Distinct effects of SDC3 and FGFRL1 on selective neurodegeneration in AD and PD.

Alzheimer's disease (AD) and Parkinson's disease (PD) are age-dependent neurodegenerative disorders. There is a profound neuronal loss in the basal forebrain cholinergic system in AD and severe dopaminergic deficiency within the nigrostriatal pathway in PD. Swedish APP (APPSWE ) and SNCAA53T mutations promote Aß generation and α-synuclein aggregation, respectively, and have been linked to the pathogenesis of AD and PD. However, the mechanisms underlying selective cholinergic and dopaminergic neurodegeneration in AD and PD are still unknown. We demonstrated that APPSWE mutation enhanced Aß generation and increased cell susceptibility to Aß oligomer in cholinergic SN56 cells, whereas SNCAA53T mutations promoted aggregates formation and potentiated mutant α-synuclein oligomer-induced cytotoxicity in MN9D cells. Furthermore, syndecan-3 (SDC3) and fibroblast growth factor receptor-like 1 (FGFRL1) genes were differentially expressed in SN56 and MN9D cells carrying APPSWE or SNCAA53T mutation. SDC3 and FGFRL1 proteins were preferentially expressed in the cholinergic nucleus and dopaminergic neurons of APPSWE and SNCAA53T mouse models, respectively. Finally, the knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA53T cells. The results demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA53T on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.

LncRNA VPS9D1-AS1 regulates miR-187-3p/fibroblast growth factor receptor-like 1 axis to promote proliferation, migration, and invasion of prostate cancer cells.

The morbidity and mortality of prostate cancer are increasing year by year, and the survival rate of prostate cancer patients after treatment is low. Therefore, investigating the molecular mechanism underlying prostate cancer is crucial for developing effective treatments. Recent studies have shown the important role of long-chain non-coding RNAs (lncRNAs) in tumorigenesis. VPS9D1-AS1 can modulate the progression of multiple cancers, but its molecular action mechanism in prostate cancer remains unknown. This study, therefore, intended to investigate the regulatory mechanism of VPS9D1-AS1 in prostate cancer. First, differentially expressed lncRNAs in prostate cancer were identified through bioinformatics approaches. The target lncRNA for the study was determined by reviewing the relevant literature and its downstream miRNA/mRNA axis was uncovered. Then, quantitative reverse transcription polymerase chain reaction was introduced to assess the expression of VPS9D1-AS1, miR-187-3p, and fibroblast growth factor receptor-like 1 (FGFRL1) at a cellular level, and Western blot was conducted to assess the protein level of FGFRL1 in cells. The results indicated that VPS9D1-AS1 and FGFRL1 were highly expressed in prostate cancer while miR-187-3p was less expressed. Besides, MTT, colony formation, wound healing, and cell invasion assays showed that silencing VPS9D1-AS1 inhibited the viability, migration ability, and invasion ability of prostate cancer cells. Dual-luciferase assay and RNA binding protein immunoprecipitation assay were performed to explore the interplay of miR-187-3p and VPS9D1-AS1 or FGFRL1. The results showed that VPS9D1-AS1 could sponge miR-187-3p, and FGFRL1 could serve as a direct target of miR-187-3p. Moreover, combined with the results of the rescue experiment, VPS9D1-AS1 was found to upregulate FGFRL1 by competitively sponging miR-187-3p to accelerate the malignant behaviors of prostate cancer cells. In conclusion, VPS9D1-AS1 could promote the phenotype progression of prostate cancer cells through targeting the miR-187-3p/FGFRL1 axis, and it has the potential to be a target for prostate cancer patients.

Fibroblast growth factor receptor-like-1: a new therapeutic target and unfavorable prognostic indicator for rectal adenocarcinoma.

Fibroblast growth factor receptor-like-1 (FGFRL1) is important to cell motility and links with tumorigenic potential in various types of cancers. To investigate the biological function and underlying mechanism of FGFRL1 in rectal adenocarcinoma, we conducted this study. TCGA and Oncomine databases were used to analyze FGFRL1 expression and its association with clinical characteristics or overall survival (OS) in rectal adenocarcinoma patients. siRNA strategy was implemented to knockdown FGFRL1 expression in rectal adenocarcinoma cells. CCK8, colony formation, wound healing, and transwell assays were implemented to measure cell behaviors. qRT-PCR and western blot were utilized to identify mRNA and protein expression levels. FGFRL1 was significantly increased in rectal adenocarcinoma tissue samples, either colon or rectum. High-regulation of FGFRL1 expression induced poorer outcome of rectal adenocarcinoma patients. Downregulation of FGFRL1 inhibited the proliferation, colony formation, migration, and invasion of SW837 cells. The MAPK pathway-related proteins, phosphorylation of MEK and ERK, were also decreased after si-FGFRL1 transfection. These findings demonstrated that FGFRL1, acting as a potential inducator, may promote the progression of rectal adenocarcinoma via activating the MAPK signaling pathway.

HuR affects chemoresistance of small cell lung cancer by regulating FGFRL1 expression.

Human antigen R (HuR), an RNA-binding protein, has been demonstrated to serve an oncogenic role in various types of cancer. Fibroblast growth factor receptor-like 1 (FGFRL1) has been shown to regulate small cell lung cancer (SCLC) chemoresistance. In the present study, the role of HuR in chemoresistance of SCLC, as well as its possible molecular mechanism involving FGFRL1, was explored by reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8 assay, flow cytometry and RNA immunoprecipitation. The results revealed that HuR expression levels were markedly upregulated in drug-resistant SCLC cell lines (H69AR and H446DDP) compared with in the parental cell lines (H69 and H446). Knockdown of HuR in drug-resistant SCLC cells enhanced drug sensitivity, cell apoptosis and cell cycle arrest. Furthermore, molecular mechanism studies indicated that HuR could bind and regulate FGFRL1 expression levels to increase FGFRL1 mRNA stability. Taken together, the present study suggested that HuR may mediate chemoresistance of SCLC by regulating FGFRL1 expression. HuR may represent a prognostic predictor and a potential target for overcoming chemoresistance in SCLC.

[Expression of fibroblast growth factor receptor like 1 protein in oral squamous cell carcinoma and its influence on tumor cell proliferation and migration].

OBJECTIVE: This study aims to investigate the expression of fibroblast growth factor receptor like 1 (FGFRL1) in oral squamous cell carcinoma (OSCC) and reveals its association with tumor cell proliferation and migration. METHODS: Western blot was performed to detect the expression of FGFRL1 protein in OSCC tissues, adjacent normal tissues, OSCC cell lines and normal epithelial cells. After knocking down of FGFRL1 in HN4 cells, CCK-8 and Ki67 assays were performed to detect cell proliferation, wounding healing assay and transwell were performed to detect cell-migration. Western blot was used to detect the expression of protein related to epithelial-mesenchymal transition (EMT). RESULTS: The expression of FGFRL1 in OSCC tissues was higher than that in adjacent nontumor tissues, respectively (t=2.820, P=0.047 8). Moreover, the expression of FGFRL1 in OSCC cells was higher than that in HOK cells. Quantitative real-time polymerase chain reaction (qRT-PCR) showed that FGFRL1 expression of FGFRL1 RNA in HOK cells was lower than that in OSCC cells. HN4 cells transfected with FGFRL1 siRNA were included in the experimental group, whereas HN4 cells treated with NC siRNA were included in the control group. CCK-8 experiment showed no significant difference between the experimental and control groups with regard to proliferation ability at 48 h (P=0.478 1) and 72 h (P=0.334 2). Migration experiment showed that the wound healing areas in the experimental group after 12 h (P=0.022 8), 24 h (P=0.005 1), and 36 h (P=0.009 5）were smaller than that in the control group. Transwell invasion assay showed that the number of invaded cells in the experimental group after 16 h (P=0.008 7) and 24 h (P=0.008 6) were lower than that in the control group. Knocking-down FGFRL1 up-regulated the expression of E-cadherin and down-regulated the expression of N-cadherin and Vimentin in HN4 cells. CONCLUSIONS: FGFRL1 expression in the OSCC tissues was significantly higher than that in the adjacent nontumor tissues. FGFRL1 expression in the OSCC cells was significantly higher than that in the HOK cells, and FGFRL1 had no effect on cell proliferation but promoted tumor cell migration and EMT.

Role of fibroblast growth factor receptors (FGFR) and FGFR like-1 (FGFRL1) in mesenchymal stromal cell differentiation to osteoblasts and adipocytes.

Fibroblast growth factors (FGF) and their receptors (FGFRs) regulate many developmental processes including differentiation of mesenchymal stromal cells (MSC). We developed two MSC lines capable of differentiating to osteoblasts and adipocytes and studied the role of FGFRs in this process. We identified FGFR2 and fibroblast growth factor receptor like-1 (FGFRL1) as possible actors in MSC differentiation with gene microarray and qRT-PCR. FGFR2 and FGFRL1 mRNA expression strongly increased during MSC differentiation to osteoblasts. FGF2 treatment, resulting in downregulation of FGFR2, or silencing FGFR2 expression with siRNAs inhibited osteoblast differentiation. During adipocyte differentiation expression of FGFR1 and FGFRL1 increased and was down-regulated by FGF2. FGFR1 knockdown inhibited adipocyte differentiation. Silencing FGFR2 and FGFR1 in MSCs was associated with decreased FGFRL1 expression in osteoblasts and adipocytes, respectively. Our results suggest that FGFR1 and FGFR2 regulate FGFRL1 expression. FGFRL1 may mediate or modulate FGFR regulation of MSC differentiation together with FGFR2 in osteoblastic and FGFR1 in adipocytic lineage.

MRNA and miRNA expression patterns associated to pathways linked to metal mixture health effects.

Metals are a threat to human health by increasing disease risk. Experimental data have linked altered miRNA expression with exposure to some metals. MiRNAs comprise a large family of non-coding single-stranded molecules that primarily function to negatively regulate gene expression post-transcriptionally. Although several human populations are exposed to low concentrations of As, Cd and Pb as a mixture, most toxicology research focuses on the individual effects that these metals exert. Thus, this study aims to evaluate global miRNA and mRNA expression changes induced by a metal mixture containing NaAsO2, CdCl2, Pb(C2H3O2)2·3H2O and to predict possible metal-associated disease development under these conditions. Our results show that this metal mixture results in a miRNA expression profile that may be responsible for the mRNA expression changes observed under experimental conditions in which coding proteins are involved in cellular processes, including cell death, growth and proliferation related to the metal-associated inflammatory response and cancer.