Cancer-associated fibroblasts secrete FGF5 to inhibit ferroptosis to decrease cisplatin sensitivity in nasopharyngeal carcinoma through binding to FGFR2.

Cisplatin (DDP)-based chemoradiotherapy is one of the standard treatments for nasopharyngeal carcinoma (NPC). However, the sensitivity and side effects of DDP to patients remain major obstacles for NPC treatment. This research aimed to study DDP sensitivity regulated by cancer-associated fibroblasts (CAFs) through modulating ferroptosis. We demonstrated that DDP triggered ferroptosis in NPC cells, and it inhibited tumor growth via inducing ferroptosis in xenograft model. CAFs secreted high level of FGF5, thus inhibiting DDP-induced ferroptosis in NPC cells. Mechanistically, FGF5 secreted by CAFs directly bound to FGFR2 in NPC cells, leading to the activation of Keap1/Nrf2/HO-1 signaling. Rescued experiments indicated that FGFR2 overexpression inhibited DDP-induced ferroptosis, and CAFs protected against DDP-induced ferroptosis via FGF5/FGFR2 axis in NPC cells. In vivo data further showed the protective effects of FGF5 on DDP-triggered ferroptosis in NPC xenograft model. In conclusion, CAFs inhibited ferroptosis to decrease DDP sensitivity in NPC through secreting FGF5 and activating downstream FGFR2/Nrf2 signaling. The therapeutic strategy targeting FGF5/FGFR2 axis from CAFs might augment DDP sensitivity, thus decreasing the side effects of DDP in NPC treatment.

Fibroblast growth factor 5 expression predicts the progression of oral squamous cell carcinoma.

BACKGROUND/PURPOSE: Fibroblast growth factor (FGF) 5 is a member of the FGF family that functions as a regulator of tissue growth and regeneration. Aberrant FGF5 expression has been previously associated with the progression of a number of different malignancies. However, its potential role in oral cancer remains unclear. In this study, we explored the relationship between the expression of FGF5 protein in oral squamous cell carcinomas (OSCCs) and the clinicopathological parameters of OSCCs and whether the expression of FGF5 protein in OSCCs could be a prognostic factor for OSCC patients. METHODS: The FGF5 protein expression was examined in 64 OSCC and 34 normal oral mucosal specimens by immunohistochemical staining. Stress induced upregulation and intracellular redistribution of FGF5 were verified using xenograft animal model and OSCC cell lines. RESULTS: The mean FGF5 protein labelling index was significantly higher in OSCC than in normal oral mucosal samples, with high FGF5 protein labelling index (>58%) being correlated with advanced stage and poor survival of OSCC patients. Apart from the peri-cytoplasmic staining pattern characteristic of paracrine growth factors, FGF5 protein was localized as distinct punctate structures in the cytoplasm of advanced stage or stressed-induced cells. This redistribution and upregulation of FGF5 protein could be sustained after termination of the stress induction in cell line and xenograft animal models. CONCLUSION: FGF5 can be induced by cellular stress and risk factors of OSCC, where high expression levels of FGF5 is potentially a useful parameter for predicting OSCC progression and patient survival.

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer.

A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.

Circ_0001715 Functions as a miR-1249-3p Sponge to Accelerate the Progression of Non-small Cell Lung Cancer via Upregulating the Level of FGF5.

Circular RNAs (circRNAs) have been widely involved in the malignant development of human cancers. Circ_0001715 was aberrantly upregulated in non-small cell lung cancer (NSCLC). However, circ_0001715 function has never been researched. This study was designed to investigate the role and mechanism of circ_0001715 in NSCLC. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to examine the levels of circ_0001715, microRNA-1249-3p (miR-1249-3p) and Fibroblast Growth Factor 5 (FGF5). The proliferation detection was conducted using colony formation assay and EdU assay. Cell apoptosis was analyzed via flow cytometry. Wound healing assay and transwell assay were used for determination of migration and invasion, respectively. The protein levels were measured through western blot. Target analysis was carried out via dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenograft tumor model was established in mice for in vivo research. The significant upregulation of circ_0001715 was detected in NSCLC samples and cells. Circ_0001715 knockdown induced the inhibitory effects on proliferation, migration and invasion but the promoting effect on apoptosis of NSCLC cells. Circ_0001715 could interact with miR-1249-3p. The regulatory role of circ_0001715 was achieved by sponging miR-1249-3p. Furthermore, miR-1249-3p targeted FGF5 and miR-1249-3p acted as a cancer inhibitor by targeting FGF5. Moreover, circ_0001715 upregulated the FGF5 level via targeting miR-1249-3p. In vivo assay showed that circ_0001715 promoted the NSCLC progression through the miR-1249-3p/FGF5 axis. The current evidence elucidated that circ_0001715 served as an oncogenic regulator in NSCLC progression by depending on the miR-1249-3p/FGF5 axis.

FGF5 protects heart from sepsis injury by attenuating cardiomyocyte pyroptosis through inhibiting CaMKII/NFκB signaling.

Sepsis accompanied by myocardial injury is an important cause of multiple organ dysfunction, and its underlying molecular mechanism is not fully clear. Although diverse effects of fibroblast growth factor (FGF) in heart have been discovered till now, the specific role of FGF5 in heart remains unclear. Therefore, our study aims to explore the possible impacts of FGF5 on sepsis-induced cardiac injury. Sepsis-induced cardiac injury was established through administration of lipopolysaccharide (LPS). The expression level of FGF5 in sepsis heart was decreased, and injection of FGF5-overexpressing adenovirus attenuated cardiac injury reflected by echocardiographic and pathological findings. Besides, FGF5 overexpression, not only in vivo heart but also in vitro cardiomyocytes, reduced the levels of oxidative stress and pyroptosis resulted from LPS. In addition, overexpression of FGF5 reduced LPS-activated the levels of phosphorylated CaMKII (p-CaMKII), p-NFκB, NLRP3, caspase-1, IL-1ß and IL-18. Furthermore, KN93, the inhibitor of CaMKII, exerted the similarly protective effects on LPS-induced pyroptosis. In summary, our study implied the beneficial effects of FGF5 on LPS-induced cardiac injury, which was at least partially attributed to the inhibition of CaMKII-mediated pyroptotic signaling.

FGF5 alleviated acute lung injury via AKT signal pathway in endothelial cells.

Acute lung injury (ALI), with high morbidity and mortality, is mainly resulted by infectious or non-infectious inflammatory stimulators, and it will further evolve into acute respiratory distress syndrome if not controlled. Fibroblast growth factors (FGFs) consist of more than 23 kinds of members, which are involved in various pathophysiological processes of body. However, the effect of FGF5, one member of FGFs, is still not certain in lipopolysaccharide (LPS)-induced ALI. In this study, we explored the possible impacts of FGF5 in LPS-induced ALI and primarily focused on endothelial cell, which was one of the most vulnerable cells in septic ALI. In the mouse group of FGF5 overexpression, LPS-induced lung injuries were mitigated, as well as the pyroptosis levels of pulmonary vascular endothelial cells. Additionally, in vitro human umbilical vein endothelial cells (HUVECs), our results showed that the level of cell pyroptosis was ameliorated with FGF5 overexpression, and AKT signal was activated with the overexpression of FGF5, whereas after administration of MK2206, an inhibitor of AKT signal, the protection of FGF5 was inhibited. Therefore, these results suggested that FGF5 exerted protective effects in endothelial cells exposed to LPS, and this protection of FGF5 could be attributed to activated AKT signal.

Inflammation-Driven Secretion Potential Is Upregulated in Osteoarthritic Fibroblast-Like Synoviocytes.

Osteoarthritis (OA) is one of the most common joint pathologies and a major cause of disability among the population of developed countries. It manifests as a gradual degeneration of the cartilage and subchondral part of the bone, leading to joint damage. Recent studies indicate that not only the cells that make up the articular cartilage but also the synoviocytes, which build the membrane surrounding the joint, contribute to the development of OA. Therefore, the aim of the study was to determine the response to inflammatory factors of osteoarthritic synoviocytes and to identify proteins secreted by them that may influence the progression of OA. This study demonstrated that fibroblast-like synoviocytes of OA patients (FLS-OA) respond more strongly to pro-inflammatory stimulation than cells obtained from control patients (FLS). These changes were observed at the transcriptome level and subsequently confirmed by protein analysis. FLS-OA stimulated by pro-inflammatory factors [such as lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) were shown to secrete significantly more chemokines (CXCL6, CXCL10, and CXCL16) and growth factors [angiopoietin-like protein 1 (ANGPTL1), fibroblast growth factor 5 (FGF5), and insulin-like growth factor 2 (IGF2)] than control cells. Moreover, the translation of proteolytic enzymes [matrix metalloprotease 3 (MMP3), cathepsin K (CTSK), and cathepsin S (CTSS)] by FLS-OA is increased under inflammatory conditions. Our data indicate that the FLS of OA patients are functionally altered, resulting in an enhanced response to the presence of pro-inflammatory factors in the environment, manifested by the increased production of the previously mentioned proteins, which may promote further disease progression.

miR­491­3p functions as a tumor suppressor in non­small cell lung cancer by targeting fibroblast growth factor 5.

The present study aimed to identify the function of miR­491­3p in regulating non­small cell lung cancer (NSCLC). Tumor tissues and adjacent normal tissues were collected from 43 patients with NSCLC. A549 and H1299 cells were transfected with microRNA (miR)­491­3p mimic, mimic negative control (NC), miR­491­3p inhibitor, inhibitor NC, pcDNA3.1­FGF5 vector and control vector. Cell counting kit­8 assay and Edu experiments were performed to assess cell viability and proliferation. Matrigel experiment, wound healing assay and flow cytometric analysis were performed to explore cell invasion, migration and apoptosis, respectively. A dual­luciferase reporter experiment was performed to identify the relationship between miR­491­3p and fibroblast growth factor 5 (FGF5). In vivo study was conducted by using nude mice. The miR­491­3p and FGF5 protein expression levels were investigated using reverse transcription­quantitative polymerase chain reaction and western blot analysis. In NSCLC tumor tissues, miR­491­3p was downregulated and FGF5 was upregulated (P<0.01). Low miR­491­3p expression and high FGF5 mRNA expression was associated with poor outcomes in patients, including advanced TNM stage and lymph node metastasis (P<0.05). upregulation of miR­491­3p suppressed viability, proliferation, invasion and migration of NSCLC cells; however, it promoted apoptosis (P<0.01). FGF5 was a target gene for miR­491­3p. miR­491­3p directly inhibited FGF5 expression. upregulation of FGF5 significantly reversed the inhibitory effects of miR­491­3p on malignant phenotypes of NSCLC cells (P<0.01). miR­491­3p overexpression suppressed the in vivo growth of NSCLC. Thus, it was identified that miR­491­3p functions as a tumor suppressor in NSCLC by directly targeting FGF5.

Circ_0041732 regulates tumor properties of triple-negative breast cancer cells by the miR-149-5p/FGF5 pathway.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancers with a high recurrence and mortality. The important factors promoting the TNBC process have not been fully identified. In this research, the role of a TNBC-related circular RNA (circRNA), circ_0041732, was revealed in TNBC cell tumor properties. METHODS: The expression levels of circ_0041732, microRNA-149-5p (miR-149-5p) and fibroblast growth factor 5 (FGF5) were detected by quantitative real-time polymerase chain reaction. The protein expression was determined by Western blot analysis or immunohistochemistry assay. Cell proliferation was detected by cell counting kit-8 and cell colony formation assays. Cell apoptosis was analyzed by flow cytometry and caspase-3 activity assays. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. Cell angiogenic capacity was investigated by a tube formation assay. The targeting relationship between miR-149-5p and circ_0041732 or FGF5 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. The impacts of circ_0041732 knockdown on tumor formation were determined by an in vivo assay. RESULTS: Circ_0041732 and FGF5 expression were significantly upregulated, whereas miR-149-5p was downregulated in TNBC tissues and cells compared with normal breast tissues and cells, respectively. Circ_0041732 silencing inhibited TNBC cell proliferation, migration, invasion, and tube formation, but induced apoptosis. Additionally, circ_0041732 regulated TNBC cell tumor properties by binding to miR-149-5p. MiR-149-5p also modulated TNBC cell tumor properties by targeting FGF5. Furthermore, circ_0041732 knockdown hindered tumor formation in vivo. CONCLUSION: Circ_0041732 silencing suppressed TNBC cell tumor properties by decreasing FGF5 expression through miR-149-5p. This finding demonstrated that circ_0041732 had the potential as a therapeutic target for TNBC.

Fibroblast growth factor 5 overexpression ameliorated lipopolysaccharide-induced apoptosis of hepatocytes through regulation of the phosphoinositide-3-kinase/protein kinase B pathway.

BACKGROUND: Sepsis is a systemic inflammatory syndrome induced by several infectious agents. Multiple organs are affected by sepsis, including the liver, which plays an important role in metabolism and immune homeostasis. Fibroblast growth factors (FGFs) participate in several biological processes, although the role of FGF5 in sepsis is unclear. METHODS: In this study, lipopolysaccharide (LPS) was administrated to mice to establish a sepsis-induced liver injury. A similar in vitro study was conducted using L-02 hepatocytes. Western blot and immunohistochemistry staining were performed to evaluate the FGF5 expression level in liver tissues and cells. Inflammatory cell infiltrations, cleaved-caspase-3 expressions, reactive oxygen species and levels of inflammatory cytokines were detected by immunofluorescence, dihydroethidium staining, and reverse transcription quantitative polymerase chain reaction analysis, respectively. Flow cytometry was used to detect the apoptosis level of cells. In addition, ribonucleic acid (RNA)-sequencing was applied to explore the possible mechanism by which FGF5 exerted effects. RESULTS: LPS administration caused FGF5 down-regulation in the mouse liver as well as in L-02 hepatocytes. Additionally, with FGF5 overexpression, liver injury and the level of hepatocyte apoptosis were ameliorated. Further, RNA sequencing performed in hepatocytes revealed the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) pathway as a possible pathway regulated by FGF5 . This was supported using an inhibitor of the PI3K/AKT pathway, which abrogated the protective effect of FGF5 in LPS-induced hepatocyte injury. CONCLUSION: The anti-apoptotic effect of FGF5 on hepatocytes suffering from LPS has been demonstrated and was dependent on the activation of the PI3K/AKT signaling pathway.

Generation of VEGF knock-in Cashmere goat via the CRISPR/Cas9 system.

Cashmere is a rare and specialised animal fibre, which grows on the outer skin of goats. Owing its low yield and soft, light, and warm properties, it has a high economic value. Here, we attempted to improve existing cashmere goat breeds by simultaneously increasing their fibre length and cashmere yield. We attempted this by knocking in the vascular endothelial growth factor (VEGF) at the fibroblast growth factor 5(FGF5) site using a gene editing technology and then studying its hair growth-promoting mechanisms. We show that a combination of RS-1 and NU7441 significantly improve the efficiency of CRISPR/Cas9-mediated, homologous-directed repair without affecting the embryo cleavage rate or the percentages of embryos at different stages. In addition, we obtained a cashmere goat, which integrated the VEGF gene at the FGF5 site, and the cashmere yield and fibre length of this gene-edited goat were improved. Through next-generation sequencing, we found that the up-regulation of VEGF and the down-regulation of FGF5 affected the cell cycle, proliferation, and vascular tone through the PI3K-AKT signalling pathway and at extracellular matrix-receptor interactions. Owing to this, the gene-edited cashmere goat showed impressive cashmere performance. Overall, in this study, we generated a gene-edited cashmere goat by integrating VEGF at the FGF5 site and provided an animal model for follow-up research on hair growth mechanisms.

Specific inhibition of FGF5-induced cell proliferation by RNA aptamers.

Fibroblast growth factor 5 (FGF5) is a crucial regulator of hair growth and an oncogenic factor in several human cancers. To generate FGF5 inhibitors, we performed Systematic Evolution of Ligands by EXponential enrichment and obtained novel RNA aptamers that have high affinity to human FGF5. These aptamers inhibited FGF5-induced cell proliferation, but did not inhibit FGF2-induced cell proliferation. Surface plasmon resonance demonstrated that one of the aptamers, F5f1, binds to FGF5 tightly (Kd = 0.7 ± 0.2 nM), but did not fully to FGF1, FGF2, FGF4, FGF6, or FGFR1. Based on sequence and secondary structure similarities of the aptamers, we generated the truncated aptamer, F5f1_56, which has higher affinity (Kd = 0.118 ± 0.003 nM) than the original F5f1. Since the aptamers have high affinity and specificity to FGF5 and inhibit FGF5-induced cell proliferation, they may be candidates for therapeutic use with FGF5-related diseases or hair disorders.

Hsa_circ_0016760 exacerbates the malignant development of non­small cell lung cancer by sponging miR­145­5p/FGF5.

Hsa_circ_0016760 expression has been reported to be increased in non­small cell lung cancer (NSCLC). The present study was designed to explore the role and mechanism of hsa_circ_0016760 in regulating NSCLC progression. In total, 60NSCLC patients were followed­up for 60 months after surgery. Hsa_circ_0016760 expression in tumor tissues and adjacent non­tumor tissues of NSCLC patients was explored by reverse transcription quantitative polymerase chain reaction (RT­qPCR). NSCLC cell proliferation was monitored by CCK­8 assay and EdU experiment. Transwell assays were used for the detection of NSCLC cell migration and invasion. The target of hsa_circ_0016760 (or miR­145­5p) was validated by luciferase reporter gene assay and RNA immunoprecipitation experiment. A xenograft model was studied with nude mice. Immunohistochemical staining was applied for the detection of Ki67 expression in xenograft tumors. Hsa_circ_0016760/miR­145­5p/FGF5 expression in tissues and cells was investigated by RT­qPCR and western blotting. Hsa_circ_0016760 was aberrantly upregulated in NSCLC, which was associated with poor prognosis of patients (P<0.05). Hsa_circ_0016760 silencing suppressed NSCLC cell proliferation, migration and invasion in vitro (P<0.01). Hsa_circ_0016760 facilitated FGF5 expression via sponging miR­145­5p. The miR­145­5p upregulation or FGF5 downregulation reversed the promoting effect of hsa_circ_0016760 on NSCLC cell proliferation, migration and invasion in vitro (P<0.01). In addition, hsa_circ_0016760 silencing inhibited tumor growth in vivo (P<0.01), and decreased Ki67 expression in xenograft tumors. In conclusion, hsa_circ_0016760 exacerbated the malignant development of NSCLC by sponging miR­145­5p/FGF5.

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.

Validation of MicroRNA-188-5p Inhibition Power on Tumor Cell Proliferation in Papillary Thyroid Carcinoma.

Given the crucial role of microRNAs in the cellular proliferation of various types of cancers, we aimed to analyze the expression and function of a cellular proliferation-associated miR-188-5p in papillary thyroid carcinoma (PTC). Here we demonstrate that miR-188-5p is downregulated in PTC tumor tissues compared with the associated noncancerous tissues. We also validate that the miR-188-5p overexpression suppressed the PTC cancer cell proliferation. In addition, fibroblast growth factor 5 (FGF5) is observed to be downregulated in the PTC tumor tissues compared with the associated noncancerous tissues. Subsequently, FGF5 is identified as the direct functional target of miR-188-5p. Moreover, the silencing of FGF5 was found to inhibit PTC cell proliferation, which is the same pattern as miR-188-5p overexpression. These results suggest that miR-188-5p-associated silencing of FGF5 inhibits tumor cell proliferation in PTC. It also highlights the importance of further evaluating miR-188-5p as a potential biomarker and therapy target in PTC.

High Expression of FGF5 Is an Independent Prognostic Factor for Poor Overall Survival and Relapse-Free Survival in Lung Adenocarcinoma.

Lung cancer is not only a serious disease but also a public problem threatening human health all over the world. Nonsmall cell lung cancer-which accounts for the majority of lung cancer-is mainly composed of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). FGF5 is a gene located in q21.21. In the past years, research on FGF5 is mainly focused on hair length and hereditary spherocytosis. In our study, bioinformatics analysis of FGF5 was performed through multiple databases. Expression of FGF5 was compared between tumor and normal tissues, association between gene expression and clinical outcomes was investigated in LUAD and LUSC separately, and potential signaling pathways were predicted. FGF5 expression was upregulated in lung cancer tissues compared with normal tissues. What is more, the high FGF5 expression group had significantly lower proportions of lymph node negative (N0) patients (77/144, 53.5%, vs. 253/358, 70.7%, p = 0.000), and is associated with worse overall survival (OS) (p < 0.0001) and relapse-free survival (RFS) (p = 0.024) in LUAD patients, which could not be seen in LUSC. The following analysis confirmed that high FGF5 expression could be an independent prognostic factor for poor OS (HR: 0.431, 95% CI: 0.312-0.597, p = 0.001) and RFS (HR: 0.678, 95% CI: 0.471-0.977, p = 0.037) in LUAD, but not in LUSC. Coexpression genes related to FGF5 were explored and potential pathways were investigated for further research. FGF5 is a tumor-associated gene that upregulated in lung cancer tissues, and could be an independent prognostic factor that have potential value for further research.

FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy.

Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure an ESCC. Nevertheless, few validated markers are available. Here, we aimed to identify a highly reproducible marker using multi-layer omics analysis. 117 ESCC samples from 67 responders and 50 non-responders were divided into screening, validation, and re-validation sets. In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip array identified four genic regions significantly associated with dCRT response. Among them, FGF5 methylation was validated to be associated with dCRT response (n = 34; P = 0.001), and further re-validated (n = 42; P = 0.020) by bisulfite-pyrosequencing. The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and FGF5 methylation had predictive power independent from clinicopathological parameters. In ESCC cell lines, FGF5 promoter methylation repressed its expression. FGF5 expression was induced by cisplatin (CDDP) treatment in three unmethylated cell lines, but not in two methylated cell lines. Exogenous FGF5 overexpression in a cell line with its methylation conferred resistance to CDDP. In non-cancerous esophageal tissues, FGF5 was not expressed, and its methylation was present in a small fraction of cells. These results showed that FGF5 methylation is a validated marker for ESCC sensitivity to dCRT.

Downregulation of miR-145-5p elevates retinal ganglion cell survival to delay diabetic retinopathy progress by targeting FGF5.

Diabetic retinopathy (DR) is a leading cause of new-onset blindness. Recent studies showed that protecting retinal ganglion cells (RGCs) from high glucose-induced injury is a promising strategy for delaying DR. This study is to investigate the role of miR-145-5p in high glucose-induced RGC injury. Here, RGCs were randomly divided into low glucose and high glucose groups. PCR assay showed miR-145-5p was significantly upregulated in high glucose group. Transfection of miR-145-5p inhibitor decreased pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) levels, elevated cell viability and proliferation, as well as suppressed cell apoptosis by ELISA, MTT, EdU proliferation, colony formation and flow cytometry assays, respectively. Moreover, dual-luciferase reporter assay confirmed FGF5 as a target gene of miR-145-5p. FGF5 knockdown could partially reverse the protective effects of miR-145-5p on RGC-5 cells. In conclusion, our results demonstrated that inhibition of miR-145-5p might be a neuroprotective target for diabetes mellitus-related DR. Abbreviations: DR: diabetic retinopathy; RGCs: retinal ganglion cells; miR-145-5p: microRNA-145-5p; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; FGF: fibroblast growth factor; ATCC: American Type Culture Collection; WT: wild type; MUT: mutant type.