CTSB promotes porcine preadipocytes differentiation by degrading fibronectin and attenuating the Wnt/β-catenin signaling pathway

The process of preadipocytes differentiation plays a vital role in adipose tissue expansion and many factors are involved in this event. Cathepsin B (CTSB), secreted from lysosome, has been reported in regulating a variety of physiological processes. In this study, we demonstrated CTSB promotes lipid accumulation and adipogenic genes expression in porcine primary preadipocytes by degrading fibronectin (Fn), a key component of extracellular matrix. Lithium chloride (LiCl) is an activator of Wnt/β-catenin signaling through stabilizing β-catenin. We found that CTSB can relieve the anti-adipogenic effects of LiCl, indicating that CTSB could impact Wnt/β-catenin signaling pathway. Interestingly, Fn is an important target gene of Wnt/β-catenin. So we considered that CTSB promote preadipocytes differentiation by suppressing these two pathways.     

Wnt/β-catenin signaling pathway in severe preeclampsia

This study aims to elucidate the mechanisms of Wnt/β-catenin signaling pathway in the development of preeclampsia (PE). The mRNA levels of Wnt1, β-catenin, c-myc and cyclinD1 were determined by real-time PCR in the placentas. Moreover, the expression levels of Wnt1, β-catenin, Dickkopf-1 (DKK1) and glycogen synthase kinase 3β (GSK-3β) proteins were detected by Western blot. Immunohistochemistry was used in placental tissue microarray to localize the expression of Wnt1, β-catenin, DKK1 proteins in the placentas of two groups. Compared with the control placentas, the mRNA levels of Wnt1, β-catenin, c-myc and cyclinD1 were decreased in the severe preeclamptic placentas. The Western blot results showed that the expression levels of Wnt1, β-catenin, and GSK-3β proteins were significantly elevated in the control group, while the expression level of DKK1 was significantly decreased. In addition, the staining intensity of Wnt1, β-catenin were weaker in the placentas of the severe PE group while the staining intensity of DKK1 was significantly stronger in the placentas of the severe PE group. Wnt/β-catenin signaling pathway may play a significant role in the pathogenesis of PE by regulating the invasion and proliferation of trophoblast.     

Nucleoredoxin promotes adipogenic differentiation through regulation of Wnt/β-catenin signaling

Nucleoredoxin (NRX) is a member of the thioredoxin family of proteins that controls redox homeostasis in cell. Redox homeostasis is a well-known regulator of cell differentiation into various tissue types. We found that NRX expression levels were higher in white adipose tissue of obese ob/ob mice and increased in the early adipogenic stage of 3T3-L1 preadipocyte differentiation. Knockdown of NRX decreased differentiation of 3T3-L1 cells, whereas overexpression increased differentiation. Adipose tissue-specific NRX transgenic mice showed increases in adipocyte size as well as number compared with WT mice. We further confirmed that the Wingless/int-1 class (Wnt)/β-catenin pathway was also involved in NRX-promoted adipogenesis, consistent with a previous report showing NRX regulation of this pathway. Genes involved in lipid metabolism were downregulated, whereas inflammatory genes, including those encoding macrophage markers, were significantly upregulated, likely contributing to the obesity in Adipo-NRX mice. Our results therefore suggest that NRX acts as a novel proadipogenic factor and controls obesity in vivo.     

LncRNA CRNDE is activated by SP1 and promotes osteosarcoma proliferation,invasion, and epithelial-mesenchymal transition via Wnt/β-catenin signaling pathway

Long noncoding RNAs (lncRNAs) were identified as a vital part in the development and progression of cancer in recent years. Colorectal neoplasia differentially expressed (CRNDE), a lncRNA, functions as an oncogene in some malignant neoplasias, but its role in the progression of osteosarcoma (OS) is still poorly understood. To dissect the difference in the expression of CRNDE, quantitative real-time polymerase chain reaction was utilized to evaluate it in OS tissues and cell lines (U2OS, MG63, and MNNG/HOS) compared with that in the adjacent normal tissues/osteoblast cells (hFOB1.19). The role of CRNDE in OS lines was assessed using Cell Counting Kit-8, colony formation, 5-ethynyl-2′-deoxyuridine staining, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, flow cytometry, Transwell assays, and Western blot, respectively. The results demonstrated that the expression of CRNDE was high in OS tissues and cell lines, and partly induced by SP1. CRNDE knockdown attenuated OS cell proliferation and invasion and induced apoptosis and G0/G1 arrest. Moreover, the expression of mesenchymal markers N-cadherin, Vimentin and Snail were downregulated, while the expression of epithelial markers E-cadherin and ZO-1 were conversely upregulated due to CRNDE knockdown. The mechanistic investigations showed that CRNDE promoted glycogen synthase kinase-3β phosphorylation to activate the Wnt/β-catenin pathway. The results suggested that lncRNA CRNDE indeed contributed to OS proliferation, invasion, and epithelial-mesenchymal transition, working as an oncogene, demonstrating that lncRNA CRNDE may be a valid therapeutic target for the OS.     

lncRNA SNHG11 promotes lung cancer cell proliferation and migration via activation of Wnt/β-catenin signaling pathway

Lung cancer ranks topmost among the most frequently diagnosed cancers. Despite increasing research, there are still unresolved mysteries in the molecular mechanism of lung cancer. Long noncoding RNA small nucleolar RNA host gene 11 (SNHG11) was found to be upregulated in lung cancer and facilitated lung cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition progression while suppressed cell apoptosis. Moreover, the high expression of SNHG11 was correlated with poor prognosis of lung cancer patients, TNM stage, and tumor size. Further assays demonstrated that SNHG11 functioned in lung cancer cells via Wnt/β-catenin signaling pathway. Subsequently, Wnt/β-catenin pathway was found to be activated through SNHG11/miR-4436a/CTNNB1 ceRNA axis. As inhibiting miR-4436 could only partly rescue the suppression of cell function induced by silencing SNHG11, it was suspected that β-catenin might enter cell nucleus through other pathways. Mechanism investigation proved that SNHG11 would directly bind with β-catenin to activate classic Wnt pathway. Subsequently, in vivo tumorigenesis was also demonstrated to be enhanced by SNHG11. Hence, SNHG11 was found to promote lung cancer progression by activating Wnt/β-catenin pathway in two different patterns, implying that SNHG11 might contribute to lung cancer treatment by acting as a therapeutic target.     

miRNA-192 and -215 activate Wnt/β-catenin signaling pathway in gastric cancer via APC

Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215. Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of miRNA-192 and -215. In summary, miRNA-192 and -215 target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.     

TRIM29 prevents hepatocellular carcinoma progression by inhibiting Wnt/β-catenin signaling pathway

TRIM29 plays an important role in many neoplasms.In this study,we aimed to elucidate its role in hepatocellular carcinoma (HCC) and explore the corresponding potential mechanism.The expression level of TRIM29 in HCC samples and hepatoma cell lines was detected.We found that TRIM29 was down-regulated in clinical HCC samples and cultured hepatoma cell lines by western blot analysis and quantitative polymerase chain reaction.In addition,we demonstrated that higher TRIM29 expression was associated with higher differentiation grade of HCC.To explore the effect of TRIM29 on hepatoma cells and its possible mechanisms,TRIM29-knockdown and overexpression cell models were constructed.The results showed that the depletion of TRIM29 promoted liver cancer cell proliferation,clone formation,migration and invasion in vitro probably through the Wnt/β-catenin signaling pathway.This study revealed the inhibitory roles of TRIM29 in HCC and the possible mechanisms.     

Wnt/β-catenin signaling and disease

The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.     

LncRNA CRNDE promotes the epithelial-mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/β-catenin signaling pathway

Colorectal neoplasia differentially expressed (CRNDE) is a significantly upregulated long noncoding RNA in hepatocellular carcinoma (HCC). CRNDE could promote cell proliferation, migration, and invasion, while its molecular mechanisms were still largely unclear. In this study, we investigated the expression and function of CRNDE. CRNDE was significantly upregulated in tumor tissues compared with adjacent normal tissues. In vitro, we revealed that knockdown of CRNDE inhibited cell proliferation, migration, and cell invasion capacities in HCC. Animal studies indicated that CRNDE knockdown represses both growth and metastasis of HCC tumors in vivo. Moreover, knockdown of CRNDE suppressed the cell epithelial-mesenchymal transition (EMT) process by increasing the expression of E-cadherin and ZO-1, whereas, decreasing the expression of N-cadherin, slug, twist, and vimentin in HCC cells. We also revealed that knockdown of CRNDE suppressed the Wnt/β-catenin signaling in HCC. Thus, CRNDE could modulate EMT of HCC cells and knockdown of CRNDE impaired the mesenchymal properties. CRNDE increased invasion of HCC cells might be through activating the Wnt/β-catenin signaling pathway.     

ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2

This study aims to elucidate the effect of ARHGAP9 on lung adenocarcinoma (LUAD) metastasis, and preliminarily explore its molecular mechanism. As a result, we found that ARHGAP9 was downregulated and correlated with poor prognosis of LUAD. ARHGAP9 knockdown promoted LUAD cell proliferation, migration and invasion, inhibited cell apoptosis and reduced G0G1 cell cycle arrest, in contrast to the results of ARHGAP9 overexpression. Further RNA sequencing analysis demonstrated that ARHGAP9 knockdown in H1299 cells significantly reduced DKK2 (dickkopf related protein 2) expression. Silencing ARHGAP9 in H1299 cells while overexpressing DKK2, DKK2 reversed the promoted effects of ARHGAP9 knockdown on LUAD cell proliferation, migration and invasion. Meanwhile, the activity of Wnt/β-catenin signaling pathway was also reduced. Taken together, these data indicated that ARHGAP9 knockdown promoted LUAD metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2. This may provide a new strategy for LUAD treatment.     

Oncogenic retinoic acid receptor γ knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/β-catenin pathway

Retinoic acid receptor γ (RARγ), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma. However, little is known about the regulatory mechanism of the RARγ expression in colorectal cancer (CRC) progression. In the present study, we found that RARγ was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in CRC specimens. Tissue microarrays showed that RARγ indicated vital clinical significance in CRC. RARγ knockdown neither affected CRC cell proliferation nor blocked the cell cycle of CRC cells. However, RARγ knockdown increased the sensitivity of CRC cells to chemotherapeutics through downregulation of multi-drug resistance 1(MDR1). Further studies suggested that RARγ knockdown resulted in downregulation of MDR1, in parallel with suppression of the Wnt/β-catenin pathway. Moreover, a significantly positive association between RARγ and MDR1 was demonstrated in CRC tissue microarrays. Collectively, these results suggested that overexpression of RARγ contributed to the multidrug chemoresistance of CRC cells, at least in part due to upregulation of MDR1 via activation of the Wnt/β-catenin pathway, indicating that RARγ might serve as a potential therapeutic target for chemoresistant CRC patients.     

LINC00365 promotes colorectal cancer cell progression through the Wnt/β-catenin signaling pathway

In the past decade, substantial evidence established that long noncoding RNAs are serious about mediating the evolution of malignancies. In previous studies, LINC00365, which has not been reported in colorectal cancer (CRC), was selected using the bioinformatics analysis in GSE109454 and GSE41655 data sets. However, the function and mechanism of LINC00365 are still obscure. In our study, LINC00365 was found upregulated in CRC specimens and intimately connected with the prognosis of patients with CRC. In addition, LINC00365 overexpression enhances the cell abilities of proliferation, migration, and invasion in vitro. Meanwhile, mechanistic studies showed that LINC00365 might involve in CRC cell progression by mediating the Wnt/β-catenin pathway. Furthermore, LINC00365 upregulation increased CDK1 protein expression. In conclusion, this study suggests that LINC00365 acts as a vital part in facilitating CRC progression and might play as a therapeutic target for patients with CRC.     

MicroRNA-27 promotes the differentiation of odontoblastic cell by targeting APC and activating Wnt/β-catenin signaling

MicroRNAs (miRNAs) play an essential role in regulating cell differentiation either by inhibiting mRNA translation or by inducing its degradation. However, the role of miRNAs in odontoblastic cell differentaion is largely unknown. In the present study, we demonstrate that the expression of miR-27 was significantly increased during MDPC-23 odontoblastic cell differentiation. Furthermore, the up-regulation of miR-27 promotes the differentiation of MDPC-23 odontoblastic cells and accelerates mineralization without cell proliferation. In addition, our results of target gene prediction revealed that the mRNA of adenomatous polyposis coli (APC) associated with Wnt/β-catenin signaling pathway has miR-27 binding site in the its 3′ UTR and is suppressed by miR-27. Subsequentially, the down-regulated APC by miR-27 triggered the activation of Wnt/β-catenin signaling through accumulation of β-catenin in the nucleus. Our data suggest that miR-27 promotes MDPC-23 odontoblastic cell differentiation by targeting APC and activating Wnt/β-catenin signaling. Therefore, miR-27 might be considered a critical candidate as an odontoblastic differentiation molecular target for the development of miRNA based therapeutic agents in the dental medicine.