Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks.

To elucidate the molecular genetic mechanisms underpinning feather color in Muscovy ducks. A cohort of 100 Muscovy ducks was meticulously selected for this research. Follicular tissues from ducks exhibiting black and white plumage served as the experimental samples. From these tissues, RNA and proteins were extracted for further analysis. The RNA underwent reverse transcription polymerase chain reaction amplification, followed by validation through western blot assays. The data revealed a significant upregulation in the expression of FN domain-containing protein 1 (FNDC1) and ADAMTS12 genes in Muscovy ducks with white plumage traits as opposed to those with black plumage traits. Specifically, individuals with pure white plumage demonstrated a markedly elevated expression of the FNDC1 gene in comparison to their pure black counterparts. Conversely, expression levels of the ADAMTS12 gene were found to be reduced in ducks with pure black plumage relative to those with pure white plumage. Notably, the expression patterns of FNDC1 and ADAMTS12 genes exhibited inconsistencies between mRNA and protein levels. This study offers significant insights into the molecular genetic mechanisms underlying feather color variation in Muscovy ducks. FNDC1 and ADAMTS12 could be considered potential targets for genetic manipulation or selective breeding strategies aimed at achieving specific feather color phenotypes in Muscovy ducks.

Investigation of the pan-cancer property of FNDC1 and its molecular mechanism to promote lung adenocarcinoma metastasis.

BACKGROUND: Fibronectin type III domain containing 1 (FNDC1) has been associated with the metastasis of many tumors, but its function in lung cancer remains uncertain. METHODS: FNDC1 expression was analyzed in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), evaluate its prognostic value. Gene Set Enrichment Analysis (GSEA) enrichment analysis of differential expression of FNDC1 in lung cancer. The expression of FNDC1 was detected in five types of lung cancer cells, and screened to establish FNDC1 stable knockdown cell strains. To observe the migration and invasion ability of lung cancer cells after FNDC1 knockdown. Finally, we used rhIL-6 to interfere with the stable knockdown of FNDC1 in A549 cells and observed the recovery of migration and invasion. RESULT: Our results showed that FNDC1 expression was increased in 21 tumor tissues, including lung cancer, and was associated with poor prognosis in five cancers, including lung adenocarcinoma (LUAD) (P < 0.05). GSEA enrichment analysis showed that FNDC1 was related to the pathways involved the JAK-STAT signaling pathway. Stable knockdown of FNDC1 in A549 and H292 cells resulted in decreased migration and invasion ability of both cells, accompanied by decreased expression of MMP-2 and Snail, and a significant decline in the expression of p-JAK2 and p-STAT3. The suppressive effect of FNDC1 knockdown on lung cancer cell metastasis counteracted by the JAK-STAT agonist rhIL-6 were presented in the nude mouse metastatic tumor model. CONCLUSION: FNDC1 is implicated in poor prognosis of a diverse range of malignant tumors, which can promote metastasis and invasion of lung cancer through the JAK2-STAT3 signaling pathway.

Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation.

Genetics for blood pressure (BP) in human and animals has been partitioned into two separate specialties. However, this divide is mechanistically-misleading. BP physiology is mechanistically participated by products of quantitative trait loci (QTLs). The key to unlocking its mechanistic mystery lies in the past with mammalian ancestors before humans existed. By pivoting from effects to causes, physiological mechanisms determining BP by six QTLs have been implicated. Our work relies on congenic knock-in genetics in vivo using rat models, and has reproduced the physiological outcome based on a QTL being molecularly equal to one gene. A gene dose for a QTL is irrelevant to physiological BP controls in causation. Together, QTLs join one another as a group in modularized Mendelian fashion to achieve polygenicity. Mechanistically, QTLs in the same module appear to function in a common pathway. Each is involved in a different step in the pathway toward polygenic hypertension. This work has implicated previously-concealed components of these pathways. This emerging concept is a departure from the human-centric precept that the level of QTL expressions, not physiology, would ultimately determine BP. The modularity/pathway paradigm breaks a unique conceptual ground for unravelling the physiological mechanisms of polygenic and quantitative traits like BP.

Rs420137, rs386360 and rs7763726 polymorphisms in fibronectin type III domain containing 1 are associated with susceptibility to coronary heart disease: Analysis in the Han population.

Background: Numerous genetic studies have shown that genes are related to the pathogenesis of coronary heart disease (CHD). The main aim of this study was to confirm whether fibronectin type III domain containing 1 (FNDC1) polymorphisms correlate with the risk of CHD. Methods: In this study, in order to assess the association between three FNDC1 single nucleotide polymorphisms (SNPs) and the risk of CHD, we conducted a case-control study involving 630 patients with CHD and 568 healthy controls using Agena MassARRAY (Agena Bioscience, San Diego, CA, USA). Genotype distribution in case and control groups was analyzed by Chi square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression models adjusted for age, sex, smoking, and alcohol consumption to assess the correlation between SNPs and CHD risk. Results: Our results indicated that FNDC1-rs420137, -rs386360, and -rs7763726 played important roles in enhancing the risk of CHD. Subgroup analysis revealed that rs420137 increased the susceptibility to CHD in males, smokers, and patients aged ≤62 years. Rs360 had an increased risk of CHD in males, patients at aged ≤62 years, smokers, and non-drinkers. Furthermore, the association of rs7763726 with increased CHD risk was also observed in males, patients aged ≤62 years, smokers, and drinkers. Last but not least, these three SNPs we selected were protective factors against hypertension in CHD individuals. Conclusion: Our research suggest that FNDC1-rs420137, -rs386360, and -rs7763726 variants may be regarded as novel biomarkers for predicting CHD risk and other specific mechanisms of action of CHD need to be further studied.

Up-regulated FNDC1 accelerates stemness and chemoradiation resistance in colorectal cancer cells.

Neoadjuvant chemoradiation (nCRT) followed by radical surgery is the preferred option for locally advanced colorectal cancer (CRC) treatment. However, chemo/radio-resistance remains a main obstacle in CRC therapy. In the study, we analyzed the mRNA expression profiling of CRC patients and revealed that the aberrant expression of fibronectin type III domain containing 1 (FNDC1) was associated with disease progression and poor prognosis in CRC. FNDC1 expression was consistently increased in multiple independent cohorts of CRC. Upregulated FNDC1 in pretreated primary tumor tissues predicted a poor response to nCRT, recurrence, and poor disease-free survival in nCRT-treated CRC patients. FNDC1 overexpression accelerated CRC cell survival on 5-FU or radiation treatment both in vitro and in vivo, whereas FNDC1 inhibition sensitized CRC cells to chemoradiation. In addition, FNDC1 accelerated stem cell-like properties of CRC cells. Furthermore, tumor tissues from non-responders exhibited higher activation of PI3K/Akt signaling than those from responders. FNDC1 depletion repressed 5-FU or irradiation-induced activation of PI3K/AKT in CRC cells. More importantly, pharmacological inhibition of PI3K/Akt signaling effectively decreased the effect of FNDC1 on chemoradiation resistance. Taken together, our study reveals the potential function of FNDC1 as a biomarker to predict nCRT sensitivity in CRC and a therapeutic target in CRC treatment.

Proteomic Architecture of Valvular Extracellular Matrix: FNDC1 and MXRA5 Are New Biomarkers of Aortic Stenosis.

This study analyzed the expression of extracellular matrix (ECM) proteins during aortic valve calcification with mass spectrometry, and further validated in an independent human cohort using RNAseq data. The study reveals that valve calcification is associated with significant disruption in ECM and metabolic pathways, and highlights a strong connection between metabolic markers and ECM remodeling. It also identifies FNDC1 and MXRA5 as novel ECM biomarkers in calcified valves, electing them as potential targets in the development and progression of aortic stenosis.

FNDC1 Promotes the Invasiveness of Gastric Cancer via Wnt/ß-Catenin Signaling Pathway and Correlates With Peritoneal Metastasis and Prognosis.

BACKGROUND: Gastric cancer (GC) has a high morbidity and mortality rate, with peritoneal metastasis (PM) identified as the main site of metastasis. Our previous study found that FNDC1 has a higher frequency of mutations in patients with PM by high-throughput sequencing assay, suggesting that it may be associated with GC invasion and PM, however the specific mechanism remains unclear. METHODS: First, the correlation between FNDC1 and PM and prognosis of GC was clarified by bioinformatics and clinicopathological analysis. Next, the effect of FNDC1 expression on the invasion and metastasis ability of GC was investigated in vivo and in vitro. Finally, the signaling pathways involved in the regulation of FNDC1 were explored. RESULTS: FNDC1 was highly expressed in GC and was associated with PM and poor prognosis. FNDC1 was also associated with epithelial-mesenchymal transition (EMT) in GC cells. Through in vivo and in vitro experiments, it was clarified that knockdown of FNDC1 could inhibit the proliferation, invasion, and migration of GC cells. In addition, it was elucidated that FNDC1 promotes EMT through the Wnt/ß-catenin signaling pathway. CONCLUSION: FNDC1 may be associated with the invasion of GC and PM after surgery. FNDC1 was highly expressed in GC tissues and cell lines, while significantly associated with poor DFS and OS in GC patients. Both univariate and multivariate analyses suggested that the expression of FNDC1 was an independent factor for GC. Knockdown of FNDC1 also significantly inhibited the proliferation, migration, and activity of GC cells. FNDC1 may promote EMT in GC cells through the regulation of Wnt/ß-catenin signaling pathway. FNDC1 has the potential to be used as a predictor of PM and may also be studied in depth as a therapeutic target for GC, which has potential clinical utility and is worthy of further validation.

Rutin suppresses FNDC1 expression in bone marrow mesenchymal stem cells to inhibit postmenopausal osteoporosis.

A previous study revealed that rutin is the main component of Eucommia flavonoids that exerts a protective effect against osteopenia. The bone density and trabecular bone number of osteoporosis model rats can be significantly improved after treatment with rutin. Further study using whole gene expression profiling revealed that FNDC1, a fibronectin type III domain-containing protein, may be a novel bone metabolism-related factor that is decreased in rutin-treated rats. The mechanism underlying the effects of rutin treatment on osteoporosis is important to explore. Micro-CT, western blotting, quantitative PCR, transmission electron microscopy, and Alizarin Red mineralization staining assays were performed to evaluate bone density, FNDC1 expression and autophagy to determine whether FNDC1 might play a significant role in rutin-inhibited trabecular bone loss in rats. FNDC1 expression was high in the osteoporosis group, whereas rutin treatment facilitated FNDC1 downregulation. In addition, rutin promoted bone marrow mesenchymal stem cell autophagy by inhibiting phosphorylated Akt in osteoporosis. In summary, our study shows that rutin could regulate FNCD1 level and autophagy through the Akt/mTOR signaling pathway to provide a novel therapeutic strategy for osteoporosis.

Overexpression of FNDC1 Relates to Poor Prognosis and Its Knockdown Impairs Cell Invasion and Migration in Gastric Cancer.

The distribution and content of fibronectin is closely related to the occurrence and development of tumors. Fibronectin is widely involved in cell migration, adhesion, proliferation, hemostasis, and tissue repair. Fibronectin type III domain containing 1, as a primary component of the structural domain of fibronectin, is closely related to the occurrence of some cancers. However, the molecular mechanism of fibronectin type III domain containing 1 in gastric cancer has not been elaborated. In this study, we analyzed the expression and prognosis of fibronectin type III domain containing 1 by collecting data from Oncomine and GEPIA database. The expression of fibronectin type III domain containing 1 in gastric cancer cells was detected by quantitative real-time polymerase chain reaction in vitro. After knockdown of fibronectin type III domain containing 1 by small interfering RNA, the proliferation, invasion, and migration of AGS (human gastric adenocarcinoma cell line) cells and the function of epithelial-mesenchymal transition were measured by Cell Counting Kit-8, colony formation, transwell, and Western blot. The results showed that fibronectin type III domain containing 1 was highly expressed in gastric cancer tissues and its overexpression was significantly correlated with the prognosis of gastric cancer. In vitro, experiments revealed that knockdown of fibronectin type III domain containing 1 could inhibit the proliferation, migration, and invasion of gastric cancer cells, possibly by changing the epithelial-mesenchymal transition pathway. The findings elaborated the biological role of fibronectin type III domain containing 1 in gastric cancer and potential mechanism of action, possibly providing a new insight for future clinical diagnosis or even molecular therapy.

Overexpression of FNDC1 in Gastric Cancer and its Prognostic Significance.

Objectives: The aims of this study were to compare the expression of fibronectin type III domain containing 1 (FNDC1) in gastric cancer (GC) and normal gastric tissue, to explore the prognostic significance of FNDC1 expression in patients with gastric adenocarcinoma, and to analyze FNDC1-related signaling pathways. Methods: The expression level of FNDC1 was initially predicted using the Oncomine and Cancer Genome Atlas databases. A Kaplan-Meier plotter database was mined to examine the clinical prognostic significance of FNDC1 mRNA in patients with GC. Subsequently, immunohistochemistry was used to measure FNDC1 protein expression levels in tissue from 90 cases of GC and paired adjacent normal tissue. Kaplan-Meier univariate and Cox multivariate survival analyses were used to determine the prognostic role of FNDC1 expression. Results: Bioinformatic data indicated that FNDC1 mRNA expression levels were significantly highly expressed in GC compared with normal gastric tissue (all P < 0.05), and patients with GC with high FNDC1 mRNA expression levels had remarkably lower overall survival (all P < 0.01). Immunohistochemical results revealed that expression levels of FNDC1 protein were significantly increased in GC compared with normal gastric tissue (P < 0.001). Additionally, Kaplan-Meier univariate and Cox multivariate survival analyses indicated that increased expression of FNDC1 was an independent predictor of poor prognosis in patients with GC (all P < 0.05). Conclusions: FNDC1 was highly expressed in GC, and high expression of FNDC1 was an independent predictor of poor prognosis in patients with GC. FNDC1 co-expressed genes were largely enriched in extracellular matrix-receptor interactions, which are closely related to tumor metastasis.

A novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in prostate cancer.

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells, and that increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of fibronectin type III domain containing 1 (FNDC1). Our studies also revealed significant overexpression of FNDC1, fibronectin (FN1) and the androgen receptor (AR) in human PCa cell lines as well as tissues, and FNDC1, FN1, and AR positively correlate with aggressive PCa. These findings, recently published in Experimental Cell Research, are the first to describe a novel miR-1207-3p/FNDC1/FN1/AR novel regulatory pathway in PCa.

Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures.

An important role has been attributed to cancer-associated fibroblasts (CAFs) in the tumorigenesis of oral squamous cell carcinoma (OSCC), the most common tumor of the oral cavity. Previous studies demonstrated that CAF-secreted molecules promote the proliferation and invasion of OSCC cells, inducing a more aggressive phenotype. In this study, we searched for differences in the secretome of CAFs and normal oral fibroblasts (NOF) using mass spectrometry-based proteomics and biological network analysis. Comparison of the secretome profiles revealed that upregulated proteins involved mainly in extracellular matrix organization and disassembly and collagen metabolism. Among the upregulated proteins were fibronectin type III domain-containing 1 (FNDC1), serpin peptidase inhibitor type 1 (SERPINE1), and stanniocalcin 2 (STC2), the upregulation of which was validated by quantitative PCR and ELISA in an independent set of CAF cell lines. The transition of transforming growth factor beta 1 (TGF-ß1)-mediating NOFs into CAFs was accompanied by significant upregulation of FNDC1, SERPINE1, and STC2, confirming the participation of these proteins in the CAF-derived secretome. Type I collagen, the main constituent of the connective tissue, was also associated with several upregulated biological processes. The immunoexpression of type I collagen N-terminal propeptide (PINP) was significantly correlated in vivo with CAFs in the tumor front and was associated with significantly shortened survival of OSCC patients. Presence of CAFs in the tumor stroma was also an independent prognostic factor for OSCC disease-free survival. These results demonstrate the value of secretome profiling for evaluating the role of CAFs in the tumor microenvironment and identify potential novel therapeutic targets such as FNDC1, SERPINE1, and STC2. Furthermore, type I collagen expression by CAFs, represented by PINP levels, may be a prognostic marker of OSCC outcome.