RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis

Gastric cancer (GC) is the most prevalent human cancer around the globe. In GC, Wnt signaling is deregulated, and receptor-like tyrosine kinase (RYK) coreceptors have been identified to interact with noncanonical Wnt ligand Wnt5a. We, therefore, aimed to evaluate the role of RYK in GC development and metastasis. GC tumor samples were collected from 250 GC patients. Expressions of RYK, as well as markers for the epithelial-mesenchymal transition (EMT), such as N-cadherin and E-cadherin, were subjected to correlation analysis with clinicopathological features. Endogenous RYK expression levels were compared in GC cell lines with ascending metastatic potentials followed by stable RYK knockdown. Effect of RYK knockdown on GC cell migration, invasion, and EMT phenotype were assessed in vitro, and on GC tumor growth in vivo in a xenograft rodent model. Particularly, liver metastasis potential of tail vein-injected GC cells was also analyzed following RYK knockdown. RYK was highly correlated with liver metastasis of GC tumors and the expression profiles of EMT markers toward the mesenchymal tendency. RYK expression was also positively correlated with the metastasis potential of GC cells. RYK knockdown not only inhibited migration, invasion, and EMT of GC cells in vitro, but also suppressed tumorigenesis and liver metastasis of GC cells in vivo using the mouse xenograft model. RYK is highly correlated with GC tumorigenesis and potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to GC. NEW & NOTEWORTHY RYK is highly correlated with gastric cancer tumorigenesis and the potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to gastric cancer.

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Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin

International Journal of Molecular Sciences ◽

10.3390/ijms20215391 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5391 ◽

Cited By ~ 5

Author(s):

Wörthmüller ◽

Salicio ◽

Oberson ◽

Blum ◽

Schwaller

Keyword(s):

Wnt Signaling ◽

Signaling Pathways ◽

Signaling Pathway ◽

Expression System ◽

Single Agent ◽

Wnt Signaling Pathway ◽

Tumor Formation ◽

Mesenchymal Transition

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.

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Dickkopf Wnt signaling pathway inhibitor 1 regulates the differentiation of mouse embryonic stem cells in vitro and in vivo

Molecular Medicine Reports ◽

10.3892/mmr.2015.4586 ◽

2015 ◽

Vol 13 (1) ◽

pp. 720-730 ◽

Cited By ~ 8

Author(s):

LIPING OU ◽

LIAOQIONG FANG ◽

HEJING TANG ◽

HAI QIAO ◽

XIAOMEI ZHANG ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cells

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The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90455.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. G1150-G1158 ◽

Cited By ~ 45

Author(s):

Sharon DeMorrow ◽

Heather Francis ◽

Eugenio Gaudio ◽

Julie Venter ◽

Antonio Franchitto ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Growth ◽

Wnt Signaling ◽

Signaling Pathway ◽

Calcium Release ◽

Wnt Signaling Pathway ◽

Xenograft Model ◽

Orphan Receptor

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca2+-dependent pathway involving protein kinase C, or a Ca2+-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH2-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

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Ellagic Acid Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting Wnt Signaling Pathway

10.21203/rs.3.rs-39319/v1 ◽

2020 ◽

Author(s):

Xiaohe Li ◽

kai huang ◽

Xiaowei Liu ◽

Hao Ruan ◽

Ling Ma ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Wnt Signaling ◽

Signaling Pathway ◽

Ellagic Acid ◽

Cell Damage ◽

Wnt Signaling Pathway ◽

Pharmacological Activities ◽

Natural Polyphenol

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality, which characterized by epithelial cell damage and fibroblasts activation. Ellagic acid (EA) is a natural polyphenol compound widely found in fruits and nuts which has demonstrated multiple pharmacological activities. Herein we showed that Ellagic acid significantly alleviated bleomycin(BLM)-induced pulmonary fibrosis in mice, and also inhibited the Wnt/β-catenin signal in primary pulmonary fibroblasts. In vitro experiments indicated that Ellagic acid apparently suppressed Wnt3a-induced myofibroblasts activation and ECM accumulation mainly via inhibiting the phosphorylation of Erk2 and Akt. Further studies showed that Ellagic acid could induce autophagy formation of myofibroblasts mainly by suppressing mTOR signaling and promote apoptosis of myofibroblasts. In vivo experiments reveled that Ellagic acid significantly inhibited myofibroblasts activation and promoted autophagy formation. Taken together, our results showed that Ellagic acid effectively attenuated BLM-induced pulmonary fibrosis in mice by suppressing myofibroblasts activation, promoting autophagy and apoptosis of myofibroblasts mainly via inhibiting Wnt signaling pathway.

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miR-544ainduces epithelial–mesenchymal transition through the activation of WNT signaling pathway in gastric cancer

Carcinogenesis ◽

10.1093/carcin/bgv106 ◽

2015 ◽

Vol 36 (11) ◽

pp. 1363-1371 ◽

Cited By ~ 54

Author(s):

Yoshimitsu Yanaka ◽

Tomoki Muramatsu ◽

Hiroyuki Uetake ◽

Ken-ichi Kozaki ◽

Johji Inazawa

Keyword(s):

Gastric Cancer ◽

Wnt Signaling ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Wnt Signaling Pathway ◽

Mesenchymal Transition

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Bisphenol-A exposure alters memory consolidation and hippocampal CA1 spine formation through Wnt signaling in vivo and in vitro

Toxicology Research ◽

10.1039/c4tx00093e ◽

2015 ◽

Vol 4 (3) ◽

pp. 686-694 ◽

Cited By ~ 5

Author(s):

Zhi-Hua Liu ◽

Ye Yang ◽

Meng-Meng Ge ◽

Li Xu ◽

Yuqing Tang ◽

...

Keyword(s):

Bisphenol A ◽

Wnt Signaling ◽

Signaling Pathway ◽

Memory Consolidation ◽

Wnt Signaling Pathway ◽

Spine Formation ◽

Hippocampal Ca1

Based on Wnt signaling pathway, this study aims to further mechanistically understand memory alteration after BPA exposure.

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Decreased expression of ATF3, orchestrated by β-catenin/TCF3, miR-17-5p and HOXA11-AS, promoted gastric cancer progression via increased β-catenin and CEMIP

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00694-9 ◽

2021 ◽

Author(s):

Guohua Xie ◽

Ping Dong ◽

Hui Chen ◽

Ling Xu ◽

Yi Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Wnt Signaling ◽

Cancer Progression ◽

Noncoding Rna ◽

High Throughput Sequencing ◽

Wnt Signaling Pathway ◽

Focal Adhesions ◽

Cell Growth And Migration

AbstractATF3 has been reported to be dysregulated in various cancers and involved in various steps of tumorigenesis. However, the mechanisms underlying the abnormal expression of ATF3 and its biological function in gastric cancer (GC) have not been well investigated. Here, we report ATF3 as one of the key regulators of GC development and progression. Patients with low ATF3 expression had shorter survival and a poorer prognosis. In vitro and in vivo assays investigating ATF3 alterations revealed a complex integrated phenotype that affects cell growth and migration. Strikingly, high-throughput sequencing and microarray analysis of cells with ATF3 silencing or of ATF3-low GC tissues indicated alterations in the Wnt signaling pathway, focal adhesions and adherens junctions. Mechanistically, the expression of β-catenin and cell migration inducing hyaluronidase 1 (CEMIP) was significantly upregulated in GC cells with downregulated ATF3, which was synergistically repressed by the β-catenin/TCF3 signaling axis and noncoding RNA miR-17-5p and HOXA11-AS. In addition, we found that WDR5 expression was promoted by TCF3 and is involved in miR-17-5p and HOXA11-AS activation in GC cells. Taken together, our findings revealed the mechanism of ATF3 downregulation and its biological role in regulating the expression of Wnt signaling-related genes during GC progression, suggesting new informative biomarkers of malignancy and therapeutic directions for GC patients.

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The Novel Tumor Suppressor Gene ZNF24 Induces THCA Cells Senescence by Regulating Wnt Signaling Pathway, Resulting in Inhibition of THCA Tumorigenesis and Invasion

Frontiers in Oncology ◽

10.3389/fonc.2021.646511 ◽

2021 ◽

Vol 11 ◽

Author(s):

Juan Xiong ◽

Panpan Jiang ◽

Li Zhong ◽

Youling Wang

Keyword(s):

Tumor Suppressor ◽

Wnt Signaling ◽

Signaling Pathway ◽

Nude Mice ◽

Treatment Options ◽

Ectopic Expression ◽

Wnt Signaling Pathway ◽

Migration And Invasion

ObjectClinically, the effective treatment options available to thyroid cancer (THCA) patients are very limited. Elucidating the features of tumor suppressor genes (TSGs) and the corresponding signal transduction cascade may provide clues for the development of new strategies for targeted therapy of THCA. Therefore, this paper aims to explore the mechanism of ZNF24 underlying promoting THCA cell senescence at molecular level.MethodsWe performed RT-PCR and Western Blotting for evaluating associated RNA and protein expression. CCK8, colony forming, wound healing and Transwell chamber assays were conducted to examine THCA cell proliferation, invasion and migration. β-galactosidase staining assay was performed to detect THCA cells senescence. The size and volume of xenotransplanted tumors in nude mice are calculated to asses ZNF24 effect in vivo.ResultsEctopic expression of ZNF24 significantly inhibited the cell viability, colony forming, migration and invasion abilities of THCA cell lines (K1/GLAG-66i and BCPAPi) (P < 0.05). ZNF24 induced BCPAPi cells senescence through regulating Wnt signaling pathway. ZNF24 inhibited Wnt signaling pathway activition by competitively binding β-catenin from LEF1/TCF1-β-catenin complex. In nude mice, both Ectopic expression of ZNF24 and 2,4-Da (the strong β-catenin/Tcf-4 inhibitor) treatment significantly decreased both the size and weight of xenotransplanted tumors when compared with control mice (P < 0.05).ConclusionResults obtained in vivo and in vitro reveal the role of ZNF24 in significantly suppressing THCA tumorigenesis and invasion by regulating Wnt signaling pathway.

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Puerarin Enhances the Anti-Tumor Effect of Cisplatin on Drug-Resistant A549 Cancer in vivo and in vitro Through Activation of the Wnt Signaling Pathway

Cancer Management and Research ◽

10.2147/cmar.s253327 ◽

2020 ◽

Vol Volume 12 ◽

pp. 6279-6289 ◽

Cited By ~ 1

Author(s):

Ping Huang ◽

Shi-Xia Du

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Drug Resistant

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Osmolytes and Macromolecular Crowders Diversely Affect the Aggregation of the Cancerrelated L106R Mutant of the Axin RGS Domain

10.26434/chemrxiv.13055507 ◽

2020 ◽

Author(s):

Tommaso Garfagnini ◽

Daniel Harries ◽

Assaf Friedler

Keyword(s):

Protein Aggregation ◽

Wnt Signaling ◽

Signaling Pathway ◽

Molten Globule ◽

Wnt Signaling Pathway ◽

Potential Contribution ◽

Cellular Environment ◽

Rgs Domain

Protein aggregation is involved in a variety of diseases, including neurodegenerative diseases and cancer. The cellular environment is crowded by a plethora of cosolutes comprising small molecules and biomacromolecules at high concentrations, which may influence the aggregation of proteins in vivo. To account for the effect of cosolutes on cancer-related protein aggregation, we studied their effect on the aggregation of the cancer-related L106R mutant of the Axin protein. Axin is a key player in the Wnt signaling pathway, and the L106R mutation in its RGS domain results in a native molten globule that tends to form native-like aggregates. This results in uncontrolled activation of the Wnt signaling pathway, leading to cancer. We monitored the aggregation process of Axin RGS L106Rin vitro in the presence of a wide ensemble of cosolutes including polyols, amino acids, betaine and polyethylene glycol (PEG) crowders. Except myo-inositol, all polyols decreased RGS L106R aggregation, with carbohydrates exerting the strongest inhibition. Conversely, betaine and PEGs enhanced aggregation. These results are consistent with the reported effects of osmolytes and crowders on the stability of molten globular proteins and with both amorphous and amyloid aggregation mechanisms. We suggest a model of Axin L106R aggregation in vivo, whereby molecularly small osmolytes keep the protein as a free solublemolecule but the increased crowding of the bound state by macromolecules induces its aggregation at the nano-scale. Our study sheds light on the potential contribution of cosolutes to the onset of cancer as a protein misfolding disease, and on the relevance of aggregation in the molecular aetiology of cancer.

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