m6A modification of CDC5L promotes lung adenocarcinoma progression through transcriptionally regulating WNT7B expression.

Cell division cycle 5-like (CDC5L) protein is implicated in the development of various cancers. However, its role in the progression of lung adenocarcinoma (LUAD) remains uncertain. Our findings revealed frequent upregulation of CDC5L in LUAD, which correlated with poorer overall survival rates and advanced clinical stages. In vitro experiments demonstrated that CDC5L overexpression stimulated the proliferation, migration, and invasion of LUAD cells, whereas CDC5L knockdown exerted suppressive effects on these cellular processes. Furthermore, silencing CDC5L significantly inhibited tumor growth and metastasis in a xenograft mouse model. Mechanistically, CDC5L activates the Wnt/ß-catenin signaling pathway by transcriptionally regulating WNT7B, thereby promoting LUAD progression. Besides, METTL14-mediated m6A modification contributed to CDC5L upregulation in an IGF2BP2-dependent manner. Collectively, our study uncovers a novel molecular mechanism by which the m6A-induced CDC5L functions as an oncogene in LUAD by activating the Wnt/ß-catenin pathway through transcriptional regulation of WNT7B, suggesting that CDC5L may serve as a promising prognostic marker and therapeutic target for LUAD.

LINC01605 promotes malignant phenotypes of cervical cancer via miR-149-3p/WNT7B axis.

BACKGROUND: Long non-coding RNAs (LncRNA) play a pivotal role in the progression of various malignancies. Despite recent identification as an oncogene associated with tumorigenesis. The precise role of LINC01605 in cervical cancer (CC) remains unclear. Therefore, the objective of this study was to investigate the influence of LINC01605 on proliferation and invasion of CC cells, while also exploring its potential underlying mechanisms. METHODS: The expression of LINC01605 in CC cell lines was analyzed using the TCGA database and qRT-PCR. Various assays, including CCK-8 and transwell analysis, were conducted on CC cells to assess the influence of LINC01605 on their proliferation, migration, and invasion capabilities. Bioinformatics and dual luciferase reporter gene assays were employed to analyze the target genes of LINC01605 and miR-149-3p. To further investigate the mechanism of action, transfection and investigation were performed using specific siRNA, miRNA mimics, or inhibitors. RESULTS: The expression of LINC01605 exhibited a significant increase in CC cell lines, and this upregulation was associated with an unfavorable prognosis. Modulating the expression of LINC01605, either by down-regulating or up-regulating it, exerted suppressive or stimulatory effects on the growth and invasion of HeLa and Siha cells. LINC01605 functioned as a competitive endogenous RNA (ceRNA) for miR-149-3p, with WNT7B being identified as a target gene of miR-149-3p. The involvement of LINC01605 in CC development is facilitated by its ability to regulate the expression of WNT7B through sequestering miR-149-3p. CONCLUSION: Our study demonstrates that LINC01605 acts as a competitive endogenous RNA in modulating the effects of WNT7B on the proliferation and invasion of CC cells by sequestering miR-149-3p. This research provides novel insights into the involvement of LINC01605 in the advancement of CC.

Plasma Wnt7b protein in rheumatoid arthritis: Detection of interstitial lung disease.

OBJECTIVE: To determine the plasma level of Wingless-related integration site 7b (Wnt7b) protein in rheumatoid arthritis (RA) patients (with and without interstitial lung disease (ILD)) and in idiopathic pulmonary fibrosis (IPF) patients and its relationship with RA disease activity and/or severity of pulmonary fibrosis. To assess the validity of plasma Wnt7b for the detection of ILD among RA patients. METHOD: This case-control study included 128 subjects (32 RA-ILD, 32 RA, 32 IPF, and 32 healthy controls). RA and RA-ILD Patients were evaluated for disease activity by DAS28 and disease activity grades were recorded according to DAS28 grades. Laboratory parameters as Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid Factor (RF), Anti-citrullinated peptide (Anti-CCP) were recorded. Plasma Wnt7b levels were measured by ELISA. Diagnosis of pulmonary fibrosis (for RA-ILD and IPF patients) was done by high resolution computed tomography (HRCT) and its severity was assessed mainly by pulmonary function test using forced vital capacity (FVC) grading. RESULTS: Comparison of Wnt7b plasma levels showed a significant difference between the studied groups with the P-value < 0.018 (RA-ILD had the highest levels). Post hoc analysis revealed a significant difference in Wnt7b plasma levels between RA-ILD and IPF groups (P = 0.008). Also, RA-ILD and control groups had a significant difference (P = 0.039). However, there was a non-significant relationship between Wnt7b plasma levels and RA disease activity as well as the severity of pulmonary fibrosis. ROC curve analysis for the plasma Wnt7b levels revealed that a level  ≥285.1 pg/ml had a sensitivity of 87.5% and a specificity of 43.8% for the detection of ILD in RA patients with positive likelihood ratio of 1.56 and negative likelihood ratio of 0.29. CONCLUSION: RA-ILD patients had significantly higher plasma Wnt7b levels than the controls and IPF patients. These data suggest that the Wnt7b secretion is augmented by the concomitant presence of RA with pulmonary fibrosis. In addition, plasma Wnt7b may be used as a highly sensitive test for the detection of immunologically induced fibrotic changes in lung tissue among RA patients.

Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway.

Long noncoding RNAs (lncRNAs) are known to participate in the pathological process of cardiac hypertrophy. This study aimed to investigate the function of the lncRNA, myosin heavy-chain associated RNA transcript (Mhrt), in cardiac hypertrophy and its possible mechanism of action. Adult mouse cardiomyocytes were treated with angiotensin II (Ang II) and transfected with Mhrt; cardiac hypertrophy was evaluated by estimating atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy-chain levels, and cell surface area by reverse transcription-quantitative polymerase chain reaction, western blotting, and immunofluorescence staining. The interaction between the Mhrt/Wnt family member 7B (WNT7B) and miR-765 was assessed using a luciferase reporter assay. Rescue experiments were performed by analyzing the role of the miR-765/WNT7B pathway underlying the function of Mhrt. The results indicated that Ang II induced hypertrophy of cardiomyocytes; however, overexpression of Mhrt alleviated the Ang II-induced cardiac hypertrophy. Mhrt acted as a sponge for miR-765 to regulate the expression of WNT7B. Rescue experiments revealed that the inhibitory effect of Mhrt on myocardial hypertrophy was abolished by miR-765. Additionally, the knockdown of WNT7B reversed the suppression of myocardial hypertrophy induced by downregulating miR-765. Taken together, Mhrt alleviated cardiac hypertrophy by targeting the miR-765/WNT7B axis.

circPTK2 promotes proliferation, migration and invasion of trophoblast cells through the miR-619/WNT7B pathway in preeclampsia.

It has been shown that the circular RNA (circRNA) circPTK2 modulates many types of diseases. However, the possible functions as well as the molecular mechanisms of circPTK2 in preeclampsia (PE) and their effects on trophoblast are unknown. Herein, we obtained the placental tissues from 20 pregnant women with PE who delivered in the Yueyang Maternal Child Medicine Health Hospital between 2019 and 2021 to serve as the PE group, and a normal group was composed of 20 healthy pregnant women with normal prenatal examinations. The circPTK2 level was significantly reduced in tissues from the PE group. The expression and localization of circPTK2 were verified using RT-qPCR. CircPTK2 silencing inhibited HTR-8/SVneo growth and migration in vitro. To investigate the underlying mechanism of circPTK2 in PE progression, dual-luciferase reporter assays were conducted. It was found that circPTK2 and WNT7B could bind directly to miR-619, and that circPTK2 affected WNT7B expression by sponging miR-619. To conclude, this study identified the functions and mechanisms of the circPTK2/miR-619/WNT7B axis in PE progression. In this way, circPTK2 has the potential to be used both in diagnostic and therapeutic settings for PE.

Wnt7b: Is It an Important Factor in the Bone Formation Process after Calvarial Damage?

OBJECTIVE: Previous studies found that Wnt7b played a unique and indispensable role in the process of osteoblast differentiation and could accelerate the repair of bone loss. However, what is the role of Wnt7B in osteogenesis? Is it possible to increase the expression of Wnt7b to promote the repair of skull defects? This study intends to provide the basic data for the application of Wnt7b in the treatment of craniomaxillofacial bone repair. METHODS: A calvarial defect mouse model that could induce Wnt7b overexpression was established. Three days after the operation, the mice in each group were intraperitoneally injected with tamoxifen (TAM) or oil eight times every other day. There were three groups. The TAMc group (R26Wnt7b/Wnt7b) was injected with tamoxifen. The Oil group (3.2 kb Col1-Cre-ERT2; R26Wnt7b/Wnt7b) was injected with oil. The TAM group (3.2 kb Col1-Cre-ERT2; R26Wnt7b/Wnt7b) was injected with tamoxifen. Four weeks after the surgery, micro-CT scanning was utilized to observe new bone formation and compare the ability to form new bone around the defect area. RESULTS: Four weeks after the operation, bone healing conditions were measured by using micro-CT scanning. The defect area of the TAM group was smaller than that of the other groups. Similarly, the bone volume fraction (BV/TV) significantly increased (p < 0.05), the trabecular number (Tb.N) increased, and the trabecular separation (Tb.Sp) decreased. CONCLUSIONS: Wnt7b participates in the bone formation process after calvarial damage, indicating the important role of Wnt7b in osteogenesis.

Amelioration of Lung Fibrosis by Total Flavonoids of Astragalus via Inflammatory Modulation and Epithelium Regeneration.

Idiopathic Pulmonary Fibrosis (IPF) is identifiable by the excessive increase of mesenchyme paired with the loss of epithelium. Total flavonoids of Astragalus (TFA), the main biologically active ingredient of the traditional Chinese medicine, Astragalus membranaceus (Huangqi), shows outstanding effects on treating pulmonary disorders, including COVID-19-associated pulmonary dysfunctions. This study was designed to evaluate the efficacy of TFA on treating pulmonary fibrosis and the possible mechanisms behind these effects. A549 cells were treated with TGF-[Formula: see text]1 and TFA to observe the potential effects of TFA on regulating alveolar epithelial cell proliferation, TGF-[Formula: see text]1-induced EMT, and the underlying mechanisms in vitro. Then, mouse pulmonary fibrosis was induced with a single intra-tracheal injection of bleomycin, and TFA was administrated by i.p. injection. Lung fibrosis was evaluated through histological and molecular analyses, and the possible mechanisms were explored using immunological methods. The results demonstrated that TFA could promote cell proliferation but inhibit TGF-[Formula: see text]1-induced EMT on A549 cells. TFA attenuated BLM-induced pulmonary fibrosis in mice by modulating inflammatory infiltration and M2 macrophage polarization; it furthermore modulated EMT through regulating the TGF-[Formula: see text]1/Smad pathway. In addition, TFA augmented the expression of the Wnt7b protein, which plays an important role in alveolar epithelium reparation. In conclusion, TFA alleviated bleomycin-induced mouse lung fibrosis by preventing the fibrotic response and increasing epithelium regeneration.

Overexpression of Wnt7b antagonizes the inhibitory effect of dexamethasone on osteoblastogenesis of ST2 cells.

INTRODUCTION: It is well established that glucocorticoid-induced osteoporosis is highly associated with preosteoblast differentiation and function. This study is based on the premise that Wnt7b can promote bone formation through Wnt signalling pathway because it can stimulate preosteoblast differentiation and increase its activity. However, it is unknown whether Wnt7b can rescue the inhibited osteoblast differentiation and function caused by exogenous glucocorticoid. MATERIAL AND METHODS: In this study we used Wnt7b overexpression ST2 cells to explore whether Wnt7bcan rescue the inhibited osteoblast differentiation and function, which can provide strong proof to investigate a new drug for curing the glucocorticoid induced osteoporosis. RESULTS/CONCLUSION: We found that Wnt7b can rescue the suppressed osteoblast differentiation and function without cell viability caused by dexamethasone.

Identification of antibody against wingless­type MMTV integration site family member 7B as a biliary cancer tumor marker.

Biliary cancer has a poor prognosis due to a lack of specific biomarkers and difficulty in diagnosis. The present study aimed to identify serum tumor markers for the diagnosis of biliary cancer via serological identification of antigens by recombinant cDNA expression cloning. Wingless­type MMTV integration site family, member 7 (WNT7B) was identified as a target antigen, suggesting the presence of serum antibodies against this antigen. Deletion mutants were then prepared to evaluate the response to serum antibodies. When serum antibody levels against WNT7B deletion mutants (WNT7B-92­2, -92­260, 2-260 and 184-260) were examined using amplified luminescence proximity homogeneous assay­linked immunosorbent assay, the levels of the antibody against WNT7B with amino acids 184­260 were higher in patients with biliary cancer than in healthy donors. Therefore, the region covering residues 184­260 of WNT7B was decomposed to generate seven peptides, and the levels of antibodies against these peptides were measured. Among them, the levels of antibodies against WNT7B234­253 and WNT7B244­260 were higher in patients with biliary cancers than in healthy donors (WNT7B234­253, P=0.0009; WNT7B244­260, P=0.0005). The levels of the antibody against the former were specifically high in patients with biliary cancer but not in those with esophageal, gastric, colorectal, pancreatic, or breast cancer. Furthermore, analysis by the cutoff value of WNT7B234­253 defined by ROC showed a high sensitivity of 70% in patients with biliary cancer. Therefore, the serum levels of the antibody against WNT7B234­253 may be useful as a marker for biliary cancer diagnosis.

Inhibition of Wnt7b reduces the proliferation, invasion, and migration of colorectal cancer cells.

OBJECTIVE: Colorectal cancer is one of the most common gastrointestinal tumors. The role of Wnt7b as a ligand of the Wnt signaling pathway in colorectal cancer remains to be studied. Through bioinformatics online analysis, we found that Wnt7b is abnormally highly expressed in a variety of gastrointestinal tumors. This study mainly explored the effects of Wnt7b regulating the Wnt/ß-catenin signaling pathway on the proliferation, migration, and invasion of SW480 cells in colorectal cancer. METHODS AND RESULTS: Applying the TCGA data set, Wnt7b was found to be highly expressed in most gastrointestinal tumor samples. Real-time quantitative PCR(q-PCR), Western blotting(WB) results showed that Wnt7b was significantly higher expressed in colorectal cancer cell lines compared with normal intestinal epithelial cells. SW480 cells transfected with the sh-Wnt7b showed successful knockdown of Wnt7b. MTT colorimetry showed the proliferation ability of sh-Wnt7b group decreased significantly compared with the non-transfected group. The results of double staining flow cytometry showed that the sh-Wnt7b group had more apoptosis. Cell scratch test showed that the cell migration rate of sh-wnt7b group considerably reduced. The Transwell invasion experiment demonstrated that the number of cell invasions in the sh-Wnt7b group decreased significantly. After SW480 cells was transfected with sh-Wnt7b, the protein levels of ß-catenin, CCND1, and CD44 in this group of cells were detected to be reduced by WB, and the same results were obtained by q-PCR detection of mRNA. CONCLUSION: Wnt7b is highly expressed in colorectal cancer cells, which may affect the proliferation, migration, and invasion of colorectal cancer cells by activating the Wnt/ß-catenin signaling pathway.

miR-342-5p inhibits odonto/osteogenic differentiation of human dental pulp stem cells via targeting Wnt7b.

OBJECTIVE: Human dental pulp stem cells (hDPSCs) constitute a promising source of stem cells in tissue engineering. However, the molecular mechanism of differentiation in hDPSCs remains largely unclear. MicroRNAs (miRNAs) play crucial roles in lineage-specific differentiation of stem cells. The present study investigated the function of miRNA-342-5p in the odonto/osteogenic differentiation of hDPSCs. METHODS: The miRNA array profiling and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) revealed the expression of miR-342-5p during odonto/osteogenic differentiation of hDPSCs. hDPSCs were treated with miR-342-5p mimic and inhibitor to investigate the regulatory roles of miR-342-5p in the differentiation of hDPSCs. Moreover, miR-342-5p inhibitor and small interference RNA (siRNA) targeting Wnt7b were applied to explore the regulatory mechanism of miR-342-5p. RESULTS: Downregulated miR-342-5p was observed during odonto/osteogenic differentiation of hDPSCs. The overexpression of miR-342-5p inhibited the odonto/osteogenic potential of DPSCs, as indicated by low levels of alkaline phosphatase activity, calcium deposition formation, and odonto/osteogenic differentiation markers, whereas silencing of miR-342-5p exhibited the opposite effect. When co-treated with siRNA targeting Wnt7b and miR-342-5p inhibitor in hDPSCs, the odonto/osteogenic potential and activation of Wnt7b/ß-catenin pathway were attenuated. CONCLUSIONS: This study showed that miR-342-5p inhibits the odonto/osteogenic differentiation of hDPSCs by interfering with Wnt/ß-catenin signaling via targeting Wnt7b.

Canonical WNT Signaling Activated by WNT7B Contributes to L-HBs-Mediated Sorafenib Resistance in Hepatocellular Carcinoma by Inhibiting Mitophagy.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, with hepatitis B virus (HBV) infection accounting for over half of all cases. HBV leads to the development of HCC according to a body of literature. Our previous research and other studies also suggest that HBV causes chemotherapeutic treatment resistance, however, the mechanism is uncertain. The WNT family, which encodes secreted signaling molecules, has been linked to carcinogenesis in a variety of malignancies, including HCC. However, little is known regarding WNT7B, a WNT ligand, in the development of HCC and HBV-induced chemoresistance. In this study, the bioinformatics analysis and immunohistochemistry (IHC) staining of clinical samples revealed that WNT7B was overexpressed in HBV-associated HCC tissues versus nontumor liver tissues, which was related to HCC patient survival. Further study in vitro showed that WNT7B and its receptor frizzled-4 (FZD4) were upregulated in response to large hepatitis B surface antigens (L-HBs). L-HBs increased canonical WNT signaling in HCC cells through WNT7B/FZD4. According to functional experiments, WNT7B enhanced the cell proliferation and metastasis in HCC. In vivo and in vitro studies investigated whether L-HBs induced sorafenib resistance by WNT7B in HCC. Interestingly, L-HBs suppressed sorafenib-induced mitophagy by increasing WNT7B/CTNNB1 signaling, resulting in chemoresistance. The findings revealed that WNT7B could be a promising molecular therapeutic target as well as a predictor of sorafenib resistance in HBV-related HCC. The suppression of HBV structural proteins such as L-HBs may play a crucial role in systemic chemotherapy resistance in HBV-associated HCC.

Niche-mediated repair of airways is directed in an occupant-dependent manner.

In injured airways of the adult lung, epithelial progenitors are called upon to repair by nearby mesenchymal cells via signals transmitted through the niche. Currently, it is unclear whether repair is coordinated by the mesenchymal cells that maintain the niche or by the airway epithelial cells that occupy it. Here, we show that the spatiotemporal expression of Fgf10 by the niche is primarily orchestrated by the niche's epithelial occupants-both those that reside prior to, and following, injury. During homeostasis, differentiated airway epithelial cells secrete Sonic hedgehog (Shh) to inhibit Fgf10 expression by Gli1+ peribronchial mesenchymal cells in the niche. After injury, remaining epithelial cells produce Wnt7b to induce Fgf10 expression in airway smooth muscle cells in the niche. We find that this reliance on a common activator of airway epithelial stem cells also allows for the recruitment of remote stem cell populations when local populations have been exhausted.

Tumor specificity of WNT ligands and receptors reveals universal squamous cell carcinoma oncogenes.

BACKGROUND: The WNT signal pathway has myriad family members, which are broadly involved in embryonic development and human cancer. Over-activation of WNT-ß-Catenin signaling promotes cancer cell proliferation and survival. However, how diverse components of WNT signaling specifically engaged in distinct tumor types remains incompletely understood. METHODS: We analyzed the transcriptomic profiling of WNT ligands and receptors/co-receptors among 26 different tumor types to identify their expression pattern, and further verified these results using clinical oral squamous cell carcinoma (OSCC) and lung squamous cell carcinoma (LUSC) samples. At the same time, we also detected WNT7B expression in oral inflammation and carcinoma, and constructed stable WNT7B knockdown OSCC cell lines to study the effects of WNT7B on the cell migration and invasion ability. RESULTS: We found a group of tumor-specific WNT members, including a panel of squamous cell carcinomas (SCCs) specific upregulated WNT ligands and receptors, WNT5A, WNT7B, FZD7 and GPC1. We further revealed a significant correlation between these protein expression characteristics and clinical outcomes of OSCC and LUSC patients. Moreover, WNT7B was demonstrated to contribute to the development of oral chronic inflammation and OSCC, partly due to promoting the invasion ability of tumor cells. CONCLUSIONS: These results demonstrate that the function of WNT ligands and receptors in specific tumors depends on the origination of tumor tissue type. Collectively, they support the use of WNT components as a highly specific target for pan-tissue-type originated tumors.

An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates.

Within the central nervous system, Wnt7a/b are unambiguously discriminated from other Wnt ligands by an endothelial receptor complex made of the glycosylphosphatidylinositol (GPI)-anchored Reck and the adhesion G protein-coupled receptor (GPCR) Gpr124. Reck is a Wnt7a/b-specific receptor, while Gpr124 facilitates the delivery of Reck-bound Wnt7a/b ligands to Frizzled, through partially characterized mechanisms. We report that, in zebrafish, the Gpr124-Frizzled interactions are dominated by intracellular scaffolds that exploit the striking molecular mimicry between Gpr124 and Frizzled intracellular domains (ICDs): an internal Dvl-binding motif and a C-terminal ETTV motif that recruits Dlg4 and Magi3. By contrast, mammalian Gpr124 receptors exhibit an ICD-independent interaction mechanism governed by species-specific attributes of their transmembrane and extracellular domains. This mechanism seemingly evolved to replace the Dvl-mediated mechanism. By contrasting zebrafish, mouse, and human Gpr124, this study provides insights into the evolution of Gpr124/Reck function across the vertebrate clade, a receptor complex uniquely implicated in Wnt ligand-specific cellular responses.

The miR-34a/WNT7B modulates the sensitivity of cholangiocarcinoma cells to p53-mediated photodynamic therapy toxicity.

Photodynamic therapy (PDT) provides apparent survival benefits for unresectable cholangiocarcinoma patients. the insufficient sensitivity of cancer cell to PDT treatment limits the clinical application. In this study, according to the GEO datasets, WNT7B expression was decreased by PDT treatment in cholangiocarcinoma samples. In cholangiocarcinoma cells, PDT treatment inhibited Wnt signaling, suppressed cell viability, and enhanced cell apoptosis. Within cholangiocarcinoma cells, PDT treatment induced p53 and miR-34a-5p expression. Under PDT treatment, p53 knockdown downregulated miR-34a-5p expression, whereas the inhibition effect of p53 knockdown on miR-34a-5p could be partially attenuated by agomir-34a-5p. p53 knockdown enhanced cell viability and suppressed cell apoptosis, whereas miR-34a-5p overexpression exerted opposite effects; miR-34a-5p overexpression partially attenuated p53 knockdown effects on PDT-treated cholangiocarcinoma cells. miR-34a-5p directly targeted WNT7B and inhibited WNT7B expression. Under PDT treatment, WNT7B knockdown inhibited the Wnt signaling and cell viability, and promoted cell apoptosis, while miR-34a-5p suppression showed the opposite trends; WNT7B knockdown partially attenuated miR-34a-5p inhibition effects on PDT-treated cholangiocarcinoma cells. In conclusion, PDT treatment induces p53-induced miR-34a transactivation to inhibit cholangiocarcinoma cell proliferation; the miR-34a-5p/WNT7B axis and Wnt signaling are involved.

WNT7B represses epithelial-mesenchymal transition and stem-like properties in bladder urothelial carcinoma.

BACKGROUND: Recurrence and metastasis are the major problems of bladder urothelial carcinoma, which mainly attribute to tumor cell stemness, epithelial-mesenchymal transition (EMT) and chemoresistance. METHODS: TCGA database was interrogated for gene mRNA expression in bladder urothelial carcinoma samples. CCLE database was interrogated for gene mRNA expression in bladder cancer cell lines. The correlation between two genes was analyzed by Pearson statistics. 37 human bladder urothelial carcinoma specimens were adopted for immunohistochemistry. Bladder cancer cells RT4, J82, and UM-UC-3 were used to carry out loss and gain of function studies. Kaplan-Meier method was performed to analyze the overall survival. FINDINGS: WNT7B is downregulated in high-grade bladder urothelial carcinomas. Low WNT7B expression is associated with unfavorable prognosis. Loss and gain of function studies showed that WNT7B inhibits bladder urothelial carcinoma cell EMT, stem-like properties and chemoresistance. FZD5, a specific receptor for WNT7B, mediates WNT7B signaling. ELF3 is a downstream component of WNT7B signaling, which transcriptionally modulates NOTCH1, a tumor suppressor in bladder urothelial carcinoma. INTERPRETATION: These data demonstrate that WNT7B/FZD5-ELF3-NOTCH1 signaling functions as a tumor-suppressing pathway in bladder urothelial carcinoma.

LncRNA MALAT1 mediates osteogenic differentiation in osteoporosis by regulating the miR-485-5p/WNT7B axis.

Introduction: Accumulating evidence demonstrates that long non-coding RNAs (lncRNAs) are associated with the development of osteoporosis. Methods: This study aimed to investigate the effects of MALAT1 on osteogenic differentiation and cell apoptosis in osteoporosis. MALAT1 level, detected by RT-qPCR, was downregulated in hindlimb unloading (HU) mice and simulated microgravity (MG)-treated MC3T3-E1 cells. Moreover, osteogenic differentiation-related factor (Bmp4, Col1a1, and Spp1) levels were measured by RT-qPCR and Western blot. ALP activity was detected, and ALP staining was performed. Cell apoptosis was assessed by flow cytometry. Results: The results revealed that MALAT1 upregulated the expression of Bmp4, Col1a1, and Spp1, and enhanced ALP activity. Knockdown of MALAT1 suppressed their expression and ALP activity, suggesting that MALAT1 promoted osteogenic differentiation. Additionally, MALAT1 inhibited apoptosis, increased Bax and caspase-3 levels, and decreased Bcl-2 level. However, knockdown of MALAT1 had opposite results. In MG cells, MALAT1 facilitated osteogenic differentiation and suppressed apoptosis. Furthermore, miR-485-5p was identified as a target of MALAT1, and WNT7B was verified as a target of miR-485-5p. Overexpression of miR-485-5p rescued the promotion of osteogenic differentiation and the inhibition of apoptosis induced by MALAT1. Knockdown of WNT7B abolished the facilitation of osteogenic differentiation and the suppression of apoptosis induced by downregulation of miR-485-5p. Discussion: In conclusion, MALAT1 promoted osteogenic differentiation and inhibited cell apoptosis through the miR-485-5p/WNT7B axis, which suggested that MALAT1 is a potential target to alleviate osteoporosis.

circ_0082375 promotes the progression of glioma by regulating Wnt7B.

Circular RNAs contribute to the progression of glioma. However, the biological role and underlying mechanism of circ_0082375 in glioma remain unclear. Quantitative real-time PCR and Western blot assay were used to evaluate the expression levels of circ_0082375, microRNA-485-5p, and Wnt family member 7B (Wnt7B). The overall survival of glioma patients was estimated by the Kaplan-Meier curve. Cell proliferation, apoptosis, invasion, and migration were detected by cell counting kit-8, 5-ethynyl-2 -deoxyuridine (EdU) staining, flow cytometry, and transwell assays, respectively. Glucose level and lactate production were determined using glucose and lactate assay kits. In vitro angiogenesis assay was used to evaluate the angiogenesis of glioma cells. The interaction between microRNA (miR)-485-5p and circ_0082375 or Wnt family member 7B (Wnt7B) was verified by dual-luciferase reporter and RNA immunoprecipitation assays. A xenograft model was used to verify the function of circ_0082375 in vivo. circ_0082375 was upregulated in glioma tissues, and it was closely related to the prognosis of glioma patients. circ_0082375 knockdown suppressed cell proliferation, migration, invasion, angiogenesis, glycolysis, and epithelial-mesenchymal transition (EMT), and promoted cell apoptosis in glioma cells. irc_0082375 was a sponge of miR-485-5p, which directly targeted Wnt7B. Knockdown of circ_0082375 inhibited the malignancy, angiogenesis, and glycolysis of glioma cells in vitro by sponging miR-485-5p. Besides, circ_0082375 knockdown hampered the growth of glioma growth by regulating the miR-485-5p/Wnt7B axis in vivo. Altogether, circ_0082375 regulated miR-485-5p/Wnt7B axis to promote the malignancy, angiogenesis, and glycolysis of glioma cells, thereby contributing to the progression of glioma.

Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring.

The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation; however, the inhibitory effect of the Wnt pathway in osteoclastogenesis is largely unknown. Here, we demonstrate that Wnt7b, a potent Wnt ligand that enhances bone formation and increases bone mass, also abolishes osteoclastogenesis in vitro. Importantly, enforced expression of Wnt in bone marrow macrophage lineage cells significantly disrupts osteoclast formation and activity, which leads to a dramatic increase in bone mass. Mechanistically, Wnt7b impacts the glucose metabolic process and AKT activation during osteoclastogenesis. Thus, we demonstrate that Wnt7b diminishes osteoclast formation, which will be beneficial for osteoporosis therapy in the future.