SOX2 on TMZ resistance. Luciferase reporter experiments were applied to identify the target genes of miR-126-3p. Western blot analysis was performed to determine the protein levels associated with Wnt/β-catenin signaling. TOP/FOP Flash assays were conducted to determine the effects of miR-126-3p or SOX2 on Wnt/β-catenin signaling.
KEY FINDINGS: miR-126-3p expression was decreased in TMZ-resistant GBM tissues and cells. High levels of miR-126-3p enhanced TMZ sensitivity by inhibiting cell viability, reducing colony forming potential and inducing apoptosis. Additionally, SOX2 was identified as a downstream target of miR-126-3p. On the contrary, SOX2 overexpression conferred TMZ resistance of GBM cells. Moreover, miR-126-3p-mediated TMZ sensitivity was reversed following increased expression of SOX2. Furthermore, miR-126-3p-induced inactivation of Wnt/β-catenin signaling was greatly abrogated by SOX2 up-regulation.
SIGNIFICANCE: MiR-126-3p sensitizes GBM cells to TMZ possibly by repressing SOX2 expression and blocking Wnt/β-catenin signaling. This study provides novel targets to overcome TMZ resistance in GBM chemotherapy.

Shen DW, Li YL, Hou YJ, et al.
MicroRNA-543 promotes cell invasion and impedes apoptosis in pituitary adenoma via activating the Wnt/β-catenin pathway by negative regulation of Smad7.
Biosci Biotechnol Biochem. 2019; 83(6):1035-1044 [PubMed] Related Publications
Pituitary adenomas (PA) are commonly occurring benign neoplasms. Identification of molecular pathway resulting in pituitary tumorigenesis remains challenges in endocrine oncology. The present study was conducted with aim of investigating the role of microRNA-543 (miR-543) in PA development. Up-regulated miR-543 and downregulated Smad7 were observed in PA tissues. Afterwards, the specific mechanism of miR-543 and Smad7 in PA were determined with the use of ectopic expression, depletion and reporter assay experiments. Smad7 was confirmed as a target gene of miR-543. HP75 cells treated with overexpressed miR-543 exhibited increased cell proliferation, migration and invasion, while decreased cell apoptosis as well as expression of Cleaved caspase-3 and Cleaved caspase-8 were observed. Suppression of miR-543 contributed to an opposite trend to the above findings. Based on the findings, the inhibition of miR-543 was found to play a tumor suppressive role in PA through the down-regulation of Wnt/β-catenin pathway by negatively regulating Smad7.

Liu J, Tian W, Zhang W, et al.
MicroRNA-142-3p/MALAT1 inhibits lung cancer progression through repressing β-catenin expression.
Biomed Pharmacother. 2019; 114:108847 [PubMed] Related Publications
MALAT1 is well documented to be highly expressed in non-small cell lung cancer (NSCLC) and its overexpression closely associates the malignant phenotype of NSCLC cells and poor prognosis of NSCLC patients. MALAT1 is also identified to enhance β-catenin expression and under the negative regulation of miR-142-3p. However, the role of miR-142-3p/MALAT1/β-catenin in the occurrence and development of NSCLC remains unclear. The objective of this study was to explore it. The results showed that miR-142-3p expression was reduced in NSCLC tissues, while β-catenin and MALAT1 expression levels were elevated. MTT, transwell chamber, flow cytometry assays demonstrated that up-regulation of miR-142-3p with mimic transfection significantly inhibited the proliferation, migration and promoted the apoptosis of NSCLC H1299 cells, and induced a G0/G1 phase arrest and S phase reduction. Besides, miR-142-3p negatively decreased MALAT1 expression as detected by RT-PCR and luciferase reporter assays. Moreover, up-regulation of miR-142-3p decreased β-catenin expression through down-regulating MALAT1 in H1299 cells. And in vivo experiment showed that miR-142-3p up-regulation, as well as the knockdown of either β-catenin or MALAT1 significantly reduced the tumorigenesis of NSCLC cells. Taken together, our study makes clear that miR-142-3p functions as a tumor suppressor in NSCLC progression through inhibiting MALAT1/β-catenin signaling.

Kaowinn S, Oh S, Moon J, et al.
CGK062, a small chemical molecule, inhibits cancer upregulated gene 2‑induced oncogenesis through NEK2 and β‑catenin.
Int J Oncol. 2019; 54(4):1295-1305 [PubMed] Free Access to Full Article Related Publications
The mechanisms through which cancer‑upregulated gene 2 (CUG2), a novel oncogene, affects Wnt/β‑catenin signaling, essential for tumorigenesis, are unclear. In this study, we aimed to elucidate some of these mechanisms in A549 lung cancer cells. Under the overexpression of CUG2, the protein levels and activity of β‑catenin were evaluated by western blot analysis and luciferase assay. To examine a biological consequence of β‑catenin under CUG2 overexpression, cell migration, invasion and sphere formation assay were performed. The upregulation of β‑catenin induced by CUG2 overexpression was also accessed by xenotransplantation in mice. We first found that CUG2 overexpression increased β‑catenin expression and activity. The suppression of β‑catenin decreased cancer stem cell (CSC)‑like phenotypes, indicating that β‑catenin is involved in CUG2‑mediated CSC‑like phenotypes. Notably, CUG2 overexpression increased the phosphorylation of β‑catenin at Ser33/Ser37, which is known to recruit E3 ligase for β‑catenin degradation. Moreover, CUG2 interacted with and enhanced the expression and kinase activity of never in mitosis gene A‑related kinase 2 (NEK2). Recombinant NEK2 phosphorylated β‑catenin at Ser33/Ser37, while NEK2 knockdown decreased the phosphorylation of β‑catenin, suggesting that NEK2 is involved in the phosphorylation of β‑catenin at Ser33/Ser37. Treatment with CGK062, a small chemical molecule, which promotes the phosphorylation of β‑catenin at Ser33/Ser37 through protein kinase C (PKC)α to induce its degradation, reduced β‑catenin levels and inhibited the CUG2‑induced features of malignant tumors, including increased cell migration, invasion and sphere formation. Furthermore, CGK062 treatment suppressed CUG2‑mediated tumor formation in nude mice. Taken together, the findings of this study suggest that CUG2 enhances the phosphorylation of β‑catenin at Ser33/Ser37 by activating NEK2, thus stabilizing β‑catenin. CGK062 may thus have potential for use as a therapeutic drug against CUG2‑overexpressing lung cancer cells.

Ahmed KI, Govardhan HB, Roy M, et al.
Cell-free circulating tumor DNA in patients with high-grade glioma as diagnostic biomarker - A guide to future directive.
Indian J Cancer. 2019 Jan-Mar; 56(1):65-69 [PubMed] Related Publications
BACKGROUND: Owing to the aggressive nature of high-grade gliomas (HGGs), its early diagnosis holds the key to a favorable prognosis. Currently, tissue biopsy is the gold standard to verify HGG's initial diagnosis and can be challenging due to its invasive nature. In this study, our objective was a noninvasive panel for timely detection of HGG and its progression using cell-free circulating tumor DNA (cfTDNA).
MATERIALS AND METHODS: Twenty-seven patients with HGG were tested with a 50-gene tumor panel. cfTDNA isolated from serum was checked for single-nucleotide variations (SNVs) or copy number alterations using targeted next-generation sequencing, with further validation of results by checking respective formalin-fixed paraffin-embedded tumor tissues for the same genetic alterations.
RESULTS: About 88.8% of the patients were detected with HGG-associated cfTDNA. Around 25% patients were detected with one, 25% patients had three, 25% patients had four, and 12.5% patients each had five and six genetic alterations. About 12 of 50 genes were detected in the serum samples. The SNVs detected included TP53 in 87.5% of patients; PIK3CA and EGFR in 50% of patients; PTEN in 37.5%; KIT and VHL in each 25% of patients; and RB1, NF2, MET, ATRX, CDK2A, and CTNNB1 each in 8.3%-16.6%. On combining EGFR, KIT, PTEN, PIK3CA, TP53, and VHL genes (Govardhan Diagnostic Genetic Module for high-grade glioma), at least one of the genetic alterations was found in 100% of patients.
Conclusion: These findings illustrate that cfTDNA is easily demonstrable and can be used as a surrogate to tissue biopsy in brain tumor.

Nie J, Jiang HC, Zhou YC, et al.
MiR-125b regulates the proliferation and metastasis of triple negative breast cancer cells via the Wnt/β-catenin pathway and EMT.
Biosci Biotechnol Biochem. 2019; 83(6):1062-1071 [PubMed] Related Publications
BACKGROUND/AIM: MiR-125b plays an important role in breast cancer. The current study was to explore the expression and function of miR-125b in triple negative breast cancer cells.
MATERIALS AND METHODS: The expression of miR-125b in human TNBC samples and cell lines were examined by qRT-PCR. MTT, scratch assays and transwell assays were utilized to observe the proliferation, migration and invasion ability. MiR-125b's target gene and downstream signaling pathways were investigated by Luciferase Reporter Assays, qRT-PCR, immunofluorescence assays and western bolt.
RESULTS: MiR-125b was highly expressed in human TNBC tissues and cell lines. Inhibiting miR-125b expression suppressed the proliferation, cell migration and invasion. The three-prime untranslated region (3´-UTR) of adenomatous polyposis coli (APC) mRNA contains miR-125b binding sites, and inhibiting miR-125b expression suppressed the activity of the intracellular Wnt/β-catenin pathways and EMT.
CONCLUSION: Inhibiting miR-125b regulates the Wnt/β-catenin pathway and EMT to suppress the proliferation and migration of MDA-MB-468 TNBC cells.

Longerich T, Endris V, Neumann O, et al.
Gut. 2019; 68(7):1287-1296 [PubMed] Related Publications
OBJECTIVE: We aimed at the identification of genetic alterations that may functionally substitute for
DESIGN: Large cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the

Zhang H, Dong R, Zhang P, Wang Y
Songorine suppresses cell growth and metastasis in epithelial ovarian cancer via the Bcl‑2/Bax and GSK3β/β‑catenin signaling pathways.
Oncol Rep. 2019; 41(5):3069-3079 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) is the most frequent cause of cancer‑associated mortality among all types of gynecological cancer. The high recurrence rate and the poor 5‑year survival rate indicate that more effective therapeutic strategies are required. The aim of the present study was to investigate the role and potential mechanisms of songorine in treating EOC. EOC cells were cultured with different concentrations of songorine, following which MTT and flow cytometric analyses were conducted to measure cell viability and apoptosis. Wound healing and Transwell assays were used to detect cell migration and invasion abilities. Furthermore, associated molecules in the glycogen synthase kinase (GSK)‑3β/β‑catenin and B‑cell lymphoma 2 (Bcl‑2)/Bcl‑2‑associated X (Bax) signaling pathways were semi‑quantified by western blotting. Finally, tumor size measurements, pathological observations, western blot analysis and toxicological evaluations were performed in SKOV‑3 tumor‑bearing BALB/c nude mice to investigate the efficacy and safety of songorine. As expected, songorine inhibited EOC cell survival, invasion and migration, promoted EOC cell apoptosis and suppressed mammalian EOC tumorigenic behavior. In particular, GSK3β inhibitor treatment restored the songorine‑induced regulation of the GSK3β/β‑catenin signaling pathway. Furthermore, in the in vitro and in vivo experiments, songorine consistently downregulated the expression of N‑cadherin, vimentin, matrix metalloproteinase (MMP)‑2, MMP‑9, phosphorylated‑GSK3β, β‑catenin and Bcl‑2, and upregulated the expression of E‑cadherin, cleaved caspase‑3, cleaved caspase‑9 and Bax. In conclusion, songorine exerted its anticancer effect through the GSK3β/β‑catenin and Bcl‑2/Bax signaling pathways. These results highlight the potential use of songorine as a novel therapeutic agent for EOC.

Singh V, Singh AP, Sharma I, et al.
Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):192-203 [PubMed] Related Publications
Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC.
Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry.
Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways.
Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways.

Xie Q, Wang S, Zhao Y, et al.
MicroRNA-216a suppresses the proliferation and migration of human breast cancer cells via the Wnt/β-catenin signaling pathway.
Oncol Rep. 2019; 41(5):2647-2656 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to investigate the potential anticancer effects of microRNA-216a on the growth of human breast cancer and the possible underlying mechanisms. The results demonstrated that serum microRNA-216a was significantly decreased in patients with breast cancer compared with healthy controls. MicroRNA-216a overexpression led to a decrease in cell proliferation and migration, as well as increases in apoptosis, caspase-3/8 activities, Bax expression and p53 protein expression in MCF-7 cells. It was also revealed that microRNA-216a suppressed Wnt and β-catenin expression in MCF-7 cells. The anticancer effects of microRNA-216a were reversed by anti-microRNA-216a by promoting the Wnt/β-catenin signaling pathway. Inactivation of the Wnt pathway increased the anticancer effects of microRNA-216a in MCF-7 cells. Collectively, the results of the present study indicated that microRNA-216a suppressed the growth of human breast cancer cells by targeting the Wnt/β‑catenin signaling pathway.

Li J, Guo L, Chai L, Ai Z
Comprehensive Analysis of Driver Genes in Personal Genomes of Clear Cell Renal Cell Carcinoma.
Technol Cancer Res Treat. 2019; 18:1533033819830966 [PubMed] Free Access to Full Article Related Publications
AIM: To characterize personal driver genes in clear cell renal cell carcinoma independent of somatic mutation frequencies.
METHODS: Personal cancer driver genes were predicted by Integrated CAncer GEnome Score in 417 patients with clear cell renal cell carcinoma using 26 786 somatic mutations from The Cancer Genome Atlas, followed by an integrated investigation on personal driver genes.
RESULTS: A total of 233 personal driver genes were determined by Integrated CAncer GEnome Score. The coexpression network analysis found 5 coexpressed modules. The blue module was significantly negatively correlated with all 5 clinical features, including cancer stage, lymph node metastasis, distant metastasis, age, and survival status (death). CTNNB1, TGFBR2, KDR, FLT1, and INSR were the hub genes in the blue module. The expression of 79 personal driver genes was significantly associated with clinical outcomes of patients with clear cell renal cell carcinoma.
CONCLUSIONS: The set of personal driver genes sheds insights into the tumorigenesis of clear cell renal cell carcinoma and paves the way for developing personalized medicine for clear cell renal cell carcinoma.

Wang J, Zhou P, Wang X, et al.
Rab25 promotes erlotinib resistance by activating the β1 integrin/AKT/β-catenin pathway in NSCLC.
Cell Prolif. 2019; 52(3):e12592 [PubMed] Related Publications
OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has significant therapeutic efficacy in non-small-cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long-term efficacy of EGFR-TKI. Our study aimed to investigate the role of ras-associated binding protein 25 (Rab25) in mediating EGFR-TKI resistance in NSCLC.
MATERIALS AND METHODS: Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell-counting kit-8 and flow cytometry. The interaction between Rab25 and β1 integrin was confirmed by co-immunoprecipitation.
RESULTS: Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with β1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane-β1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/β-catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR-TKI treatment in NSCLC patients.
CONCLUSIONS: Rab25 mediates erlotinib resistance by activating the β1 integrin/AKT/β-catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR-TKI.

Götzel K, Chemnitzer O, Maurer L, et al.
In-depth characterization of the Wnt-signaling/β-catenin pathway in an in vitro model of Barrett's sequence.
BMC Gastroenterol. 2019; 19(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: An altered Wnt-signaling activation has been reported during Barrett's esophagus progression, but with rarely detected mutations in APC and β-catenin (CTNNB1) genes.
METHODS: In this study, a robust in-depth expression pattern analysis of frizzled receptors, co-receptors, the Wnt-ligands Wnt3a and Wnt5a, the Wnt-signaling downstream targets Axin2, and CyclinD1, as well as the activation of the intracellular signaling kinases Akt and GSK3β was performed in an in vitro cell culture model of Barrett's esophagus. Representing the Barrett's sequence, we used normal esophageal squamous epithelium (EPC-1, EPC-2), metaplasia (CP-A) and dysplasia (CP-B) to esophageal adenocarcinoma (EAC) cell lines (OE33, OE19) and primary specimens of squamous epithelium, metaplasia and EAC.
RESULTS: A loss of Wnt3a expression was observed beginning from the metaplastic cell line CP-A towards dysplasia (CP-B) and EAC (OE33 and OE19), confirmed by a lower staining index of WNT3A in Barrett's metaplasia and EAC, than in squamous epithelium specimens. Frizzled 1-10 expression analysis revealed a distinct expression pattern, showing the highest expression for Fzd2, Fzd3, Fzd4, Fzd5, Fzd7, and the co-receptor LRP5/6 in EAC cells, while Fzd3 and Fzd7 were rarely expressed in primary specimens from squamous epithelium.
CONCLUSION: Despite the absence of an in-depth characterization of Wnt-signaling-associated receptors in Barrett's esophagus, by showing variations of the Fzd- and co-receptor profiles, we provide evidence to have a significant role during Barrett's progression and the underlying pathological mechanisms.

Yao Y, Hua Q, Zhou Y, Shen H
CircRNA has_circ_0001946 promotes cell growth in lung adenocarcinoma by regulating miR-135a-5p/SIRT1 axis and activating Wnt/β-catenin signaling pathway.
Biomed Pharmacother. 2019; 111:1367-1375 [PubMed] Related Publications
Circular RNAs (circRNAs) are involved in the tumorigenesis and progression of human cancers. However, little is known about the biological role and mechanism of circRNAs in lung adenocarcinoma (LAC). In the present study, we applied microarray analysis to screen for LAC-specific circRNAs. Top ten upregulated circRNAs were chosen for qRT-PCR analysis. Among them, circ_0001946 was significantly overexpressed in both LAC tissues and cell lines. In addition, the expression level of circ_0001946 was positively correlated with TNM stage and tumor size. Using Kaplan-Meier analysis, we found that circ_0001946 expression was negatively related with the overall survival of LAC patients. Next, we treated LAC cells with circ_0001946-specific shRNAs and found that knockdown of circ_0001946 inhibited LAC cell growth in vitro and in vivo. Mechanism investigation revealed that circ_0001946 was located in the cytoplasm of LAC cells and acted as a molecular sponge of miR-135a-5p to upregulate Sirtuin 1 (SIRT1) expression. Rescue assays further validated the role of circ_0001946-miR-135a-5p-SIRT1 axis in LAC progression. Additionally, SIRT1 has been demonstrated to be a positive regulator of Wnt/β-catenin signaling pathway. Western blot analysis revealed that circ_0001946 regulated SIRT1/Wnt/β-catenin signaling pathway. In conclusion, our findings suggested that circ_0001946 might be a potential biomarker for the diagnosis or treatment of LAC.

Wen SY, Chen YY, Deng CM, et al.
Nerigoside suppresses colorectal cancer cell growth and metastatic potential through inhibition of ERK/GSK3β/β-catenin signaling pathway.
Phytomedicine. 2019; 57:352-363 [PubMed] Related Publications
BACKGROUND: Nerigoside (NG), a cardenolide isolated from a commonfolk medicine, Nerium oleander Linn. (Apocynaceae), has not been explored for its biological effects. To date, cardenolides have received considerable attention in pharmacology studies due to their direct effects of apoptosis-induction or growth-inhibitory against tumor in vitro and in vivo. Whether and how NG exerts anticancer effects against colorectal cancer remains to be elucidated.
PURPOSE: The aim of this study was to investigate the anticancer effect of NG in human colorectal cancer cells.
METHODS: To test anticancer effect, we compared potency of NG in two colorectal cancer cell lines, HT29 and SW620 by WST-1 and colony proliferation assays. And we investigated mechanism of anticancer activities by analyzing players in apoptotic and ERK/GSK3β/β-catenin signaling pathways in HT29 and SW620 cells treated with NG.
RESULTS: In this study, we showed that NG markedly suppressed the cell viability and colony formation of colorectal cancer cells HT29 and SW620, with no significant toxic effect on non-cancer cells NCM460. Annexin V-FITC/PI and CFSE labeling results revealed that NG suppressed cell proliferation in low concentration, along with reducing expression of PCNA, while NG induced apoptosis in high concentration,. Meanwhile, NG significantly arrested cell migration by reversal of EMT and cell cycle on G2/M. Then, we found that the ERK and GSK3β/β-catenin signaling pathway were noticeably blocked in CRC cells after treatment with NG. According to western blot, NG upregulated the expression of p-GSK3β/GSK3β and decreased especially the expression of β-catenin in nuclear. In addition, Wnt signaling and its target genes were suppressed in response to NG. Then, the Ser9 phosphorylation of GSK3β can be reduced / raised by GÖ 6983 / LiCl, respectively. Thus, we further confirmed that the GSK3β/β-catenin axis is involved in NG-prevented cell proliferation.
CONCLUSION: NG inhibited the growth of colorectal cancer cells by suppressing ERK/GSK3β/β-catenin signaling pathway. And the GSK3β/β-catenin axis is involved in preventing cell proliferation and migration by NG-treatment. These results suggest that NG may be used to treat colorectal cancer, with better outcome by combining with GSK3β inhibitor to block Wnt pathway.

Chen YJ, Jiang HT, Wang TF
Influence of Docosahexaenoic Acid on Proliferation and Apoptosis in Human HepG2 Cell Line.
Ann Clin Lab Sci. 2019; 49(1):72-78 [PubMed] Related Publications
OBJECTIVE: This study aims to investigate the effect of different concentrations of docosahexaenoic acid (DHA) on proliferation and apoptosis in HepG2 cell lines, and to research the possible molecular mechanisms.
METHODS: DHA concentration was 0 g/mL in the negative control group, and 15, 30, 45, 60 and 75 ug/mL, respectively, in the experimental groups. CCK-8 and flow cytometry methods were used to observe the growth inhibition and apoptosis rates of HepG2 cells cultured
RESULTS: In the concentration range of 0-45 ug/mL, the action time was 24 hours. DHA could inhibit the growth of HepG2 cells, and there were significant differences between the experimental and control groups (
CONCLUSION: DHA could promote apoptosis and inhibit the proliferation of HepG2 cells. The possible mechanism was related with the down-regulated protein expression of β-catenin and the mRNA expression of c-myc.

Wang J, Gerrard G, Poskitt B, et al.
Targeted next generation sequencing of pancreatic solid pseudopapillary neoplasms show mutations in Wnt signaling pathway genes.
Pathol Int. 2019; 69(4):193-201 [PubMed] Related Publications
Solid pseudopapillary neoplasms of the pancreas are rare neoplasms that have been shown to harbor recurrent somatic pathogenic variants in the beta-catenin gene, CTNNB1. Here, we used targeted next generation sequencing to analyze these tumors for other associated mutations. Six cases of solid pseudopapillary neoplasms were studied. DNA extracted from formalin-fixed paraffin embedded tissue blocks was analyzed using the Ion Torrent platform, with the 50-gene Ampliseq Cancer Hotspot Panel v2 (CHPv2), with further variant validation performed by Sanger sequencing. Four tumors (67%) were confirmed to harbor mutations within CTNNB1, two with c.109T > G p.(Ser37Ala) and two with c.94G > A p.(Asp32Asn). One case showed a frameshift deletion in the Adenomatous Polyposis Coli gene, APC c.3964delG p.(Glu1322Lysfs*93) with a variant allele frequency of 42.6%. Sanger sequencing on non-tumoral tissue confirmed the variant was somatic. The patient with the APC mutation developed metastasis and died. In addition to the four cases harboring CTNNB1 variants, we found a case characterized by poor outcome, showing a rare frameshift deletion in the APC gene. Since the APC product interacts with beta-catenin, APC variants may, in addition to CTNNB1, contribute to the pathogenesis of solid pseudopapillary neoplasms via 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.

Xiu DH, Liu GF, Yu SN, et al.
Long non-coding RNA LINC00968 attenuates drug resistance of breast cancer cells through inhibiting the Wnt2/β-catenin signaling pathway by regulating WNT2.
J Exp Clin Cancer Res. 2019; 38(1):94 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer is one the most common cancers, making it the second leading cause of cancer-related death among women. Long non-coding RNAs (lncRNAs), with tightly regulated expression patterns, also serve as tumor suppressor during tumorigenesis. The present study aimed to elucidate the role of LINC00968 in breast cancer via WNT2-mediated Wnt2/β-catenin signaling pathway.
METHODS: Breast cancer chip GSE26910 was utilized to identify differential expression in LINC00968 and WNT2. The possible relationship among LINC00968, transcriptional repressor HEY and WNT2 was analyzed and then verified. Effects of LINC00968 on activation of the Wnt2/β-catenin signaling pathway was also tested. Drug resistance, colony formation, cell migration, invasion ability and cell apoptosis after transfection were also determined. Furthermore, tumor xenograft in nude mice was performed to test tumor growth and weight in vivo.
RESULTS: WNT2 expression exhibited at a high level, whereas LINC00968 at a low expression in breast cancer which was also associated with poor prognosis in patients. LINC00968 targeted and negatively regulated WNT2 potentially via HEY1. Either overexpressed LINC00968 or silenced inhibited activation of the Wnt2/β-catenin signaling pathway, thereby reducing drug resistance, decreasing colony formation ability, as well as suppressing migration and invasion abilities of breast cancer cells in addition to inducing apoptosis. Lastly, in vivo experiment suggested that LINC00968 overexpression also suppressed transplanted tumor growth in nude mice.
CONCLUSION: Collectively, overexpressed LINC00968 contributes to reduced drug resistance in breast cancer cells by inhibiting the activation of the Wnt2/β-catenin signaling pathway through silencing WNT2. This study offers a new target for the development of breast cancer treatment.

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.
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