Integration Site Family Member 5A Research Articles

Wnt5a-Ror2 signaling mediates root resorption

This study aimed to investigate the role of wingless-type MMTV integration site family member 5a (Wnt5a)-receptor tyrosine kinase-like orphan receptor 2 (Ror2) signaling in root resorption. The messenger RNA (mRNA) expression of Wnt5a, Ror2, and RANKL in periodontal ligament cells (PDLCs) under compression force (CF) with or without Ror2 small interfering RNA (siRNA) were measured by quantitative reverse transcription-polymerase chain reaction, and these proteins released into culture supernatants were measured using enzyme-linked immunosorbent assay. Then these PDLC-conditioned media under CF with or without Ror2 siRNA were used to culture osteoclast precursors to detect osteoclastogenesis effects via tartrate-resistant acid phosphatase staining. In invivo studies, the odontoclast number and the root resorption volume under excessive CF with or without Ror2 siRNA were investigated by tartrate-resistant acid phosphatase immunohistochemical staining and microcomputed tomography. The protein levels for Wnt5a, Ror2, and receptor activator of nuclear factor-kappa B ligand (RANKL) in the periodontal ligament tissues were also detected using immunohistochemical staining. Finally, the odontoclast number, root resorption volume, and the mRNA and protein expressions were compared between immature and mature teeth. The mRNA production and protein release level of Wnt5a, Ror2, and RANKL increased after CF, whereas they were significantly downregulated with Ror2 siRNA. The osteoclast number increased treating with culture medium from PDLC applying CF, but the increase was inhibited after adding Ror2 siRNA. In the animal model, the odontoclast number and root resorption volume significantly increased in the CF group but decreased in the CF with the Ror2 siRNA group. The protein levels of Wnt5a, Ror2, and RANKL in periodontal ligament were upregulated under excessive CF, and the pathway was inhibited with Ror2 siRNA. In the immature tooth group, the odontoclast number, root resorption volume, and the mRNA and protein expressions of Wnt5a-Ror2 signaling were reduced. Wnt5a-Ror2 signaling in PDLCs enhanced by excessive CF could promote RANKL release and induce precursor differentiation, partly leading to increased odontoclast activity and ultimate root resorption. The less resorption of the immature tooth may be due to odontoclastogenesis inhibition by decreased expression of Wnt5a-Ror2 signaling.

Increased Secreted Frizzled-Related Protein 5 mRNA Expression in the Adipose Tissue of Women with Nonalcoholic Fatty Liver Disease Associated with Obesity

Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipocytokine secreted by adipocytes that seems to be linked with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the role of the SFRP5-wingless-MMTV integration site family member 5a (WNT5A) pathway, closely related to adipogenesis, in subcutaneous (SAT) and visceral adipose tissues (VAT) and its relationship with obesity-related NAFLD. Our cohort was composed of 60 women with morbid obesity (MO), who underwent hypocaloric diet, subclassified according to their hepatic histopathology and 15 women with normal weight. We observed increased SFRP5 mRNA expression in VAT and lower WNT5A expression in SAT in MO compared to normal weight. We found elevated SFRP5 expression in nonalcoholic steatohepatitis (NASH) in SAT and in mild simple steatosis (SS) and NASH in VAT. We observed higher WNT5A expression in SS compared to normal liver in SAT, and a peak of WNT5A expression in mild SS. To conclude, we reported increased SFRP5 mRNA expression in SAT and VAT of NAFLD-related to obesity subjects, suggesting an implication of the SFRP5-WNT5A pathway in NAFLD pathogenesis, probably due to the adipose tissue-liver axis. Since the mechanisms by which this potential interaction takes place remain elusive, more research in this field is needed.

Association between bone turnover markers and periodontitis: A population-based cross-sectional study.

To examine the associations between bone turnover markers and periodontitis in two cross-sectional population-based studies. We used data from two independent adult samples (N= 4993), collected within the Study of Health in Pomerania project, to analyse cross-sectional associations of N-procollagen type 1 amino-terminal propeptide (P1NP), C-terminal cross-linking telopeptide, osteocalcin, bone-specific alkaline phosphatase (BAP), fibroblast growth factor 23, wingless-type mouse mammary tumour virus integration site family member 5a (WNT5A), and sclerostin values with periodontitis. Confounder-adjusted gamma and fractional response regression models were applied. Positive associations were found for P1NP with mean pocket probing depth (PPD; ; 95% confidence interval [CI]: 1.001-1.015), mean clinical attachment loss (mean CAL; ; 95% CI: 1.011-1.044), and proportion of sites with bleeding on probing (%BOP; ; 95% CI: 1.005-1.109). Similar associations were seen for BAP with %BOP ( ; 95% CI: 1.042-1.205), proportion of sites with PPD ≥4 mm (%PPD4) ( ; 95% CI: 1.005-1.161), and sclerostin with %BOP ( ; 95% CI: 1.005-1.704). WNT5A was inversely associated with mean PPD ( ; 95% CI: 0.920-0.993) and %PPD4 ( ; 95% CI: 0.642-0.982). This study revealed scattered associations of P1NP, BAP, WNT5A, and sclerostin with periodontitis, but the results are contradictory in the overall context. Associations reported in previous studies could not be confirmed.

Increased Level of Serum Wingless-Type Mouse Mammary Tumor Virus Integration Site Family Member 5a in Patients with Cutaneous Lichen Planus.

PurposeCutaneous lichen planus (CLP) is an autoinflammatory skin disorder, and it is associated with metabolic syndrome. Wingless-type mouse mammary tumor virus integration site family member 5a (Wnt5a) is a potential factor in metabolic complications and it was shown to be upregulated in CLP lesions. Whether Wnt5a is altered in the circulation of patients with CLP is unclear. This study aimed to measure serum Wnt5a level in patients with CLP and to assess its relationship with body mass index (BMI).MethodsWe included 46 adult patients with CLP and 38 healthy adults as control. Serum Wnt5a was measured using enzyme-linked immunosorbent assay.ResultsThe mean serum Wnt5a was significantly higher in patients than controls (all P-value <0.001). The mean serum Wnt5a levels in obese (BMI between 30 and 40) patients were significantly higher than lean (BMI between 20 and 25) patients (P-value <0.001). Compared to lean patients with CLP, the concentration of serum Wnt5a levels was increased gradually with BMI score (all P-value <0.05).ConclusionSerum Wnt5a might be a potential biomarker for CLP and it was associated with BMI. An increase in serum Wnt5a may contribute to the development of metabolic comorbidity in CLP patients.

The Emerging Role of Sfrp5 and Wnt5a in the Pathogenesis of Obesity: Implications for a Healthy Diet and Lifestyle.

In recent decades, the prevalence of obesity has risen dramatically worldwide among all age groups. Obesity is characterized by excess fat accumulation and chronic low-grade inflammation. The adipose tissue functions as a metabolically active endocrine organ secreting adipokines. A novel duo of adipokines, the anti-inflammatory secreted frizzled-related protein 5 (Sfrp5) and the proinflammatory wingless type mouse mammary tumor virus (MMTV) integration site family member 5A (Wnt5a), signal via the non-canonical Wnt pathway. Recent evidence suggests that Sfpr5 and Wnt5a play a key role in the pathogenesis of obesity and its metabolic complications. This review summarizes the current knowledge on the novel regulatory system of anti-inflammatory Sfrp5 and pro-inflammatory Wnt5a, and their relation to obesity and obesity-related complications. Future studies are required to investigate the potential role of Sfrp5 and Wnt5a as biomarkers for monitoring the response to lifestyle interventions and for predicting the development of cardiometabolic risk factors. These adipokines may also serve as novel therapeutic targets for obesity-related disorders.

Dual role of WNT5A in promoting endothelial differentiation of glioma stem cells and angiogenesis of glioma derived endothelial cells.

Glioma is a devastating cancer with a rich vascular network. No anti-angiogenic treatment is available for prolonging the overall survival of glioma patients. Recent studies have demonstrated that the endothelial differentiation of glioma stem cells (GSCs) into glioma-derived endothelial cells (GDECs) may be a novel target for anti-angiogenic therapy in glioma; however, the underlying mechanisms of this process remain unknown. Here, we report that wingless-related integration site (WNT) family member 5A (WNT5A) plays significant roles in GSC endothelial differentiation and GDECs angiogenesis. WNT5A is preferentially secreted by GDECs, and inhibition of WNT5A suppresses angiogenesis and tumorigenesis in GDECs. Silencing of WNT5A in GDECs also disrupts the impact of GDECs on stimulating GSC endothelial differentiation. Frizzled-4 is a receptor that mediates the effect of WNT5A on GSC endothelial differentiation and angiogenesis of GDECs via GSK3β/β-catenin/epithelial-mesenchymal transition signalling. The shWNT5A@cRGD-DDD liposomes, targeting WNT5A, exert anti-angiogenic effects in vivo. In this study, we identified that WNT5A has a dual functional role in modulating the endothelial differentiation of GSCs and angiogenesis of GDECs, indicating that WNT5A is a potential target for anti-angiogenesis-based therapeutics in glioma.

Maternal Cytokines CXCL12, VEGFA, and WNT5A Promote Porcine Oocyte Maturation via MAPK Activation and Canonical WNT Inhibition.

Maternal regulatory factors endow the oocyte with developmental competence in vivo, which might be absent in current in vitro maturation (IVM) systems, thereby compromising oocyte quality. In the present study, by employing RNA sequencing data analysis, we expect to identify potential contributing factors to support porcine oocyte maturation through binding to their receptors on the oolemma. Here, C-X-C motif chemokine ligand 12 (CXCL12), vascular endothelial growth factor A (VEGFA), and Wingless-type MMTV integration site family member 5A (WNT5A), termed CVW, are selected and confirmed to be important maternal cytokines for porcine oocyte maturation. Combined supplementation of CVW promotes the nuclear maturation percentage from 57.2% in controls to 75.9%. More importantly, these maternal cytokines improve the developmental potential of matured oocytes by parthenogenesis, fertilization, and cloning, as their blastocyst formation efficiencies and total cell numbers are increased. CVW supplementation also enlarges perivitelline space and promotes cumulus expansion, which results in a more complete transzonal projection retraction on the zona pellucida, and a reduced incidence of polyspermy in fertilized oocytes. Meanwhile, inhibiting the CVW receptor-mediated signaling pathways severely impairs oocyte meiotic resumption and cumulus expansion during IVM. We further determine that maturation improvement by CVW is achieved through activating the MAPK pathway in advance and inhibiting the canonical WNT pathway at the end of the IVM period. These findings provide a new combination of three cytokines to promote the porcine IVM process, which also holds potential to be used in human assisted reproduction technologies as well as in other species.

Identification of Nonylphenol and Glucolipid MetabolismRelated Proteins in the Serum of Type 2 Diabetes Patients

To identify serum nonylphenol (NP) and glucolipid metabolism-related proteins in Type 2 diabetes (T2D) patients. We performed a hospital-based, case-control study in patients admitted to the Department of Endocrinology, Hospital of Zunyi Medical University, Zunyi City, China from Mar to Nov of 2014. The study included 112 T2D cases diagnosed in accordance with the 2013 WHO Expert Committee Diabetes Diagnosing Criteria, and 125 healthy individuals with normal fasting blood glucose (FBG) when receiving physical examination in the same period in the Municipal Physical Examination Center. Blood samples from subjects in the 2 groups underwent detection of biochemical indices, including FBG, blood fat, and NP. Glucolipid metabolism-related proteins, including estrogen receptor (ER), sterol regulatory element-binding protein-1c (SREBP-1c), wingless-type MMTV integration site family member 5a (Wnt5a), and peroxisome proliferator-activated receptor-γ (PPAR-γ). These indices were compared between the 2 groups to analyze the correlation between serum NP levels and glucolipid metabolic proteins. The subjects in the diabetes group had higher triglycerides (TG), total cholesterol (TC), NP, ER, SREBP-1c, Wnt5a, FBG, and TG levels than the healthy group, but lower levels of low-density lipoprotein cholesterol (LDL-C) and PPAR-γ than the healthy group. No significant differences in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were found between the two groups. The serum NP levels were shown to be positively correlated with SREBP-1c but negatively correlated with PPAR-γ. The serum NP levels of T2D patients is higher than the levels in healthy controls, and its levels correlate with SREBP-1c and PPAR-γ levels.

Maternal Inulin Supplementation Alters Hepatic DNA Methylation Profile and Improves Glucose Metabolism in Offspring Mice.

ScopeAs a prebiotic, inulin may have a protective effect on glucose metabolism. However, the mechanism of inulin treatment on glucose intolerance in offspring exposed to a maternal high-fat (HF) diet is still not clear. Here, we examined the hepatic DNA methylation profile to determine how maternal inulin supplementation modified glucose metabolism in offspring mice.ProceduresFemale mice were fed a HF diet, control diet (CON), or a HF diet with inulin supplementation (HF-inulin) during gestation and lactation. Upon weaning, pup livers were obtained. A hepatic genome DNA methylation array was performed.ResultsPups exposed to a maternal HF diet exhibited glucose intolerance and insulin resistance. Maternal inulin treatment moderated glucose metabolism. A DNA methylation array identified differentially methylated regions associated with 970 annotated genes from pups exposed to a HF diet in response to maternal inulin treatment. In particular, the wingless-type MMTV integration site family member 5A (Wnt5a) gene was hypermethylated, and the phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (Pik3c2a), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (Pik3c2b), and phosphoinositide-3-kinase regulatory subunit 2 (Pik3r2) genes were hypomethylated in inulin-treated pups. Consistently, hepatic Wnt5a gene expression was reduced and Pik3c2a, Pik3c2b, and Pik3r2 gene expression were increased in the inulin group.ConclusionMaternal inulin treatment improved glucose intolerance by changing DNA methylation and gene expression of Wnt5a and Pi3k in mice exposed to a maternal HF diet.

Wingless-type MMTV integration site family member 5a: a novel biomarker regulated in type 2 diabetes mellitus and diabetic kidney disease

ObjectivesType 2 diabetes mellitus (T2DM) is sustained by insulin resistance (IR) and reduced β-cell mass, which is largely due to insulin secretory dysfunction. Wnt5a protein is essential to islet formation and β-cell migration in the development of pancreas in vertebrates. Levels of the Wnt5a protein antagonist plasma secreted frizzled-related protein 5 (Sfrp5) were elevated in patients with T2DM. However, the association between Wnt5a, T2DM patients and diabetic kidney disease (DKD) is unknown. We aim to investigate the circulating Wnt5a levels in in different clinical stages of T2DM and evaluate its correlation of duration of diabetes mellitus chronic complication.MethodsA total of 329 participants (187 males, 142 females; age range 40 to 80 years) were enrolled in this study. Serum Wnt5a levels were measured by an enzyme-linked immunosorbent assay (ELISA). The demographic and clinical parameters evaluated in subjects with new onset T2DM, onset T2DM after treatment and DKD at different clinical phases.ResultsWnt5a was significantly down-regulated in newly diagnosed T2DM patients and gradually increased after 3 months of treatment. Interesting, serum wnt5a was gradually increased in patients with long-term diabetes and kidney disease compared to patients with T2DM and onset DKD.ConclusionsWe speculated that the Wnt5a protein might regulate islet function and be involved in the onset of diabetes as a protective factor. It may be one of the inflammatory factors adversely involved in the progression of diabetic nephropathy.

Wingless-type MMTV integration site family member5a is a key inhibitor of islet stellate cells activation.

Aims/IntroductionType 2 diabetes mellitus is a chronic metabolic disorder characterized by islet β‐cell dysfunction, which might result from the activation of islet stellate cells (ISCs). Our recent study showed that a specific population of ISCs is prone to be activated in type 2 diabetes mellitus accompanied by reduced secretion of insulin. The wingless‐type MMTV integration site family member 5a (Wnt5a)/frizzled‐5 signaling pathway might play an important role in this process. The present study aimed to explore the effects of Wnt5a on the activation of ISCs isolated from db/db mice.Materials and Methods ISCs were isolated from db/db mice and matched db/m mice. Immunohistochemistry and western blotting analysis were applied for the determination of Wnt5a expression. Exogenous Wnt5a and lentivirus containing the target gene Wnt5a short hairpin ribonucleic acid were used as a molecular intervention. The experiment of transwell and wound healing was used to evaluate the migration of the isolated ISCs.ResultsOur data showed that the expression of Wnt5a and frizzled‐5 was decreased in the ISCs isolated from db/db mice compared with db/m mice. Both the exogenous Wnt5a and the overexpression of Wnt5a could inhibit the outgrowth rate of ISCs from islets, and its viability, migration and α smooth muscle actin expression. These changes were associated with the inactivation of the Smad2/3 signaling pathway in a frizzled‐5‐dependent manner.ConclusionsOur observations revealed a potential role of Wnt5a in preventing ISC activation. The maintenance of quiescent ISCs might be a desirable outcome of therapeutic strategies for diabetes mellitus.

Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function.

Background Emerging evidence suggests that T2DM is attributable to the dysfunction of β-cells and the activation of islet stellate cells (ISCs). The wingless-type MMTV integration site family member 5a (Wnt5a)/frizzled 5 (Fzd5) signalling pathway might take part in this process. Our study is aimed at defining the status of ISCs during β-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. We examined the effects of the status of ISCs on β-cell insulin secretion in normoglycemic db/m and hyperglycaemic db/db mice. Methods iTRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. Results We showed a significant reduction in insulin secretion by β-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd5 were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. Conclusion Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function.

Role of wnt5a in Metabolic Inflammation in Humans.

Common nutrition-associated diseases like obesity and type 2 diabetes are linked to chronic low-grade inflammation. The secreted glycopeptide wingless-type mouse mammary tumor virus integration site family member 5a (wnt5a) has been implicated in metabolic inflammation in rodent models, suggesting a potential treatment target. Data on the role of wnt5a in human physiology have yielded conflicting results. Serum concentrations of wnt5a were measured in a cross-sectional cohort of 896 people to gain deeper insights into wnt5a physiology. Serum concentrations of wnt5a were measured by ELISA and related to several phenotyping and genotyping data. In vitro experiments were performed in THP-1 macrophages to examine potential molecular mechanisms. Wnt5a levels were significantly positively correlated to IL-6 and triglyceride levels. In subjects with diabetes, wnt5a levels were elevated and significantly correlated with fasting plasma glucose concentrations. Although wnt5a levels were not influenced by common single-nucleotide polymorphisms in the human wnt5a gene, environmental factors significantly altered wnt5a concentrations, as follows: (1) wnt5a levels were reduced in subjects with high nutritional load of the long-chain eicosatetraenoic acid independent of the total caloric intake and overall composition of the macronutrients, and (2) wnt5a levels were lower in humans with a high gut microbiome α diversity. In vitro experiments revealed that stimulation of the IL-6 receptor or the long-chain fatty acid receptor GPR40 directly affected wnt5a expression in human macrophages. Our data suggest that wnt5a is important in linking inflammation to metabolism. The nutrition and the microbiome might be interesting targets to prevent and/or treat wnt5a-mediated metabolic inflammation.

Expression of hepatic Wnt5a and its clinicopathological features in patients with hepatocellular carcinoma

BackgroudWingless-type MMTV integration site family member 5a (Wnt5a) is involved in carcinogenesis. However, little data are available in Wnt5a signaling with hepatocellular carcinoma (HCC). In the present study, we investigated the expression of hepatic Wnt5a in HCC and the role of Wnt5a in HCC progression and outcome. MethodsWnt5a expression and cellular distribution in HCCs and their matched paracancerous tissues from 87 patients were analyzed with tissue microarray and immunohistochemistry and compared with hepatic Wnt3a signaling. Wnt5a expression was categorized into low or high based on immunohistochemistry. Overall survival rate of HCC patients was estimated in correlation with the hepatic Wnt5a level using Kaplan–Meier method; the survival difference between patients with low and those with high Wnt5a was compared with log-rank test; and prognostic analysis was carried out with Cox regression. ResultsTotal incidence of Wnt5a expression in the HCC tissues was 70.1%, which was significantly lower (χ2 = 13.585, P < 0.001) than that in their paracancerous tissues (88.5%). Significant difference of Wnt5a intensity was found between HCC and their paracancerous tissues (Z = 8.463, P < 0.001). Wnt5a intensity was inversely correlated with Wnt3a signaling (r = −0.402, P < 0.001) in HCC tissues. A decrease of Wnt5a expression in relation to the clinical staging from stage I to IV and low or no staining at advanced HCC were observed. Wnt5a level was related to periportal embolus (χ2 = 11.069, P < 0.001), TNM staging (χ2 = 8.852, P < 0.05), 5-year survival (χ2 = 4.961, P < 0.05), and confirmed as an independent prognosis factor of HCC patients (hazard ratio: 1.957; 95% confidence interval: 1.109–3.456; P < 0.05). ConclusionsThe decrease of hepatic Wnt5a signaling is associated with HCC progression and poor prognosis.

Vitamin D3 supplementation improves serum SFRP5 and Wnt5a levels in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial.

Objective: To explore the effect of vitamin D3 on novel serum adipokines, secreted frizzled-related protein 5 (SFRP5) and Wingless-Type MMTV Integration Site Family Member 5a (Wnt5a) levels in Type 2 Diabetes Mellitus (T2DM) patients. Methods: Forty patients (16 women and 24 men) with type 2 diabetes participated in this double-blind, randomized, placebo-controlled clinical trial study. Participants were randomly assigned to receive 4000 IU vitamin D3 (n = 20) or placebo (n = 20) daily for 2 months. Anthropometric indices, fasting blood glucose (FBS), hemoglobin A1c (HbA1c), insulin, serum tumor necrosis factor (TNF)-α, Wnt5a, SFRP5, physical activity, lipid profile, dietary intake, and serum calcidiol were assessed at the baseline and after 8 weeks. Results: In the group receiving Vitamin D, a significant increase in Calicidiol (15.03 ± 10.44 vs. 27.33 ± 11.2 ng/dl; P = < 0.001), SFRP5 (3.6 ± 0.46 vs. 3.98 ± 0.59 ng/ml; P = 0.01), and Wnt5a (0.33 ± 0.129 vs. 0.29 ± 0.047; P = 0.03) was observed. After two months supplementation, there were significant between-group differences in Calicidiol (27.33 ± 11.2 vs. 17.9 ± 12.95 ng/dl; P = 0.01), TNF-α (89.22 ± 34.28 vs. 164.93 ± 120.45 ng/ml; P = 0.006), Wnt5a (0.29 ± 0.047 vs. 0.33 ± 0.09; P = 0.04), and HbA1c (6.6 ± 0.96 % vs. 7.64 ± 1.15 %; p = 0.002). Moreover, the net changes (end - baseline) of Calicidiol (P = < 0.001), SFRP5 (P = 0.04), Wnt5a (P = 0.005), TNF-α (P = 0.01), insulin (P = 0.03), and QUICKI (P = 0.01) was significant between the groups. There were no significant effects on FBS and homeostasis model of assessment-estimated insulin resistance (HOMA-IR). Conclusion: 8 weeks of vitamin D3 supplementation for patients with type 2 diabetes may increase serum anti-inflammatory adipokine SFRP5 but decrease serum pro-inflammatory Wnt5a and TNF-α.

MicroRNA 26b promotes colorectal cancer metastasis by downregulating phosphatase and tensin homolog and wingless-type MMTV integration site family member 5A.

Invasion and metastasis are crucially important factors in the survival of malignant tumors. Epithelial‐mesenchymal transition (EMT) is an early step in metastatic progression and the presence of cancer stem cells is closely related to tumor survival, proliferation, metastasis, and recurrence. Herein we report that ectopic overexpression of microRNA 26b (miR‐26b) in colorectal cancer (CRC) cell lines promoted EMT and stem cell‐like phenotypes in vitro. Furthermore, miR‐26b directly targeted and suppressed multiple tumor suppressors, including phosphatase and tensin homolog (PTEN) and wingless‐type MMTV integration site family member 5A (WNT5A). Notably, miR‐26b is markedly upregulated in tumor samples from patients with lymphatic metastases. These results indicate that miR‐26b promotes CRC metastasis by downregulating PTEN and WNT5A, and may represent a therapeutic target for metastatic CRC.

Decreased Wnt5a Expression is a Poor Prognostic Factor in Triple-Negative Breast Cancer.

BackgroundWingless-type MMTV integration site family member 5A (Wnt5a) has been documented to either overexpress or be lost in several malignancies. Our study aimed to investigate the expression and clinical significance of Wnt5a protein in triple-negative breast cancer (TNBC).Material/MethodsBy using immunohistochemistry, Wnt5a expression was evaluated in 90 TNBC specimens. The association between Wnt5a expression and clinic-pathological factors was assessed by using the chi-square test. The survival analysis of patients was conducted by using the Kaplan-Meier and log-rank tests. Cox regression was utilized for the univariate and multivariate analyses of prognostic factors.ResultsResults showed that negative Wnt5a expression correlated with positive lymph node metastasis (LNM) (P=0.007) and Ki67 proliferation (P=0.002). Patients with negative Wnt5a expression had significantly poorer recurrence-free survival (RFS) than patients with positive Wnt5a expression (P=0.008). Multivariate Cox regression analysis revealed that decreased Wnt5a expression was an independent prognostic factor for RFS (P=0.014).ConclusionsNegative Wnt5a protein expression might contribute to the tumor progression and poor prognosis of TNBC and might be a new therapy target in TNBC.

Balanced duo of anti-inflammatory SFRP5 and proinflammatory WNT5A in children

Secreted frizzled-related protein 5 (SFRP5) is an adipokine protecting against obesity-related insulin resistance and diabetes. SFRP5 binds to wingless type mouse mammary tumor virus (MMTV) integration site family member 5A (WNT5A) to improve insulin sensitivity. We performed the first study of SFRP5 and WNT5A simultaneously in children. Prepubertal children (n = 342) were assessed for circulating SFRP5 (all subjects) and circulating WNT5A (210 subjects), and associations were sought with metabolic markers. In conditioned media of adipose tissue explants from 12 additional children, SFRP5 and WNT5A were studied further. The concentrations of SFRP5 and WNT5A correlated positively in serum and in conditioned media (all P < 0.001). Lower level of circulating SFRP5 (lowest quartile) was associated with higher BMI (15% increase, P < 0.0001) and lower level of high-molecular-weight adiponectin (26% decrease, P = 0.002). Circulating WNT5A related closely with insulin resistance assessed by the homeostasis model assessment for insulin resistance and hepatic markers (alanine transaminase and gamma glutamyl transpeptidase), particularly in children with lower circulating SFRP5 levels (all P < 0.004). SFRP5 and WNT5A comprise a balanced duo that may regulate metabolic homeostasis in prepubertal children.

Effects of fibroblast growth factor 9 on steroidogenesis and control of FGFR2IIIc mRNA in porcine granulosa cells.

The objectives of this study were to investigate the effects of fibroblast growth factor 9 (FGF9) on hormone-stimulated porcine granulosa cell proliferation and steroid production and to further elucidate the hormonal and developmental control of FGFR2IIIc gene expression in granulosa cells. Porcine ovaries were collected from a local slaughterhouse and granulosa cells were collected from small to medium (1 to 5 mm) follicles for 5 in vitro studies that were conducted. Cells were cultured for 48 h in 5% fetal calf serum plus 5% porcine serum and then treated with various combinations of FSH, IGF-I, FGF9, Sonic hedgehog (SHH), cortisol, PGE2, and/or wingless-type mouse mammary tumor virus integration site family member 5A (WNT5A) in serum-free medium for an additional 24 or 48 h. Medium was collected for analysis of steroid concentration via RIA, or RNA was collected for gene expression analysis of FGFR2IIIc via quantitative reverse transcription PCR. Fibroblast growth factor 9 stimulated (P < 0.05) IGF-I-induced estradiol production in the presence of FSH and testosterone. However, FGF9 had inconsistent effects on progesterone production, stimulating progesterone production in the presence of FSH and testosterone but inhibiting progesterone production in the presence of IGF-I, FSH, and testosterone. Cell numbers were increased (P < 0.05) by FGF9 in the presence of IGF-I and FSH but not in the presence of FSH and absence of IGF-I. For FGFR2IIIc mRNA studies, granulosa cells were treated with FSH, IGF-I, FGF9, SHH, cortisol, PGE2, or WNT5A. Follicle-stimulating hormone alone had no effect (P > 0.10) whereas IGF-I increased (P < 0.05) FGFR2IIIc mRNA abundance. Cortisol, PGE2, SHH, and WNT5A had no effect (P > 0.10) on FGFR2IIIc gene expression whereas FGF9 in the presence of FSH and IGF-I inhibited (P < 0.05) FGFR2IIIc gene expression. In an in vivo study, granulosa cells from large (7 to 14 mm) follicles had greater (P < 0.05) abundance of FGFR2IIIc mRNA than small (1 to 3 mm) or medium (4 to 6 mm) follicles. In conclusion, IGF-I-induced FGFR2IIIc mRNA may be a mechanism for increased responses to FGF9 in FSH plus IGF-I-treated granulosa cells. Fibroblast growth factor 9 and IGF-I may work together as amplifiers of follicular growth and granulosa cell differentiation by stimulating estradiol production and concomitantly stimulating granulosa cell growth in pigs.

Circulating secreted frizzled‐related protein 5 (Sfrp5) and wingless‐type MMTV integration site family member 5a (Wnt5a) levels in patients with type 2 diabetes mellitus

Secreted frizzled-related protein 5 (Sfrp5), an endogenous inhibitor of wingless-type MMTV integration site family (Wnt) signalling, is an anti-inflammatory adipokine whose expression is perturbed in models of obesity and type 2 diabetes mellitus (T2DM). Wnt member 5a (Wnt5a) is a representative ligand, and recent reports suggest that Wnt5a is involved in inflammatory diseases and metabolic disorders. The aim of this study was to investigate whether plasma Wnt5a and Sfrp5 levels are altered in patients with T2DM. Plasma Sfrp5 and Wnt5a concentrations were measured through enzyme-linked immunosorbent assay in type 2 diabetic and nondiabetic subjects. A total of 82 patients with T2DM and 42 nondiabetic subjects were studied. Plasma Sfrp5 levels were found to be elevated in patients with T2DM (9.4 ± 9.0 vs 7.4 ± 10.9 ng/mL, p = 0.006). In contrast, Wnt5a levels were decreased (6.8 ± 12.6 vs 9.1 ± 4.0 ng/dL, p < 0.001). Increasing concentrations of Sfrp5 were independently and significantly associated with T2DM. Multiple logistic regression analysis revealed Sfrp5 as an independent association factor for T2DM, even after full adjustment of known biomarkers. In a multiple linear regression analysis, only the fasting glucose level was positively associated with the plasma Sfrp5 level. Our results indicate that Sfrp5 may play a role in the pathogenesis of T2DM.