Gene Summary

Gene:ACTN4; actinin, alpha 4
Summary: Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 16 March, 2015


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 (1990-2015)
Graph generated 16 March 2015 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.

  • Carcinoma
  • Actins
  • Wound Healing
  • Lung Cancer
  • Messenger RNA
  • Amino Acid Sequence
  • Skin
  • Mutation
  • Adenocarcinoma
  • Oligonucleotide Array Sequence Analysis
  • Proportional Hazards Models
  • T-Lymphocytes, Cytotoxic
  • World Health Organization
  • Gene Dosage
  • Cancer Gene Expression Regulation
  • Chromosome 19
  • Disease Progression
  • ras Proteins
  • Gene Amplification
  • Cell Movement
  • Tumor Markers
  • beta Catenin
  • Molecular Sequence Data
  • RHOA
  • Actinin
  • Down-Regulation
  • Young Adult
  • Cytoplasm
  • Gene Expression
  • Cadherins
  • Immunohistochemistry
  • FISH
  • Transfection
  • Neoplasm Metastasis
  • Microfilament Proteins
  • Cell Nucleus
  • Neoplastic Cell Transformation
  • ACTN4
  • Neoplasm Invasiveness
  • DNA, Complementary
  • Signal Transduction
Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: ACTN4 (cancer-related)

Watabe Y, Mori T, Yoshimoto S, et al.
Copy number increase of ACTN4 is a prognostic indicator in salivary gland carcinoma.
Cancer Med. 2014; 3(3):613-22 [PubMed] Free Access to Full Article Related Publications
Copy number increase (CNI) of ACTN4 has been associated with poor prognosis and metastatic phenotypes in various human carcinomas. To identify a novel prognostic factor for salivary gland carcinoma, we investigated the copy number of ACTN4. We evaluated DNA copy number of ACTN4 in 58 patients with salivary gland carcinoma by using fluorescent in situ hybridization (FISH). CNI of ACTN4 was recognized in 14 of 58 patients (24.1%) with salivary gland carcinoma. The cases with CNI of ACTN4 were closely associated with histological grade (P = 0.047) and vascular invasion (P = 0.033). The patients with CNI of ACTN4 had a significantly worse prognosis than the patients with normal copy number of ACTN4 (P = 0.0005 log-rank test). Univariate analysis by the Cox proportional hazards model showed that histological grade, vascular invasion, and CNI of ACTN4 were independent risk factors for cancer death. Vascular invasion (hazard ratio [HR]: 7.46; 95% confidence interval [CI]: 1.98-28.06) and CNI of ACTN4 (HR: 3.23; 95% CI: 1.08-9.68) remained as risk factors for cancer death in multivariate analysis. Thus, CNI of ACTN4 is a novel indicator for an unfavorable outcome in patients with salivary gland carcinoma.

Kang K, Song DG, Lee EH, et al.
Secretome profiling reveals the signaling molecules of apoptotic HCT116 cells induced by the dietary polyacetylene gymnasterkoreayne B.
J Agric Food Chem. 2014; 62(11):2353-63 [PubMed] Related Publications
Dietary polyacetylenes from various foods have been receiving attention as promising cancer chemopreventive agents. However, until now, the detailed molecular mechanism and the regulatory proteins underlying these effects have not been elucidated. We investigated the effects of gymnasterkoreayne B (GKB), a model dietary polyacetylene from wild vegetables, on the programmed cell death of HCT116 human colorectal cancer cells. GKB inhibited HCT116 cell proliferation by inducing apoptotic cell death. GKB treatment resulted in ROS accumulation, leading to the activation of both intrinsic and extrinsic apoptotic pathway. We also found that FN1, TGFB1, APP, SERPINE1, HSPD1, SOD1, TXN, and ACTN4 may act as secretory signaling molecules during GKB-induced apoptotic cell death using LC-MS/MS identification followed by spectrum counting, statistical calculation, and gene ontology analysis. The secretory proteins suggested in this study may be promising candidates involved in apoptotic cell death of cancer cells induced by GKB that warrant further functional study.

Noro R, Honda K, Tsuta K, et al.
Distinct outcome of stage I lung adenocarcinoma with ACTN4 cell motility gene amplification.
Ann Oncol. 2013; 24(10):2594-600 [PubMed] Related Publications
BACKGROUND: Even if detected at an early stage, a substantial number of lung cancers relapse after curative surgery. However, no method for distinguishing such tumors has yet been established.
PATIENTS AND METHODS: The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridization on tissue microarrays comprising 543 surgically resected adenocarcinomas of the lung.
RESULTS: Amplification (an increase in the copy number by ≥ 2.0 fold) of the ACTN4 gene was detected in two of seven lung adenocarcinoma cell lines and 79 (15%) of 543 cases of pathological stage I-IV lung adenocarcinoma. Multivariate analysis revealed that ACTN4 gene amplification was the most significant independent factor associated with an extremely high risk of death (hazard ratio, 6.78; P = 9.48 × 10(-5), Cox regression analysis) among 290 patients with stage I lung adenocarcinoma. The prognostic significance of ACTN gene amplification was further validated in three independent cohorts totaling 1033 patients.
CONCLUSIONS: Amplification of the ACTN4 gene defines a small but substantial subset of patients with stage I lung adenocarcinoma showing a distinct outcome. Such patients require intensive medical attention and might benefit from postoperative adjuvant chemotherapy.

Han C, Zhao R, Kroger J, et al.
Caspase-2 short isoform interacts with membrane-associated cytoskeleton proteins to inhibit apoptosis.
PLoS One. 2013; 8(7):e67033 [PubMed] Free Access to Full Article Related Publications
Caspase-2 (casp-2) is the most conserved caspase across species, and is one of the initiator caspases activated by various stimuli. The casp-2 gene produces several alternative splicing isoforms. It is believed that the long isoform, casp-2L, promotes apoptosis, whereas the short isoform, casp-2S, inhibits apoptosis. The actual effect of casp-2S on apoptosis is still controversial, however, and the underlying mechanism for casp-2S-mediated apoptosis inhibition is unclear. Here, we analyzed the effects of casp-2S on DNA damage induced apoptosis through "gain-of-function" and "loss-of-function" strategies in ovarian cancer cell lines. We clearly demonstrated that the over-expression of casp-2S inhibited, and the knockdown of casp-2S promoted, the cisplatin-induced apoptosis of ovarian cancer cells. To explore the mechanism by which casp-2S mediates apoptosis inhibition, we analyzed the proteins which interact with casp-2S in cells by using immunoprecipitation (IP) and mass spectrometry. We have identified two cytoskeleton proteins, Fodrin and α-Actinin 4, which interact with FLAG-tagged casp-2S in HeLa cells and confirmed this interaction through reciprocal IP. We further demonstrated that casp-2S (i) is responsible for inhibiting DNA damage-induced cytoplasmic Fodrin cleavage independent of cellular p53 status, and (ii) prevents cisplatin-induced membrane blebbing. Taken together, our data suggests that casp-2S affects cellular apoptosis through its interaction with membrane-associated cytoskeletal Fodrin protein.

Hsu KS, Kao HY
Alpha-actinin 4 and tumorigenesis of breast cancer.
Vitam Horm. 2013; 93:323-51 [PubMed] Free Access to Full Article Related Publications
Alpha-actinins (ACTNs) were originally identified as cytoskeletal proteins which cross-link filamentous actin to establish cytoskeletal architect that protects cells from mechanical stress and controls cell movement. Notably, unlike other ACTNs, alpha-actinin 4 (ACTN4) displays unique characteristics in signaling transduction, nuclear translocation, and gene expression regulation. Initial reports indicated that ACTN4 is part of the breast cancer cell motile apparatus and is highly expressed in the nucleus. These results imply that ACTN4 plays a role in breast cancer tumorigenesis. While several observations in breast cancer and other cancers support this hypothesis, little direct evidence links the tumorigenic phenotype with ACTN4-mediated pathological mechanisms. Recently, several studies have demonstrated that in addition to its role in coordinating cytoskeleton, ACTN4 interacts with signaling mediators, chromatin remodeling factors, and transcription factors including nuclear receptors. Thus, ACTN4 functions as a versatile promoter for breast cancer tumorigenesis and appears to be an ideal drug target for future therapeutic development.

Buglyó G, Méhes G, Vargha G, et al.
WT1 microdeletion and slowly progressing focal glomerulosclerosis in a patient with male pseudohermaphroditism, childhood leukemia, Wilms tumor and cerebellar angioblastoma.
Clin Nephrol. 2013; 79(5):414-8 [PubMed] Related Publications
The Wilms tumor 1 (WT1) gene is currently in focus by pediatric nephrologists as its mutations are associated with nephrotic syndrome, especially as part of complex clinical entities like Denys-Drash or Frasier syndrome. Renal failure may also develop in young WAGR patients, whose condition is attributed to a deletion at chromosomal region 11p13. However, only limited data exist on WT1 microdeletions. A 30-year-old male patient, with a history of genital malformations, a Wilms tumor manifested during the treatment of acute lymphoid leukemia (ALL) at the age of 4, and a cerebellar angioblastoma, was referred with proteinuria and a reduced glomerular filtration rate (GFR). Kidney biopsy revealed FSGS. Although all WT1 exons were amplified with polymerase chain reaction (PCR) and sequenced, none of them showed a mutation. However, an formalin-fixed, paraffin- embedded (FFPE) tissue sample of the patient's childhood Wilms tumor showed WT1- positivity restricted to the renal tumor cells, so the WT1 gene was investigated further. Using quantitative reverse transcription PCR (qRT-PCR), the gene was found to be present in only one copy in the patient's genomic DNA sample, while both copies were detected in both parents. In the patient's sister, the proximal region of WT1 was shown to have an extra copy. Evidence suggests that a heterozygous microdeletion of the gene WT1 is responsible for the patient's disease. It seems reasonable to assume a possible abnormality affecting meiotic crossing over at the WT1 locus in one of the parents.

Fukushima S, Yoshida A, Honda K, et al.
Immunohistochemical actinin-4 expression in infiltrating gliomas: association with WHO grade and differentiation.
Brain Tumor Pathol. 2014; 31(1):11-6 [PubMed] Related Publications
Actinin-4 is an isoform of nonmuscular α-actinin and actin-bundling protein that plays an important role in cancer invasion and metastasis by enhancing cellular motility. Recent studies have revealed an association between several clinicopathological profiles and actinin-4 overexpression in human cancers. In this study, we investigated the immunohistochemical actinin-4 expression in 39 infiltrating gliomas. The specimens included three diffuse astrocytomas, three oligodendrogliomas, one oligoastrocytoma, two anaplastic astrocytomas, four anaplastic oligodendrogliomas, three anaplastic oligoastrocytomas, 17 glioblastomas, four gliosarcomas, and two glioblastomas with oligodendroglial component. All seven World Health Organization (WHO) grade II tumors were negative for actinin-4, whereas 20 of 22 tumors with strong actinin-4 expression were WHO grade IV. Actinin-4 expression was significantly associated with histological grade (P < 0.0001) and proliferative activity measured by Ki-67 staining (P = 0.0045). Notably, actinin-4 expression was more pronounced in high-grade astrocytic tumors than oligodendroglial tumors (P < 0.0001). Additionally, pseudopalisading cells in glioblastoma exhibited stronger actinin-4 expression than the rest, likely reflecting enhanced cellular motility in pseudopalisades. This study is the first to demonstrate significant correlation between actinin-4 expression and tumor grade using clinical glioma samples. Although diagnostic utility of this marker awaits future exploration, actinin-4 may help distinguish between astrocytic and oligodendroglial lines of differentiation.

Guaragna MS, Lutaif AC, Bittencourt VB, et al.
Frasier syndrome: four new cases with unusual presentations.
Arq Bras Endocrinol Metabol. 2012; 56(8):525-32 [PubMed] Related Publications
Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis.

Yamamoto S, Tsuda H, Honda K, et al.
ACTN4 gene amplification and actinin-4 protein overexpression drive tumour development and histological progression in a high-grade subset of ovarian clear-cell adenocarcinomas.
Histopathology. 2012; 60(7):1073-83 [PubMed] Related Publications
AIMS:   Actinin-4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin-4 alterations contribute to the tumorigenesis of ovarian clear-cell adenocarcinomas (CCAs).
METHODS AND RESULTS:   Fluorescence in-situ hybridization analysis demonstrated that ACTN4 amplification (≥4 ACTN4 copies in ≥40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin-4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P < 0.05). From the 27 ACTN4-amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin-4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin-4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low-level gains of ACTN4 and actinin-4 overexpression, respectively. In 12 of 23 ACTN4-amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology.
CONCLUSION:   Accumulative genomic gains of ACTN4, causing actinin-4 protein overexpression, drive the development and progression of ovarian CCAs with high-grade histology.

Khurana S, Chakraborty S, Cheng X, et al.
The actin-binding protein, actinin alpha 4 (ACTN4), is a nuclear receptor coactivator that promotes proliferation of MCF-7 breast cancer cells.
J Biol Chem. 2011; 286(3):1850-9 [PubMed] Free Access to Full Article Related Publications
Alpha actinins (ACTNs) are known for their ability to modulate cytoskeletal organization and cell motility by cross-linking actin filaments. We show here that ACTN4 harbors a functional LXXLL receptor interaction motif, interacts with nuclear receptors in vitro and in mammalian cells, and potently activates transcription mediated by nuclear receptors. Whereas overexpression of ACTN4 potentiates estrogen receptor α (ERα)-mediated transcription in transient transfection reporter assays, knockdown of ACTN4 decreases it. In contrast, histone deacetylase 7 (HDAC7) inhibits estrogen receptor α (ERα)-mediated transcription. Moreover, the ACTN4 mutant lacking the CaM (calmodulin)-like domain that is required for its interaction with HDAC7 fails to activate transcription by ERα. Chromatin immunoprecipitation (ChIP) assays demonstrate that maximal associations of ACTN4 and HDAC7 with the pS2 promoter are mutually exclusive. Knockdown of ACTN4 significantly decreases the expression of ERα target genes including pS2 and PR and also affects cell proliferation of MCF-7 breast cancer cells with or without hormone, whereas knockdown of HDAC7 exhibits opposite effects. Interestingly, overexpression of wild-type ACTN4, but not the mutants defective in interacting with ERα or HDAC7, results in an increase in pS2 and PR mRNA accumulation in a hormone-dependent manner. In summary, we have identified ACTN4 as a novel, atypical coactivator that regulates transcription networks to control cell growth.

Zhang Y, Tong X
Expression of the actin-binding proteins indicates that cofilin and fascin are related to breast tumour size.
J Int Med Res. 2010 May-Jun; 38(3):1042-8 [PubMed] Related Publications
This study was designed to investigate the expression of four actin-binding proteins, alpha-actinin-4, cofilin 1, fascin and elongation factor 1-alpha 2 (eEF1A2), in samples of breast cancer from 112 patients with different stages of breast cancer (stages T0 - T1, T2 and T3) compared with normal control tissues (n = 33). Levels of eEF1A2 and alpha-actinin-4 mRNA appeared to be unrelated to tumour size, except for a significant down-regulation of alpha-actinin-4 mRNA in T3 cases. Significant up-regulation of cofilin 1 mRNA was associated with stages T0 - T1 and T2; up-regulation seen at stage T3 was not significant compared with control tissue. Fascin mRNA levels were significantly reduced at all three tumour stages (T0 - T1, T2 and T3) compared with control tissue. In conclusion, some components of the actin cytoskeletal system might hold significant potential as targets in future cancer therapies.

Sinha A, Sharma S, Gulati A, et al.
Frasier syndrome: early gonadoblastoma and cyclosporine responsiveness.
Pediatr Nephrol. 2010; 25(10):2171-4 [PubMed] Related Publications
Frasier syndrome is characterized by progressive glomerulopathy that is unresponsive to corticosteroids, male pseudohermaphroditism, and an increased risk of genitourinary tumors. Of 21 girls with steroid-resistant nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) who were screened for mutations in the WT1 gene, two showed Frasier syndrome. Both patients had donor splice-site mutations in intron 9 of the WT1 gene and a male karyotype (46, XY). Long-term therapy with cyclosporine resulted in partial remission in both cases. One patient showed foci of gonadoblastoma in the excised dysgenetic gonads. This report highlights the need for screening for mutations in the WT1 gene in girls with steroid-resistant FSGS. Patients with Frasier syndrome might benefit from early gonadectomy.

Quick Q, Skalli O
Alpha-actinin 1 and alpha-actinin 4: contrasting roles in the survival, motility, and RhoA signaling of astrocytoma cells.
Exp Cell Res. 2010; 316(7):1137-47 [PubMed] Related Publications
Alpha-actinin is a prominent actin filament associated protein for which different isoforms exist. Here, we have examined whether the two highly homologous non-muscle alpha-actinin isoforms 1 and 4 exhibit functional differences in astrocytoma cells. The protein levels of these isoforms were differentially regulated during the development and progression of astrocytomas, as alpha-actinin 1 was higher in astrocytomas compared to normal brains whereas alpha-actinin 4 was elevated in high-grade astrocytomas compared to normal brains and low grade astrocytomas. RNAi demonstrated contrasted contributions of alpha-actinin 1 and 4 to the malignant behavior of U-373, U-87 and A172 astrocytoma cells. While alpha-actinin 1 appeared to favor the expansion of U-373, U-87 and A172 astrocytoma cell populations, alpha-actinin 4 played this role only for U-373 cells. On the other hand, downregulation of alpha-actinin 4, but not 1, reduced cell motility, adhesion, cortical actin, and RhoA levels. Finally, in the three astrocytoma cell lines examined, alpha-actinin 1 and 4 had contrasted biochemical properties as alpha-actinin 4 was significantly more abundant in the actin cytoskeleton than alpha-actinin 1. Collectively, these findings suggest that alpha-actinin 1 and 4 are differentially regulated during the development and progression of astrocytomas because each of these isoforms uniquely contributes to distinct malignant properties of astrocytoma cells.

Sakairi T, Abe Y, Kajiyama H, et al.
Conditionally immortalized human podocyte cell lines established from urine.
Am J Physiol Renal Physiol. 2010; 298(3):F557-67 [PubMed] Free Access to Full Article Related Publications
Evidence suggests that loss of podocytes into urine contributes to development of glomerular diseases; shed podocytes are frequently viable and proliferate in culture conditions. To determine the phenotypic characteristics of viable urinary cells derived from human subjects, we established long-term urinary cell culture from two patients with focal segmental glomerulosclerosis and two healthy volunteers, via transformation with the thermosensitive SV40 large T antigen (U19tsA58) together with human telomerase (hTERT). Characterization of arbitrarily selected two clonal cell lines from each human subject was carried out. mRNA expression for the podocyte markers synaptopodin, nestin, and CD2AP were detected in all eight clones. Podocin mRNA was absent from all eight clones. The expression of nephrin, Wilms' tumor 1 (WT1), and podocalyxin mRNA varied among the clones, which may be due to transformation and/or cloning. These results suggest that podocyte cell lines can be established consistently from human urine. The generation of podocyte cell lines from urine of patients and healthy volunteers is novel and will help to advance studies of podocyte cell biology. Further improvements in the approaches to cell transformation and/or cell culture techniques are needed to allow cultured podocytes to fully reproduce in vivo characteristics.

Yamada S, Yanamoto S, Yoshida H, et al.
RNAi-mediated down-regulation of alpha-actinin-4 decreases invasion potential in oral squamous cell carcinoma.
Int J Oral Maxillofac Surg. 2010; 39(1):61-7 [PubMed] Related Publications
alpha-actinin-4, originally identified as an actin-binding protein associated with cell motility, invasion, and metastasis of cancer cells, appears to be overexpressed in various human epithelial carcinomas, including colorectal, breast, esophageal, ovarian, and non-small cell lung carcinomas. The authors evaluated whether alpha-actinin-4 might be appropriate as a molecular target for cancer gene therapy. In 64 primary oral squamous cell carcinomas (OSCCs) and 10 normal oral mucosal specimens, and in seven human OSCC cell lines, alpha-actinin-4 expression was evaluated immunologically and correlations with clinicopathologic factors were examined. Overexpression of alpha-actinin-4 was detected in 38 of 64 oral squamous cell carcinomas (70%); significantly more frequently than in normal oral mucosa. The expression of alpha-actinin-4 was significantly associated with invasion potential defined by the Matrigel invasion assay. Cancer cell lines with higher alpha-actinin-4 expression had greater invasive potential. An RNAi-mediated decrease in alpha-actinin-4 expression reduced the invasion potential. These results indicated that the overexpression of alpha-actinin-4 was associated with an aggressive phenotype of OSCC. The study indicated that alpha-actinin-4 could be a potential molecular target for gene therapy by RNAi targeting for OSCC.

Pan S, Chen R, Reimel BA, et al.
Quantitative proteomics investigation of pancreatic intraepithelial neoplasia.
Electrophoresis. 2009; 30(7):1132-44 [PubMed] Free Access to Full Article Related Publications
Patients with pancreatic cancer are usually diagnosed at late stages, when the disease is incurable. Pancreatic intraepithelial neoplasia (PanIN) 3 is believed to be the immediate precursor lesion of pancreatic adenocarcinoma, and would be an ideal stage to diagnose patients, when intervention and cure are possible and patients are curable. In this study, we used quantitative proteomics to identify dysregulated proteins in PanIN 3 lesions. Altogether, over 200 dysregulated proteins were identified in the PanIN 3 tissues, with a minimum of a 1.75-fold change compared with the proteins in normal pancreas. These dysregulated PanIN 3 proteins play roles in cell motility, the inflammatory response, the blood clotting cascade, the cell cycle and its regulation, and protein degradation. Further network analysis of the proteins identified c-MYC as an important regulatory protein in PanIN 3 lesions. Finally, three of the overexpressed proteins, laminin beta-1, galectin-1, and actinin-4 were validated by immunohistochemistry analysis. All three of these proteins were overexpressed in the stroma or ductal epithelial cells of advanced PanIN lesions as well as in pancreatic cancer tissue. Our findings suggest that these three proteins may be useful as biomarkers for advanced PanIN and pancreatic cancer if further validated. The dysregulated proteins identified in this study may assist in the selection of candidates for future development of biomarkers for detecting early and curable pancreatic neoplasia.

Bockenhauer D, van't Hoff W, Chernin G, et al.
Membranoproliferative glomerulonephritis associated with a mutation in Wilms' tumour suppressor gene 1.
Pediatr Nephrol. 2009; 24(7):1399-401 [PubMed] Related Publications
Wilms' tumour suppressor gene 1 (WT1) encodes a transcription factor required for normal development of the genitourinary system. In the kidney, mutations in WT1 can cause diffuse mesangial sclerosis or focal segmental glomerulosclerosis. Here, we report on a girl with a mutation in WT1, who developed membranoproliferative glomerulonephritis (MPGN) 3 years after completion of treatment for Wilms' tumour. This finding extends the spectrum of glomerular disease seen with WT1 mutations and could have implications for the screening of children with MPGN.

Yamamoto S, Tsuda H, Honda K, et al.
Actinin-4 gene amplification in ovarian cancer: a candidate oncogene associated with poor patient prognosis and tumor chemoresistance.
Mod Pathol. 2009; 22(4):499-507 [PubMed] Related Publications
Actinin-4, an isoform of non-muscular alpha-actinin, enhances cell motility by bundling the actin cytoskeleton. We previously reported a prognostic implication of high immunohistochemical expression of actinin-4 protein in ovarian cancers. Chromosomal gain or amplification of the 19q12-q13 region has been reported in ovarian cancer. We hypothesized that the actinin-4 (ACTN4) gene might be a target of the 19q12-q13 amplicon and play an essential role of ovarian cancer progression. In total, 136 advanced-stage ovarian cancers were investigated for the copy number of the ACTN4 gene on chromosome 19q13, using fluorescence in situ hybridization, and the correlation of the ACTN4 copy number with actinin-4 protein immunoreactivity and major clinicopathological factors was investigated. A higher copy number (> or =4 copies) of the ACTN4 gene was detected in 29 (21%) cases and was highly associated with the intensity of actinin-4 immunoreactivity (P<0.0001), a high histological tumor grade (P=0.030), a clear-cell adenocarcinoma histology (P=0.012), resistance to first-line chemotherapies (P=0.028), and poor patient outcome (P=0.0011). Univariate analyses using the Cox regression model showed that a higher ACTN4 gene copy number was able to predict patient outcome more accurately than high actinin-4 immunoreactivity (relative risk: 2.48 vs 1.55). Multivariate analysis showed that a higher copy number of the ACTN4 gene and the degree of residual disease were independent prognostic factors for overall patient survival. The actinin-4 gene may be a target of the 19q amplicon, acting as a candidate oncogene, and serve as a predictor of poor outcome and tumor chemoresistance in patients with advanced-stage ovarian cancers.

Burmeister T, Meyer C, Schwartz S, et al.
The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group.
Blood. 2009; 113(17):4011-5 [PubMed] Related Publications
MLL translocations in adult B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) are largely restricted to the immature CD10(-) immunophenotypes. MLL-AF4 is known to be the most frequent fusion transcript, but the exact frequencies of MLL aberrations in CD10(-) adult BCP-ALL are unknown. We present a genetic characterization of 184 BCR-ABL(-) CD10(-) adult ALL cases (156 cyIg(-), 28 cyIg(+)) diagnosed between 2001 and 2007 at the central diagnostic laboratory of the GMALL study group. Patient samples were investigated by RT-PCR for MLL-AF4, MLL-ENL, and MLL-AF9 and by long-distance inverse polymerase chain reaction, thus also allowing the identification of unknown MLL fusion partners at the genomic level. MLL-AF4 was detected in 101 (54.9%) and MLL-ENL in 11 (6.0%) cases. In addition, rare MLL fusion genes were found: 2 MLL-TET1 cases, not previously reported in ALL, 1 MLL-AF9, 1 MLL-PTD, a novel MLL-ACTN4, and an MLL-11q23 fusion. Chromosomal breakpoints were determined in all 118 positive cases, revealing 2 major breakpoint cluster regions in the MLL gene. Characteristic features of MLL(+) patients were significantly lower CD10 expression, expression of the NG2 antigen, a higher white blood count at diagnosis, and female sex. Proposals are made for diagnostic assessment.

Kikuchi S, Honda K, Tsuda H, et al.
Expression and gene amplification of actinin-4 in invasive ductal carcinoma of the pancreas.
Clin Cancer Res. 2008; 14(17):5348-56 [PubMed] Related Publications
PURPOSE: An invasive growth pattern is one of the hallmarks of pancreatic ductal carcinoma. Actinin-4 is an actin-binding protein associated with enhanced cell motility, invasive growth, and lymph node metastasis. Actinin-4 might play an important role in the development and progression of pancreatic cancer.
EXPERIMENTAL DESIGN: The expression of actinin-4 was examined immunohistochemically in 173 cases of invasive pancreatic ductal carcinoma. The copy number of the actinin-4 (ACTN4) gene was calculated by fluorescence in situ hybridization. The expression of actinin-4 was stably knocked down by short hairpin RNA, and tumorigenicity was evaluated by orthotopic implantation into mice with severe combined immunodeficiency.
RESULTS: The expression level of actinin-4 was increased in 109 (63.0%) of 173 cases of pancreatic cancer. Kaplan-Meier survival curves revealed that patients with increased expression of actinin-4 had a significantly poorer outcome (P=0.00001, log-rank test). Multivariate analysis by the Cox proportional hazard model showed that high expression of actinin-4 was the most significant independent negative predictor of survival (hazard ratio, 2.33; P=0.000009). Amplification (defined as more than four copies per interphase nucleus) of the ACTN4 gene was detected in 11 (37.9%) of 29 cases showing increased expression of actinin-4. Knockdown of actinin-4 expression inhibited the destructive growth of cancer cells in the pancreatic parenchyma.
CONCLUSION: Recurrent amplification of chromosome 19q13.1-2 has been reported in pancreatic cancer, but the exact target gene has not been identified. Actinin-4 contributes to the invasive growth of pancreatic ductal carcinoma, and ACTN4 is one of the candidate oncogenes in this chromosome locus.

Agarwal SK, Simonds WF, Marx SJ
The parafibromin tumor suppressor protein interacts with actin-binding proteins actinin-2 and actinin-3.
Mol Cancer. 2008; 7:65 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Germline and somatic inactivating mutations in the HRPT2 gene occur in the inherited hyperparathyroidism-jaw tumor syndrome, in some cases of parathyroid cancer and in some cases of familial hyperparathyroidism. HRPT2 encodes parafibromin. To identify parafibromin interacting proteins we used the yeast two-hybrid system for screening a heart cDNA library with parafibromin as the bait.
RESULTS: Fourteen parafibromin interaction positive preys representing 10 independent clones encoding actinin-2 were isolated. Parafibromin interacted with muscle alpha-actinins (actinin-2 and actinin-3), but not with non-muscle alpha-actinins (actinin-1 and actinin-4). The parafibromin-actinin interaction was verified by yeast two-hybrid, GST pull-down, and co-immunoprecipitation. Yeast two-hybrid analysis revealed that the N-terminal region of parafibromin interacted with actinins. In actin sedimentation assays parafibromin did not dissociate skeletal muscle actinins from actin filaments, but interestingly, parafibromin could also bundle/cross-link actin filaments. Parafibromin was predominantly nuclear in undifferentiated proliferating myoblasts (C2C12 cells), but in differentiated C2C12 myotubes parafibromin co-localized with actinins in the cytoplasmic compartment.
CONCLUSION: These data support a possible contribution of parafibromin outside the nucleus through its interaction with actinins and actin bundling/cross-linking. These data also suggest that actinins (and actin) participate in sequestering parafibromin in the cytoplasmic compartment.

Mazzocca A, Liotta F, Carloni V
Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma.
Gastroenterology. 2008; 135(1):244-256.e1 [PubMed] Related Publications
BACKGROUND & AIMS: Human hepatocellular carcinoma (HCC) can invade the portal vein and metastasize to other parts of the liver. Currently, the molecular and cellular mechanisms underlying intrahepatic metastasis of HCC are poorly understood. Tumor invasiveness could be considered an aspect of dysregulated motility, and the mechanisms that inhibit cell movement are considered to counteract the spreading of cancer cells through the liver. Accumulating observations suggest that the CD81 tetraspanin may have an inhibitory effect on cell movement.
METHODS: In the present study using both loss- and gain-of-gene function approaches, we verified that the functional interaction of tetraspanin CD81 with type II phosphoinositide 4-kinase (PI4KII) suppressed HCC cell motility by promoting the formation of CD81-enriched vesicles, non-endosomal intracellular structures, that sequestered actinin-4 with consequent remodeling of actin cytoskeleton.
RESULTS: We reported that HCC cells expressing CD81 showed an inability to metastasize compared with HCC cells with undetectable levels of CD81.
CONCLUSIONS: Taken together, these findings indicate that CD81 functions as a molecular organizer of membrane microdomains, whereby proteins such as PI4KII control actin remodeling and cell motility, establishing a role for these genes as negative modifiers of oncogenicity and HCC progression.

Barbolina MV, Adley BP, Kelly DL, et al.
Motility-related actinin alpha-4 is associated with advanced and metastatic ovarian carcinoma.
Lab Invest. 2008; 88(6):602-14 [PubMed] Free Access to Full Article Related Publications
Advanced and metastatic ovarian cancer is a leading cause of death from gynecologic malignancies. A more detailed understanding of the factors controlling invasion and metastasis may lead to novel anti-metastatic therapies. To model cellular interactions that occur during intraperitoneal metastasis, comparative cDNA microarray analysis and confirmatory real-time reverse transcription PCR (RT-PCR) were employed to uncover changes in gene expression that may occur in late stage ovarian cancer in response to microenvironmental cues, particularly native three-dimensional collagen I. Gene expression in human ovarian carcinoma tissues was evaluated on the RNA and protein level using real-time RT-PCR and immunohistochemistry. Cell invasion and migration were evaluated in a collagen invasion assay and a scratch wound assay. Three-dimensional collagen I culture led to differential expression of several genes. The role of actinin alpha-4 (ACTN4), a cytoskeleton-associated protein implicated in the regulation of cell motility, was examined in detail. ACTN4 RNA and protein expression were associated with advanced and metastatic human ovarian carcinoma. This report demonstrates that a cytoskeletal-associated protein ACTN4 is upregulated by three-dimensional collagen culture conditions, leading to increased invasion and motility of ovarian cancer cells. Expression of ACTN4 in human ovarian tumors was found to be associated with advanced-stage disease and peritoneal metastases.

Brito GC, Fachel AA, Vettore AL, et al.
Identification of protein-coding and intronic noncoding RNAs down-regulated in clear cell renal carcinoma.
Mol Carcinog. 2008; 47(10):757-67 [PubMed] Related Publications
The clear cell subtype of renal cell carcinoma (RCC) is the most lethal and prevalent cancer of the urinary system. To investigate the molecular changes associated with malignant transformation in clear cell RCC, the gene expression profiles of matched samples of tumor and adjacent non-neoplastic tissue were obtained from six patients. A custom-built cDNA microarray platform was used, comprising 2292 probes that map to exons of genes and 822 probes for noncoding RNAs mapping to intronic regions. Intronic transcription was detected in all normal and neoplastic renal tissues. A subset of 55 transcripts was significantly down-regulated in clear cell RCC relative to the matched nontumor tissue as determined by a combination of two statistical tests and leave-one-out patient cross-validation. Among the down-regulated transcripts, 49 mapped to untranslated or coding exons and 6 were intronic relative to known exons of protein-coding genes. Lower levels of expression of SIN3B, TRIP3, SYNJ2BP and NDE1 (P < 0.02), and of intronic transcripts derived from SND1 and ACTN4 loci (P < 0.05), were confirmed in clear cell RCC by Real-time RT-PCR. A subset of 25 transcripts was deregulated in additional six nonclear cell RCC samples, pointing to common transcriptional alterations in RCC irrespective of the histological subtype or differentiation state of the tumor. Our results indicate a novel set of tumor suppressor gene candidates, including noncoding intronic RNAs, which may play a significant role in malignant transformations of normal renal cells.

Craig DH, Haimovich B, Basson MD
Alpha-actinin-1 phosphorylation modulates pressure-induced colon cancer cell adhesion through regulation of focal adhesion kinase-Src interaction.
Am J Physiol Cell Physiol. 2007; 293(6):C1862-74 [PubMed] Related Publications
Physical forces including pressure, strain, and shear can be converted into intracellular signals that regulate diverse aspects of cell biology. Exposure to increased extracellular pressure stimulates colon cancer cell adhesion by a beta(1)-integrin-dependent mechanism that requires an intact cytoskeleton and activation of focal adhesion kinase (FAK) and Src. alpha-Actinin facilitates focal adhesion formation and physically links integrin-associated focal adhesion complexes with the cytoskeleton. We therefore hypothesized that alpha-actinin may be necessary for the mechanical response pathway that mediates pressure-stimulated cell adhesion. We reduced alpha-actinin-1 and alpha-actinin-4 expression with isoform-specific small interfering (si)RNA. Silencing of alpha-actinin-1, but not alpha-actinin-4, blocked pressure-stimulated cell adhesion in human SW620, HT-29, and Caco-2 colon cancer cell lines. Cell exposure to increased extracellular pressure stimulated alpha-actinin-1 tyrosine phosphorylation and alpha-actinin-1 interaction with FAK and/or Src, and enhanced FAK phosphorylation at residues Y397 and Y576. The requirement for alpha-actinin-1 phosphorylation in the pressure response was investigated by expressing the alpha-actinin-1 tyrosine phosphorylation mutant Y12F in the colon cancer cells. Expression of Y12F blocked pressure-mediated adhesion and inhibited the pressure-induced association of alpha-actinin-1 with FAK and Src, as well as FAK activation. Furthermore, siRNA-mediated reduction of alpha-actinin-1 eliminated the pressure-induced association of alpha-actinin-1 and Src with beta(1)-integrin receptor, as well as FAK-Src complex formation. These results suggest that alpha-actinin-1 phosphorylation at Y12 plays a crucial role in pressure-activated cell adhesion and mechanotransduction by facilitating Src recruitment to beta(1)-integrin, and consequently the association of FAK with Src, to enhance FAK phosphorylation.

Nowee ME, Snijders AM, Rockx DA, et al.
DNA profiling of primary serous ovarian and fallopian tube carcinomas with array comparative genomic hybridization and multiplex ligation-dependent probe amplification.
J Pathol. 2007; 213(1):46-55 [PubMed] Related Publications
Primary serous ovarian carcinoma (OVCA) and serous Fallopian tube carcinoma (FTC), both belonging to the BRCA-linked tumour spectrum, share many properties and are treated similarly. However, a detailed molecular comparison has been lacking. We hypothesized that comparative genomic studies of serous OVCAs and FTCs should point to gene regions critically involved in their tumorigenesis. Array comparative genomic hybridization (array CGH) analysis indicated that serous OVCAs and serous FTCs displayed common but also more distinctive patterns of recurrent changes. Targeted gene identification using a dedicated multiplex ligation-dependent probe amplification (MLPA) probe set directly identified EIF2C2 on 8q as a potentially important driver gene. Other previously unappreciated gained/amplified genes included PSMB4 on 1q, MTSS1 on 8q, TEAD4 and TSPAN9 on 12p, and BCAS4 on 20q. SPINT2 and ACTN4 on 19q were predominantly found in FTCs. Gains/amplifications of CCNE1 and MYC, often in conjunction with changes in genes of the AKT pathway, EVI1 and PTK2, seemed to be involved at earlier stages, whereas changes of ERBB2 were associated with advanced stages. The only BRCA1-mutated FTC shared common denominators with the sporadic tumours. In conclusion, the data suggest that serous OVCAs and FTCs, although related, exhibit differences in genomic profiles. In addition to known pathways, new genes/pathways are likely to be involved, with changes in an miRNA-associated gene, EIF2C2, as one important new feature. Dedicated MLPA sets constitute potentially important tools for differential diagnosis and may provide footholds for tailored therapy.

Hatakeyama H, Kondo T, Fujii K, et al.
Protein clusters associated with carcinogenesis, histological differentiation and nodal metastasis in esophageal cancer.
Proteomics. 2006; 6(23):6300-16 [PubMed] Related Publications
We examined the proteomic background of esophageal cancer. We used laser microdissection to obtain tumor tissues from 72 esophageal squamous cell carcinoma cases and adjacent normal tissues in 57 of these cases. The 2D-DIGE generated quantitative expression profiles with 1730 protein spots. Based on the intensity of the protein spots, unsupervised classification distinguished the tumor tissues from their normal counterparts, and subdivided the tumor tissues according to their histological differentiation. We identified 498 protein spots with altered intensity in the tumor tissues, which protein identification by LC-MS/MS showed to correspond to 217 gene products. We also found 41 protein spots that were associated with nodal metastasis, and identified 33 proteins corresponding to the spots, including cancer-associated proteins such as alpha-actinin 4, hnRNP K, periplakin, squamous cell carcinoma antigen 1 and NudC. The identified cancer-associated proteins have been previously reported to be individually involved in a range of cancer types, and our study observed them collectively in a single type of malignancy, esophageal cancer. As the identified proteins are involved in important biological processes such as cytoskeletal/structural organization, transportation, chaperon, oxidoreduction, transcription and signal transduction, they may function in a coordinate manner in carcinogenesis and tumor progression of esophageal cancer.

Love JD, DeMartini SD, Coppola CP
Prophylactic bilateral salpingo-oopherectomy in a 17-year-old with Frasier syndrome reveals gonadoblastoma and seminoma: a case report.
J Pediatr Surg. 2006; 41(11):e1-4 [PubMed] Related Publications
Mutations in the Wilms' tumor gene are present in children with Frasier syndrome, Denys-Drash syndrome, WAGR syndrome, and some cases of Wilms' tumor. The Wilms' tumor gene product, WT1, is necessary for normal urogenital development. Frasier syndrome is an association between focal segmental glomerulosclerosis, beginning in the second and third decade, male to female sex reversal, and dysgenetic gonads. We report a case of Frasier syndrome in a 17-year-old adolescent girl with renal failure, kidney transplant, and dysgenetic gonads, with development of gonadoblastoma and dysgerminoma (seminoma). The diagnosis of Frasier syndrome was based on nephrotic syndrome with diffuse mesangial sclerosis leading to chronic renal failure, dysgenetic gonads, 46 XY karyotype in a phenotypic female, and a mutation in the Wilms' tumor gene. Prophylactic laparoscopic bilateral salpingo-oopherectomy revealed gonadoblastoma and seminoma in opposite atrophic ovaries as well as a hypoplastic uterus. Early prophylactic resection of dysgenetic gonads is indicated in children with Frasier syndrome to prevent the development of germ cell malignancy.

Kanemoto K, Ishikura K, Ariyasu D, et al.
WT1 intron 9 splice acceptor site mutation in a 46,XY male with focal segmental glomerulosclerosis.
Pediatr Nephrol. 2007; 22(3):454-8 [PubMed] Related Publications
The Wilms' tumor suppressor gene (WT1) plays crucial roles in urogenital and gonadal development. Germline mutations of WT1 have been reported in patients with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Based on clinical overlaps reported to date, it has been suggested that these two syndromes should be considered as part of a spectrum of diseases caused by WT1 gene mutations, rather than as separate diseases. We report a new mutation in an intron 9 splice acceptor site (IVS -1G-->) in a Japanese 46,XY male patient with focal segmental glomerulosclerosis (FSGS) and bilateral cryptorchism. The clinical phenotype of this patient resembled FS without male pseudohermaphroditism. Interestingly, although the patient's right kidney was diagnosed with FSGS, his left kidney showed severe hypoplasia. There are no previous case reports of FSGS and renal hypoplasia in the same individual with a WT1 mutation. The findings for this case further suggest that the renal phenotype has various manifestations and is not always decided by the type of WT1 mutation. The possibility that the position of the WT1 mutation may influence the course of the nephropathy should be evaluated in a larger patient cohort.

Jasavala R, Martinez H, Thumar J, et al.
Identification of putative androgen receptor interaction protein modules: cytoskeleton and endosomes modulate androgen receptor signaling in prostate cancer cells.
Mol Cell Proteomics. 2007; 6(2):252-71 [PubMed] Related Publications
We have developed a novel androgen receptor (AR) expression system in the 293 human embryonic kidney cell line that recapitulates AR biochemical activity as a steroid hormone receptor in prostate cancer cells. We used this system to identify putative AR-binding proteins in the cytosolic and nuclear compartments of mammalian cells using a large scale co-immunoprecipitation strategy coupled to quantitative mass spectrometry. For example, the heat shock 70 and 90 chaperones, which are known regulators of steroid hormone receptor, were identified as AR-binding proteins. AR purification enriched for proteins involved in RNA processing, protein transport, and cytoskeletal organization, suggesting a functional link between AR and these protein modules in mammalian cells. For example, AR purification in the nuclear compartment led to the specific enrichment of alpha-actinin-4, clathrin heavy chain, and serine-threonine protein kinase C delta. Short interfering RNA knockdown studies and co-transcriptional reporter assays revealed that clathrin heavy chain possessed co-activator activity during AR-mediated transcription, whereas alpha-actinin-4 and protein kinase C delta displayed both co-activator and co-repressor activity during AR-mediated transcription that was dependent upon their relative expression levels. Lastly immunohistochemical staining of prostate tissue showed that alpha-actinin-4 levels decreased in the nucleus of high grade cancerous prostate samples, suggesting its possible deregulation in advanced prostate cancers as previously observed in late stage metastatic breast cancers. Taken together, these findings suggest AR binds to specific protein modules in mammalian cells and that these protein modules may provide a molecular framework for interrogating AR function in normal and cancerous prostate epithelial cells.

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