FLNA

Gene Summary

Gene:FLNA; filamin A
Aliases: FLN, FMD, MNS, OPD, ABPX, CSBS, CVD1, FGS2, FLN1, NHBP, OPD1, OPD2, XLVD, XMVD, FLN-A, ABP-280
Location:Xq28
Summary:The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:filamin-A
Source:NCBIAccessed: 29 August, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • HEK293 Cells
  • Cell Proliferation
  • KMT2A
  • X Chromosome Inactivation
  • siRNA
  • Young Adult
  • Biomarkers, Tumor
  • Skin Pigmentation
  • Filamins
  • Protein Binding
  • Melanoma
  • RTPCR
  • Protein Structure, Tertiary
  • RNA Interference
  • Phosphorylation
  • Bladder Cancer
  • Nuclear Proteins
  • Infant
  • DNA Sequence Analysis
  • Mutation
  • MAP Kinase Signaling System
  • Prostate Cancer
  • Lymphatic Metastasis
  • X Chromosome
  • Adenocarcinoma
  • Down-Regulation
  • Signal Transduction
  • Neoplasm Invasiveness
  • Breast Cancer
  • Microfilament Proteins
  • Tumor Burden
  • Cell Movement
  • Cancer Gene Expression Regulation
  • Acute Myeloid Leukaemia
  • Neoplasm Proteins
  • Contractile Proteins
  • Androgen Receptors
  • Gene Expression Profiling
  • Insertional Mutagenesis
  • Immunohistochemistry
  • Cytoskeleton
  • Disease Progression
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FLNA (cancer-related)

Xu C, Yu X, Zhu Y, et al.
Overexpression of calpain‑1 predicts poor outcome in patients with colorectal cancer and promotes tumor cell progression associated with downregulation of FLNA.
Oncol Rep. 2019; 41(6):3424-3434 [PubMed] Related Publications
Several studies have demonstrated that calpain‑1 is involved in a variety of pathophysiological processes, including tumorigenesis. However, the clinical relevance and role of calpain‑1 in colorectal cancer (CRC) are unclear. Filamin A (FLNA) is an actin‑binding protein that participates in cancer progression and can be cleaved by calpain‑1. In the present study, the protein expression levels of calpain‑1 and FLNA were detected by immunohistochemistry in 467 matched cancerous and paracancerous tissues from patients with CRC. The staining results and the clinicopathological characteristics of the patients were comprehensively analyzed. A high expression level of calpain‑1 was strongly associated with age, metastasis, Dukes stage and survival time but not with sex, histologic grade, tumour location or tumor size. By contrast, a low expression level of FLNA was significantly associated with tumor size, histological grade, metastasis, Dukes stage and survival time, but not with age, sex, or tumor location. Kaplan‑Meier survival analysis demonstrated that patients with calpain‑1 overexpression had a shorter mean overall survival (OS) than patients with lower levels of calpain‑1 expression. Unlike high levels of calpain‑1, high levels of FLNA were associated with longer OS than lower levels of FLNA expression. Furthermore, calpain‑1 expression was inversely correlated with FLNA expression. The relationship between calpain‑1 and FLNA was further confirmed using CRC cell lines in vitro. When calpain‑1 expression decreased in CRC cells, FLNA expression increased. Furthermore, calpain‑1 knockdown in CRC cells resulted in decreased proliferation, colony formation, migration and invasion. The present findings suggest that calpain‑1 overexpression predicted a poor outcome in patients with CRC and promoted tumor progression, possibly via FLNA downregulation.

Lim SZ, Ng CCY, Rajasegaran V, et al.
Genomic profile of breast sarcomas: a comparison with malignant phyllodes tumours.
Breast Cancer Res Treat. 2019; 174(2):365-373 [PubMed] Related Publications
PURPOSE: We aimed to investigate the genomic profile of breast sarcomas (BS) and compare with that of malignant phyllodes tumours (MPT).
METHODS: DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) specimens from 17 cases of BS diagnosed at Singapore General Hospital from January 1991 to December 2014. Targeted deep sequencing and copy number variation (CNV) analysis on 16 genes, which included recurrently mutated genes in phyllodes tumours and genes associated with breast cancer, were performed on these samples. Genetic alterations (GA) observed were summarised and analysed.
RESULTS: Nine cases met the quality control requirements for both targeted deep sequencing and CNV analysis. Three (33.33%) were angiosarcomas and 6 (66.67%) were non-angiosarcomas. In the non-angiosarcoma group, 83.33% (n = 5) of the patients had GA in the TERT gene. The other commonly mutated genes in this group of tumours were MED12 (n = 4, 66.67%), BCOR (n = 4, 66.67%), KMT2D (n = 3, 50%), FLNA (n = 3, 50%) and NF1 (n = 3, 50%). In contrast, none of the angiosarcomas had mutations or copy number alterations in TERT, MED12, BCOR, FLNA or NF1. Eighty percent of patients with GA in TERT (n = 5) had concurrent mutations in MED12. Sixty percent (n = 3) of these cases also demonstrated GA in NF1, PIK3CA or EGFR which are known cancer driver genes.
CONCLUSIONS: The non-angiosarcoma group of BS was found to share similar GA as those described for MPT, which may suggest a common origin and support their consideration as a similar group of tumours with regard to management and prognostication.

Tian Y, Xu Y, Wang H, et al.
Comprehensive analysis of microarray expression profiles of circRNAs and lncRNAs with associated co-expression networks in human colorectal cancer.
Funct Integr Genomics. 2019; 19(2):311-327 [PubMed] Free Access to Full Article Related Publications
Increasing data demonstrate that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) play important roles in tumorigenesis. However, the mechanisms in colorectal cancer (CRC) remain unclear. Here, hundreds of significantly expressed circRNAs, and thousands of lncRNAs as well as mRNAs were identified. By qRT-PCR, one abnormal circRNA, lncRNA, and three mRNAs were verified in 24 pairs of tissues and blood samples, respectively. Then, by GO analysis, we found that the gene expression profile of linear counterparts of upregulated circRNAs in human CRC tissues preferred positive regulation of GTPase activity, cellular protein metabolic process, and protein binding, while that of downregulated circRNAs of CRC preferred positive regulation of cellular metabolic process, acetyl-CoA metabolic process, and protein kinase C activity. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that p53 signaling pathway was an important pathway in upregulated protein-coding genes, whereas cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway was the top enriched KEGG pathway for downregulated transcripts. Furthermore, lncRNA-mRNA co-expression analysis demonstrated that downregulated lncRNA uc001tma.3 was negatively with CDC45 and positively with ELOVL4, BVES, FLNA, and HSPB8, while upregulated lncRNA NR_110882 was positively with FZD2. In addition, lncRNA-transcription factor (TF) co-expression analysis showed that the most relevant TFs were forkhead box protein A1 (FOXA1), transcription initiation factor TFIID submint 7 (TAF7), and adenovirus early region 1A(E1A)-associated protein p300 (EP300). Our findings offer a fresh view on circRNAs and lncRNAs and provide the foundation for further study on the potential roles of circRNAs and lncRNAs in colorectal cancer.

Ruan W, Zhai Y, Yu K, et al.
Coated microneedles mediated intradermal delivery of octaarginine/BRAF siRNA nanocomplexes for anti-melanoma treatment.
Int J Pharm. 2018; 553(1-2):298-309 [PubMed] Related Publications
BRAF is the most frequently mutated gene in skin melanoma. Applying BRAF siRNA (siBraf) to silencing BRAF gene is a current frontline therapy for melanoma. However, delivery of macromolecular siRNA into the tumor site and introduction of siRNA into the tumor cells remain as challenges. In this study, we for the first time developed a siBraf delivery system based on cell penetrating peptide octaarginine (R8) nanocomplexes combined with coated microneedles (MNs), i.e. R8/siBraf coated MNs, for targeted anti-melanoma treatment. The R8/siBraf nanocomplexes were optimized based on the internalization of siBraf by A375 cells. In vitro A375 cell experiments presented that R8/siBraf can enhance siBraf transfection, silence BRAF gene, and inhibit tumor cells growth, comparable to polyethylenimine (PEI)/siBraf. R8/siBraf coated MNs can effectively deliver R8/siBraf into the disease site. In vivo anti-melanoma experiments indicated that R8/siBraf coated MNs can significantly inhibit the melanoma development, induce the tumor cells apoptosis, and suppress their proliferation. The BRAF gene in tumor were also significantly silenced in vivo. SiBraf intradermal delivery via combining MNs and R8 nanocomplexes is a promising approach for skin melanoma treatment, which exploited both virtues of MNs and cell penetrating peptide to obtain the targeting inhibition efficacy on skin melanoma.

Ji ZM, Yang LL, Ni J, et al.
Silencing Filamin A Inhibits the Invasion and Migration of Breast Cancer Cells by Up-regulating 14-3-3σ.
Curr Med Sci. 2018; 38(3):461-466 [PubMed] Related Publications
Filamin A and 14-3-3-σ are closely associated with the development of breast cancer. However, the exact relationship between them is still unknown. The present study aimed to examine the interaction of filamin A with 14-3-3-σ in the invasion and migration of breast cancer. RNA interference technology was employed to silence filamin A in MDA-MB-231 cells. Real-time PCR and Western blotting were used to detect the expression of filamin A and 14-3-3-σ at mRNA and protein levels, respectively. Double immunofluorescence was applied to show their colocalization morphologically. Wound healing assay and Trans-well assay were used to testify the migration and invasion of MDA-MB-231 cells in filamin A-silenced cells. The results showed that silencing filamin A significantly increased the mRNA and protein levels of 14-3-3σ. In addition, double immunofluorescence displayed that filamin A and 14-3-3σ were predominantly colocalized in the cytoplasm of MDA-MB-231 cells. Silencing filamin A led to the enhanced fluorescence of 14-3-3σ. Furthermore, cell functional experiments showed that silencing filamin A inhibited the migration and invasion of MDA-MB-231 cells in vitro. In conclusion, silencing filamin A may inhibit the invasion and migration of breast cancer cells by upregulating 14-3-3σ.

Kokate SB, Dixit P, Poirah I, et al.
Testin and filamin-C downregulation by acetylated Siah2 increases invasiveness of Helicobacter pylori-infected gastric cancer cells.
Int J Biochem Cell Biol. 2018; 103:14-24 [PubMed] Related Publications
Helicobacter pylori is the strongest known risk-factor for gastric cancer. However, its role in gastric cancer metastasis remains unclear. Previously we have reported that H. pylori promotes gastric cancer invasiveness by stabilizing the E3 ubiquitin ligase Siah2 which is mediated by Siah2 acetylation at Lys 139 (K

Collins RRJ, Barth B, Megison S, et al.
ACTG2-Associated Visceral Myopathy With Chronic Intestinal Pseudoobstruction, Intestinal Malrotation, Hypertrophic Pyloric Stenosis, Choledochal Cyst, and a Novel Missense Mutation.
Int J Surg Pathol. 2019; 27(1):77-83 [PubMed] Related Publications
Primary visceral myopathy caused by a pathogenic mutation in the gene encoding the enteric smooth muscle actin gamma 2 ( ACTG2) affects gastrointestinal and genitourinary tracts and often presents as chronic intestinal pseudoobstruction. We present a case of pediatric onset chronic intestinal pseudoobstruction associated with a novel missense ACTG2 mutation c.439G>T/p.G147C. In addition to the known disease manifestations of feeding intolerance and intestinal malrotation, our patient had a late-onset hypertrophic pyloric stenosis and a late-onset choledochal cyst, the former of which has not previously been described in patients with ACTG2-associated visceral myopathy.

Treppiedi D, Jobin ML, Peverelli E, et al.
Single-Molecule Microscopy Reveals Dynamic FLNA Interactions Governing SSTR2 Clustering and Internalization.
Endocrinology. 2018; 159(8):2953-2965 [PubMed] Related Publications
The cytoskeletal protein filamin A (FLNA) has been suggested to play an important role in the responsiveness of GH-secreting pituitary tumors to somatostatin receptor subtype 2 (SSTR2) agonists by regulating SSTR2 expression and signaling. However, the underlying mechanisms are unknown. In this study, we use fast multicolor single-molecule microscopy to image individual SSTR2 and FLNA molecules at the surface of living cells with unprecedented spatiotemporal resolution. We find that SSTR2 and FLNA undergo transient interactions, which occur preferentially along actin fibers and contribute to restraining SSTR2 diffusion. Agonist stimulation increases the localization of SSTR2 along actin fibers and, subsequently, SSTR2 clustering and recruitment to clathrin-coated pits (CCPs). Interfering with FLNA-SSTR2 binding with a dominant-negative FLNA fragment increases SSTR2 mobility, hampers the formation and alignment of SSTR2 clusters along actin fibers, and impairs both SSTR2 recruitment to CCPs and SSTR2 internalization. These findings indicate that dynamic SSTR2-FLNA interactions critically control the nanoscale localization of SSTR2 at the plasma membrane and are required for coupling SSTR2 clustering to internalization. These mechanisms explain the critical role of FLNA in the control of SSTR2 expression and signaling and suggest the possibility of targeting SSTR2-FLNA interactions for the therapy of pharmacologically resistant GH-secreting pituitary tumors.

Liberati D, Marzinotto I, Brigatti C, et al.
No evidence of pancreatic ductal adenocarcinoma specific autoantibodies to Ezrin in a liquid phase LIPS immunoassay.
Cancer Biomark. 2018; 22(2):351-357 [PubMed] Related Publications
BACKGROUND: Sensitive and specific biomarkers of Pancreatic Ductal Adenocarcinoma (PDAC) are desperately needed to allow early diagnosis and improve patient's survival. Ezrin autoantibodies were recently described as present in 93% of PDAC patients and 40% of healthy subjects who later developed PDAC. However, another prospective study failed to replicate these findings. Both studies were based on the use of a solid phase ELISA immunoassay.
OBJECTIVE: We aimed at re-evaluating the usefulness of Ezrin autoantibodies as PDAC biomarkers using the Luciferase Immuno Precipitation System (LIPS), an alternative immunoassay format that found successful application for the measurement of autoantibodies against pancreatic autoantigens.
METHODS: We produced a Nanoluciferase™ tagged Ezrin (NLuc-Ezrin). NLuc-Ezrin was then used as antigen in LIPS to test for Ezrin autoantibodies patients affected by PDAC (n= 40), other pancreatic diseases (OPD, n= 50), and healthy controls (n= 60).
RESULTS: Overall, binding in liquid phase to Ezrin by serum antibodies was rare and low titer. Furthermore, we did not find statistically significant differences in the prevalence of Ezrin autoantibodies between patients affected by either PDAC or OPD compared to control.
CONCLUSIONS: Our results do not confirm the usefulness of Ezrin autoAbs as biomarker of PDAC.

Pudova EA, Kudryavtseva AV, Fedorova MS, et al.
HK3 overexpression associated with epithelial-mesenchymal transition in colorectal cancer.
BMC Genomics. 2018; 19(Suppl 3):113 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) is a common cancer worldwide. The main cause of death in CRC includes tumor progression and metastasis. At molecular level, these processes may be triggered by epithelial-mesenchymal transition (EMT) and necessitates specific alterations in cell metabolism. Although several EMT-related metabolic changes have been described in CRC, the mechanism is still poorly understood.
RESULTS: Using CrossHub software, we analyzed RNA-Seq expression profile data of CRC derived from The Cancer Genome Atlas (TCGA) project. Correlation analysis between the change in the expression of genes involved in glycolysis and EMT was performed. We obtained the set of genes with significant correlation coefficients, which included 21 EMT-related genes and a single glycolytic gene, HK3. The mRNA level of these genes was measured in 78 paired colorectal cancer samples by quantitative polymerase chain reaction (qPCR). Upregulation of HK3 and deregulation of 11 genes (COL1A1, TWIST1, NFATC1, GLIPR2, SFPR1, FLNA, GREM1, SFRP2, ZEB2, SPP1, and RARRES1) involved in EMT were found. The results of correlation study showed that the expression of HK3 demonstrated a strong correlation with 7 of the 21 examined genes (ZEB2, GREM1, TGFB3, TGFB1, SNAI2, TWIST1, and COL1A1) in CRC.
CONCLUSIONS: Upregulation of HK3 is associated with EMT in CRC and may be a crucial metabolic adaptation for rapid proliferation, survival, and metastases of CRC cells.

Pan J, Ruan W, Qin M, et al.
Intradermal delivery of STAT3 siRNA to treat melanoma via dissolving microneedles.
Sci Rep. 2018; 8(1):1117 [PubMed] Free Access to Full Article Related Publications
Hyperactivity of signal transducer and activity of transcription 3 (STAT3) plays a crucial role in melanoma invasion and metastasis. Gene therapy applying siRNA targeting STAT3 is a potential therapeutic strategy for melanoma. In this article, we first fabricated safe and novel dissolving microneedles (MNs) for topical application of STAT3 siRNA to enhance the skin penetration of siRNA and used polyethylenimine (PEI, 25 kDa) as carrier to improve cellular uptake of siRNA. The results showed that MNs can effectively penetrate skin and rapidly dissolve in the skin. In vitro B16F10 cell experiments presented that STAT3 siRNA PEI complex can enhance cellular uptake and transfection of siRNA, correspondingly enhance gene silencing efficiency and inhibit tumor cells growth. In vivo experiments indicated that topical application of STAT3 siRNA PEI complex delivered by dissolving MNs into skin can effectively suppress the development of melanoma through silencing STAT3 gene, and the inhibition effect is dose-dependent. STAT3 siRNA delivery via dissolving MNs is a promising approach for skin melanoma treatment with targeting inhibition efficacy and minimal adverse effects.

Wang Z, Li C, Jiang M, et al.
Filamin A (FLNA) regulates autophagy of bladder carcinoma cell and affects its proliferation, invasion and metastasis.
Int Urol Nephrol. 2018; 50(2):263-273 [PubMed] Related Publications
PURPOSE: This research intended to explore the effect of FLNA on cell proliferation, invasion and migration in bladder carcinoma (BC).
METHODS: Microarray analysis was performed with the TCGA data, and the results were confirmed on 20 paired BC tissues and adjacent tissues using qRT-PCR and immunohistochemistry. Transmission electron microscope (TEM) and cell fluorescence assay were used to observe the quantity of autophagosomes. The expression of autophagy-related protein (LC3-I/II, p62) was detected by western blot. Cell proliferation was detected using CCK-8 and colony formation. The invasion and migration ability of the cell were tested by transwell and wound-healing assay. Tumor xenograft in BALB/c nude mice and HE staining were utilized to probe into the effects of FLNA-induced regulation of volume, weight and metastasis of tumors.
RESULTS: We confirmed that FLNA was down-regulated in BC tissues. TEM and fluorescence analysis proved that FLNA overexpression promoted autophagy in BC cells. Colony formation assay and CCK-8 experiment showed that FLNA overexpression suppressed the proliferation of BC cells. In addition, FLNA blocked cell cycle and promoted apoptosis of BC cell. Transwell assay and wound-healing assay further proved that FLNA suppressed invasion and migration ability in BC cell. Meanwhile, in vivo study indicated that FLNA inhibited the tumor growth.
CONCLUSION: Overexpression of FLNA suppressed the proliferation, migration and invasion of the BC cell, suggesting the potential role of FLNA in clinical treatment.

Vokuhl C, Nourkami-Tutdibi N, Furtwängler R, et al.
ETV6-NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study.
Pediatr Blood Cancer. 2018; 65(4) [PubMed] Related Publications
BACKGROUND: Congenital mesoblastic nephroma (MN) is a rare pediatric renal tumor representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically: classical, cellular, and mixed. A frequent genetic alteration is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular MN. The aim of this study was to determine translocation status of a large cohort of MN with respect to tumor subtype and outcome.
PROCEDURE: In total, clinical data from 111 patients were available. Sixty-seven tumors were classical MN (51%), 29 cellular MN (31%), and 15 were mixed MN (18%). From these 111 cases, 79 were analyzed by FISH and RT-PCR.
RESULTS: All classical and mixed MN were translocation negative. Seventeen out of 29 (58%) cellular MN harbored the ETV6-NTRK3 translocation. Five-year relapse-free survival (RFS) and overall survival (OS) were 93.2% and 96.8% for the complete cohort. All seven relapses occurred in translocation negative tumors. Five-year RFS was significantly inferior for cellular and mixed MN compared to classic MN (89%, 80%, and 98%), whereas 5-year OS was similar (93%, 96%, and 98%). Within the group of cellular MN, patients having translocation-positive tumors had a significantly superior RFS (5-year RFS: 100% vs. 73%).
CONCLUSION: The majority of cellular MNs harbor the ETV6-NTKR3 gene fusion, whereas all classic- and mixed-type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS.

Zhang Y, Zhu T, Liu J, et al.
FLNa negatively regulated proliferation and metastasis in lung adenocarcinoma A549 cells via suppression of EGFR.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(2):164-170 [PubMed] Related Publications
Filamin A (FLNa) is a ubiquitously expressed cytoplasmic protein, which composes of an N-terminal actin binding domain (ABD) followed by 24 Ig-like repeats. FLNa functions as a cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and serves as a signaling intermediate. Recent studies have identified FLNa as a scaffold protein that interacts with over 90 proteins and plays vital roles in cellular signaling transduction. Mutations or defects in human FLNa gene have been shown to cause numerous developmental defects. Moreover, aberrant expression of FLNa has been observed in many cancers, such as parathyroid tumor, cervical cancer, and breast cancer. However, its role in lung adenocarcinoma has seldom been discussed. In the present study, our in vitro and in vivo studies demonstrated that silencing FLNa expression in lung cancer cell line A549 cells promoted proliferation, migration, and invasiveness of A549 cells by enhancing the activation of epidermal growth factor receptor and ERK signaling pathway. These results shed light on novel functions of FLNa in lung cancer and uncovered novel mechanisms, these results provided possible targets for the prediction and treatment for lung adenocarcinoma.

Fernández L, Tenorio J, Polo-Vaquero C, et al.
In-frame Variants in FLNA Proximal Rod 1 Domain Associate With a Predominant Cardiac Valvular Phenotype.
Rev Esp Cardiol (Engl Ed). 2018; 71(7):545-552 [PubMed] Related Publications
INTRODUCTION AND OBJECTIVES: X-linked cardiac valvular dysplasia is a rare form of male-specific congenital heart defect mainly characterized by myxomatous degeneration of the atrioventricular valves with variable hemodynamic consequences. It is caused by genetic defects in FLNA-encoded filamin A, a widely expressed actin-binding protein that regulates cytoskeleton organization. Filamin A loss of function has also been associated with often concurring neurologic and connective tissue manifestations, with mutations in the first half of the Rod 1 domain apparently expressing the full cardiac phenotype. We contribute to previous genotype-phenotype correlations with a multidisciplinary approach in a newly-described family.
METHODS: Cardiologic, dysmorphologic, and genetic evaluation of available members were complemented with transcriptional and X-chromosome inactivation studies.
RESULTS: A novel FLNA mutation c.1066-3C>G cosegregated with a male-expressed, apparently isolated, cardiac phenotype with no skewed X-inactivation pattern in female carriers. This variant was shown to result in an in-frame deletion of 8 amino acid residues near the N-terminal region of the protein.
CONCLUSIONS: A nonimprinted, partial loss of function of filamin A proximal Rod 1 domain seems to be the pathogenetic mechanism of cardiac valvular dysplasia, with some cases occasionally expressing associated extracardiac manifestations.

Blum A, Yehuda H, Geron N, Meerson A
Elevated Levels of miR-122 in Serum May Contribute to Improved Endothelial Function and Lower Oncologic Risk Following Bariatric Surgery.
Isr Med Assoc J. 2017; 19(10):620-624 [PubMed] Related Publications
BACKGROUND: Weight loss surgery is the most effective treatment for obesity, and it reduces cardiovascular and cancer risk through poorly understood mechanisms. MicroRNAs (miRNAs) are short RNA molecules that regulate the stability and translation of many mRNAs. We hypothesized that levels of specific circulating miRNAs are altered following surgery and may contribute to lower cancer risk.
OBJECTIVES: To investigate the change of miRNA following surgery.
METHODS: All patients underwent gastric "sleeve operation". RNA was isolated from sera of 21 patients (14 men, 7 women) before and 3 months after surgery. Sera were combined into two pools, which served for cDNA library construction followed by miSeq sequencing. The levels of candidate miRNAs were validated in the individual samples by QRT-PCR.
RESULTS: Serum miR-122 was significantly up-regulated 3 months post-bariatric surgery in sera of patients, whose endothelial function had greatly improved. In addition, serum miR-122 levels correlated positively with endothelial function as measured by FMD. The changes in miR-122 levels from pre-surgery to 3 months post-surgery also tended to correlate with the respective changes in FMD.
CONCLUSIONS: The serum miR-122/miR-451 ratio may serve as a marker for endothelial function in obese patients. miR-122 is the dominant miRNA in the liver and a known tumor suppressor. Our findings suggest a role for circulating miR-122 in the maintenance of vascular endothelial cells (VECs) and in the prevention of cancer. Further studies are required to elucidate the mechanism of its secretion into circulation and its absorption by VECs, as well as its relevant cellular targets.

Yang X, Cheng Z, Zhang L, et al.
Prion Protein Family Contributes to Tumorigenesis via Multiple Pathways.
Adv Exp Med Biol. 2017; 1018:207-224 [PubMed] Related Publications
A wealth of evidence suggests that proteins from prion protein (PrP) family contribute to tumorigenesis in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), breast cancer, glioblastoma, colorectal cancer, gastric cancer, melanoma, etc. It is well documented that PrP is a biomarker for PDAC, breast cancer, and gastric cancer. However, the underlying mechanisms remain unclear. The major reasons for cancer cell-caused patient death are metastasis and multiple drug resistance, both of which connect to physiological functions of PrP expressing in cancer cells. PrP enhances tumorigenesis by multiple pathways. For example, PrP existed as pro-PrP in most of the PDAC cell lines, thus increasing cancer cell motility by binding to cytoskeletal protein filamin A (FLNa). Using PDAC cell lines BxPC-3 and AsPC-1 as model system, we identified that dysfunction of glycosylphosphatidylinositol (GPI) anchor synthesis machinery resulted in the biogenesis of pro-PrP. In addition, in cancer cells without FLNa expression, pro-PrP can modify cytoskeleton structure by affecting cofilin/F-actin axis, thus influencing cancer cell movement. Besides pro-PrP, we showed that GPI-anchored unglycosylated PrP can elevate cell mobility by interacting with VEGFR2, thus stimulating cell migration under serum-free condition. Besides affecting cancer cell motility, overexpressed PrP or doppel (Dpl) in cancer cells has been shown to increase cell proliferation, multiple drug resistance, and angiogenesis, thus, proteins from PrP gene family by affecting important processes via multiple pathways for cancer cell growth exacerbating tumorigenesis.

Wills ES, Te Morsche RHM, van Reeuwijk J, et al.
Liver cyst gene knockout in cholangiocytes inhibits cilium formation and Wnt signaling.
Hum Mol Genet. 2017; 26(21):4190-4202 [PubMed] Related Publications
Mutations in the PRKCSH, SEC63 and LRP5 genes cause autosomal dominant polycystic liver disease (ADPLD). The proteins products of PRKCSH (alias GIIB) and SEC63 function in protein quality control and processing in the endoplasmic reticulum (ER), while LRP5 is implicated in Wnt/β-catenin signaling. To identify common denominators in the PLD pathogenesis, we mapped the PLD interactome by affinity proteomics, employing both HEK293T cells and H69 cholangiocytes. Identification of known complex members, such as glucosidase IIA (GIIA) for PRKCSH, and SEC61A1 and SEC61B for SEC63, confirmed the specificity of the analysis. GANAB, encoding GIIA, was very recently identified as an ADPLD gene. The presence of GIIA in the LRP5 complex pinpoints a potential functional connection with PRKCSH. Interestingly, all three PLD-associated protein complexes included filamin A (FLNA), a multifunctional protein described to play a role in ciliogenesis as well as canonical Wnt signalling. As ciliary dysfunction may also contribute to hereditary liver cyst formation, we evaluated the requirement of PRKCSH and SEC63 for ciliogenesis and Wnt signaling. By CRISPR/Cas9 induced knockdown of both ADPLD genes in HEK293T cells and H69 cholangiocytes, we identified that their depletion results in defective ciliogenesis. However, only H69 knockouts displayed reduced Wnt3a activation. Our results suggest that loss of PRKCSH and SEC63 leads to general defects in ciliogenesis, while quenching of the Wnt signaling cascade is cholangiocyte-restricted. Interactions of all three PLD-associated protein complexes with FLNA may mark a common link between the ADPLD proteins and the cystogenic processes driving this disease.

Wieczorek K, Wiktorska M, Sacewicz-Hofman I, et al.
Filamin A upregulation correlates with Snail-induced epithelial to mesenchymal transition (EMT) and cell adhesion but its inhibition increases the migration of colon adenocarcinoma HT29 cells.
Exp Cell Res. 2017; 359(1):163-170 [PubMed] Related Publications
Filamin A (FLNA) is actin filament cross-linking protein involved in cancer progression. Its importance in regulating cell motility is directly related to the epithelial to mesenchymal transition (EMT) of tumor cells. However, little is known about the mechanism of action of FLNA at this early stage of cancer invasion. Using immunochemical methods, we evaluated the levels and localization of FLNA, pFLNA[Ser2152], β1 integrin, pβ1 integrin[Thr788/9], FAK, pFAK[Y379], and talin in stably transfected HT29 adenocarcinoma cells overexpressing Snail and looked for the effect of Snail in adhesion and migration assays on fibronectin-coated surfaces before and after FLNA silencing. Our findings indicate that FLNA upregulation correlates with Snail-induced EMT in colorectal carcinoma. FLNA localizes in the cytoplasm and at the sites of focal adhesion (FA) of invasive cells. Silencing of FLNA inhibits Snail-induced cell adhesion, reduces the size of FA sites, induces the relocalization of talin from the cytoplasm to the membrane area and augments cell migratory properties. Our findings suggest that FLNA may not act as a classic integrin inhibitor in invasive carcinoma cells, but is involved in other pro-invasive pathways. FLNA upregulation, which correlates with cell metastatic properties, maybe an additional target for combination therapy in colorectal carcinoma tumor progression.

Maes B, Willemse J, Broekmans A, et al.
Targeted next-generation sequencing using a multigene panel in myeloid neoplasms: Implementation in clinical diagnostics.
Int J Lab Hematol. 2017; 39(6):604-612 [PubMed] Related Publications
INTRODUCTION: Detection of mutations in patients with myeloid neoplasms (MNs) has shown great potential for diagnostic and prognostic purposes. Next-generation sequencing (NGS) is currently implemented for the diagnostic profiling of the four major MN subgroups.
METHODS: First, we validated the targeted NGS approach using the TruSight Myeloid panel. Next, we screened 287 patients with a clinical suspicion of MN and 61 follow-up patients with documented MN.
RESULTS: Validation of the NGS workflow resulted in maximal precision, accuracy, sensitivity, and specificity for gene variants with an allele frequency of at least 5% and a minimal read depth of 300. In our diagnostic screen, we identified at least one somatic mutation in 89% of patients with proven MN. Of the 155 newly diagnosed MN cases, 126 (81%) showed at least one mutation, confirming clonality. Moreover, the co-occurrence of mutated genes in the different MN subentities facilitates their classification and justifies the diagnostic use of a pan-myeloid panel. Furthermore, several of these mutations provide additional prognostic information independently of traditional prognostic scoring systems.
CONCLUSION: Pan-myeloid targeted NGS fits elegantly in the routine diagnostic approach of MNs allowing for an improved diagnosis, subclassification, and prognosis.

Kumar R, Samal SK, Routray S, et al.
Identification of oral cancer related candidate genes by integrating protein-protein interactions, gene ontology, pathway analysis and immunohistochemistry.
Sci Rep. 2017; 7(1):2472 [PubMed] Free Access to Full Article Related Publications
In the recent years, bioinformatics methods have been reported with a high degree of success for candidate gene identification. In this milieu, we have used an integrated bioinformatics approach assimilating information from gene ontologies (GO), protein-protein interaction (PPI) and network analysis to predict candidate genes related to oral squamous cell carcinoma (OSCC). A total of 40973 PPIs were considered for 4704 cancer-related genes to construct human cancer gene network (HCGN). The importance of each node was measured in HCGN by ten different centrality measures. We have shown that the top ranking genes are related to a significantly higher number of diseases as compared to other genes in HCGN. A total of 39 candidate oral cancer target genes were predicted by combining top ranked genes and the genes corresponding to significantly enriched oral cancer related GO terms. Initial verification using literature and available experimental data indicated that 29 genes were related with OSCC. A detailed pathway analysis led us to propose a role for the selected candidate genes in the invasion and metastasis in OSCC. We further validated our predictions using immunohistochemistry (IHC) and found that the gene FLNA was upregulated while the genes ARRB1 and HTT were downregulated in the OSCC tissue samples.

Lentes J, Thomay K, Schneider DT, et al.
Identification of a Cryptic Insertion ins(11;X)(q23;q28q12) Resulting in a KMT2A-FLNA Fusion in a 13-Month-Old Child with Acute Myelomonocytic Leukemia.
Cytogenet Genome Res. 2016; 150(3-4):281-286 [PubMed] Related Publications
In pediatric acute myeloid leukemia (AML), chromosomal abnormalities leading to a disruption of the lysine methyltransferase 2A (KMT2A) gene in 11q23 are the most frequent rearrangements. Here, we report on the identification of a novel cryptic insertion, ins(11;X)(q23;q28q12), resulting in a translocation of the KMT2A gene in 11q23, leading to a KMT2A-FLNA fusion in a 13-month-old boy with de novo acute myelomonocytic leukemia, who died 38 days after diagnosis. The patient presented a complex karyotype 48∼49,Y,del(X)(q12),+del(X)(q12),+8,ins(11;X)(q23; q28q12),+19. The identified fusion gene was predicted to be out-of-frame (fusion of portions of KMT2A exon 11 with FLNA exon 11). However, RT-PCR experiments demonstrated that a potentially functional transcript was generated by alternative splicing where KMT2A exon 10 was spliced in-frame to the truncated FLNA exon 11. This case report helps to better understand the rare but potentially severe impact of KMT2A- FLNA fusions in infants with AML to improve prognostic stratification of therapy and clinical management.

Ganser A, Heuser M
Therapy-related myeloid neoplasms.
Curr Opin Hematol. 2017; 24(2):152-158 [PubMed] Related Publications
PURPOSE OF REVIEW: Advances in the genetic characterization of patients with therapy-related myeloid neoplasms (t-MNs) have changed our understanding of the pathogenesis of these diseases. In addition, extensive sequencing studies have identified recurrent mutations with diagnostic and prognostic impact. Thus, the revised version of the WHO classification combines therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute myeloid leukemia (t-AML) in the one entity of t-MNs because of their similar pathogenesis, rapid progression from t-MDS to t-AML, and their equally poor prognosis.
RECENT FINDINGS: Fifteen percent of t-AML patients present with favorable risk fusion genes, whereas 50% have adverse cytogenetics. The most frequent molecular aberration in t-AML and t-MDS affects TP53 (33%). Selection of a pre-existing treatment-resistant hematopoietic stem cell clone with TP53 mutation has been shown as an important mechanism in the development of t-MNs and explains the high frequency of TP53 mutations in these patients. Following previous cytotoxic therapy, patients develop specific vulnerabilities, which become especially evident as high nonrelapse mortality of t-MN patients after allogeneic hematopoietic cell transplantation.
SUMMARY: Patients are treated according to their genetic risk profile. Assessment of minimal residual disease helps to guide allogeneic transplantation for patients with favorable risk and genetic markers.

Mingione A, Verdelli C, Ferrero S, et al.
Filamin A is reduced and contributes to the CASR sensitivity in human parathyroid tumors.
J Mol Endocrinol. 2017; 58(2):91-103 [PubMed] Related Publications
Parathyroid tumors display reduced sensitivity to extracellular calcium ([Ca

Tsui JC, Lau CP, Cheung AC, et al.
Differential expression of filamin B splice variants in giant cell tumor cells.
Oncol Rep. 2016; 36(6):3181-3187 [PubMed] Free Access to Full Article Related Publications
Giant cell tumor of bone (GCT) is the most commonly reported non-malignant bone tumor in Hong Kong. This kind of tumor usually affects people aged 20-40 years. Also, it is well known for recurrence locally, especially when the tumor cannot be removed completely. Filamins are actin-binding proteins which contain three family members, filamin A, B and C. They are the products of three different genes, FLNA, FLNB and FLNC, which can generate various transcript variants in different cell types. In this study, we focused on the effects of FLNBv2 and FLNBv4 toward GCT cells. The only difference between FLNBv2 and FLNBv4 is that FLNBv4 does not contain hinge 1 region. We found that the relative abundance of FLNBv4 varies among different GCT cell lines while the expression level of FLNBv4 in normal osteoblasts was only marginally detectable. In the functional aspect, overexpression of FLNBv4 led to upregulation of RANKL, OCN, OPG and RUNX2, which are closely related to GCT cell survival and differentiation. Moreover, FLNBv4 can have a negative effect on cell viability of GCT cells when compare with FLNBv2. In conclusion, splicing variants of FLNB are differentially expressed in GCT cells and may play a role in the proliferation and differentiation of tumor cells.

La Padula V, Staszewski O, Nestel S, et al.
HSPB3 protein is expressed in motoneurons and induces their survival after lesion-induced degeneration.
Exp Neurol. 2016; 286:40-49 [PubMed] Related Publications
The human small heat shock proteins (HSPBs) form a family of molecular chaperones comprising ten members (HSPB1-HSPB10), whose functions span from protein quality control to cytoskeletal dynamics and cell death control. Mutations in HSPBs can lead to human disease and particularly point mutations in HSPB1 and HSPB8 are known to lead to peripheral neuropathies. Recently, a missense mutation (R7S) in yet another member of this family, HSPB3, was found to cause an axonal motor neuropathy (distal hereditary motor neuropathy type 2C, dHMN2C). Until now, HSPB3 protein localization and function in motoneurons (MNs) have not yet been characterized. Therefore, we studied the endogenous HSPB3 protein distribution in the spinal cords of chicken and mouse embryos and in the postnatal nervous system (central and peripheral) of chicken, mouse and human. We further investigated the impact of wild-type and mutated HSPB3 on MN cell death via overexpressing these genes in ovo in an avian model of MN degeneration, the limb-bud removal. Altogether, our findings represent a first step for a better understanding of the cellular and molecular mechanisms leading to dHMN2C.

Liu W, Zeng L, Li N, et al.
Quantitative proteomic analysis for novel biomarkers of buccal squamous cell carcinoma arising in background of oral submucous fibrosis.
BMC Cancer. 2016; 16:584 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In South and Southeast Asian, the majority of buccal squamous cell carcinoma (BSCC) can arise from oral submucous fibrosis (OSF). BSCCs develop in OSF that are often not completely resected, causing local relapse. The aim of our study was to find candidate protein biomarkers to detect OSF and predict prognosis in BSCCs by quantitative proteomics approaches.
METHODS: We compared normal oral mucosa (NBM) and paired biopsies of BSCC and OSF by quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to discover proteins with differential expression. Gene Ontology and KEGG networks were analyzed. The prognostic value of biomarkers was evaluated in 94 BSCCs accompanied with OSF. Significant associations were assessed by Kaplan-Meier survival and Cox-proportional hazards analysis.
RESULTS: In total 30 proteins were identified with significantly different expression (false discovery rate < 0.05) among three tissues. Two consistently upregulated proteins, ANXA4 and FLNA, were validated. The disease-free survival was negatively associated with the expression of ANXA4 (hazard ratio, 3.4; P = 0.000), FLNA (hazard ratio, 2.1; P = 0.000) and their combination (hazard ratio, 8.8; P = 0.002) in BSCCs.
CONCLUSION: The present study indicates that iTRAQ quantitative proteomics analysis for tissues of BSCC and OSF is a reliable strategy. A significantly up-regulated ANXA4 and FLNA could be not only candidate biomarkers for BSCC prognosis but also potential targets for its therapy.

Di Biase S, Lee C, Brandhorst S, et al.
Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity.
Cancer Cell. 2016; 30(1):136-146 [PubMed] Free Access to Full Article Related Publications
Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8(+) tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8(+)-dependent tumor cytotoxicity.

Huang C, Miller RT, Freter CE
Signaling regulation and role of filamin A cleavage in Ca2+-stimulated migration of androgen receptor-deficient prostate cancer cells.
Oncotarget. 2017; 8(3):3840-3853 [PubMed] Free Access to Full Article Related Publications
Ca2+, a ubiquitous cellular signal, and filamin A, an actin-binding protein, play an important role in the regulation of cell adhesion, shape and motility. Using transwell filters to analyze cell migration, we found that extracellular Ca2+ (Cao2+) promotes the migration of androgen receptor (AR)-deficient and highly metastatic prostate cancer cell lines (DU145 and PC-3) compared to AR-positive and relatively less metastatic prostate cancer cells (LNCaP). Furthermore, we found that expression of filamin A is up-regulated in DU145 and PC-3 cells, and that Cao2+ significantly induces the cleavage of filamin A. Silencing expression of Ca2+-sensing receptor (CaR) and p115RhoGEF, and treating with leupeptin, a protease inhibitor, and ALLM, a calpain specific inhibitor, we further demonstrate that Cao2+-induced filamin A cleavage occurs via a CaR- p115RhoGEF-calpain dependent pathway. Our data show that Cao2+ via CaR- mediated signaling induces filamin A cleavage and promotes the migration in AR-deficient and highly metastatic prostate cancer cells.

Saikia S, Barooah P, Bhattacharyya M, et al.
Polymorphisms in Heat Shock Proteins A1B and A1L (HOM) as Risk Factors for Oesophageal Carcinoma in Northeast India.
Asian Pac J Cancer Prev. 2015; 16(18):8227-33 [PubMed] Related Publications
BACKGROUND: To investigate polymorphisms in heat shock proteins A1B and A1L (HOM) and associated risk of oesophageal carcinoma in Northeast India.
MATERIALS AND METHODS: The study includes oesophageal cancer (ECA) patients attending general outpatient department (OPD) and endoscopic unit of Gauhati Medical College. Patients were diagnosed based on endoscopic and histopathological findings. Genomic DNA was typed for HSPA1B1267 and HSPA1L2437 SNPs using the polymerase chain reaction with restriction fragment length polymorphisms.
RESULTS: A total of 78 cases and 100 age-sex matched healthy controls were included in the study with a male: female ratio of 5:3 and a mean age of 61.4±8.5 years. Clinico-pathological evaluation showed 84% had squamous cell carcinoma and 16% were adenocarcinoma. Dysphagia grades 4 (43.5%) and 5 (37.1%) were observed by endoscopic and hispathological evaluation. The frequency of genomic variation of A1B from wild type A/A to heterozygous A/G and mutant G/G showed a positive association [chi sq=19.9, p= <0.05] and the allelic frequency also showed a significant correlation [chi sq=10.3, with cases vs. controls, OR=0.32, p≤0.05]. The genomic variation of A1L from wild T/T to heterozygous T/C and mutant C/C were found positively associated [chi sq= 7.02, p<0.05] with development of ECA. While analyzing the allelic frequency, there was no significant association [chi sq= 3.19, OR=0.49, p=0.07]. Among all the risk factors, betel quid [OR =9.79, Chi square= 35.0, p<0.05], tobacco [OR = 2.95, chi square=10.6, p<0.05], smoking [OR=3.23, chi square=10.1, p<0.05] demonstrated significant differences between consumers vs. non consumers regarding EC development. Alcohol did not show any significant association [OR= 1.34, chi square=0.69, p=0.4] independently.
CONCLUSIONS: It can be concluded that the present study provides marked evidence that polymorphisms of HSP70 A1B and HSP70 A1L genes are associated with the development of ECA in a population in Northeast India, A1B having a stronger influence. Betel quid consumption was found to be a highly significant risk factor, followed by smoking and tobacco chewing. Although alcohol was not a potent risk factor independently, alcohol consumption along with tobacco, smoking and betel nut was found to contribute to development of ECA.

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