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Entity | Cancer |
Note | ACTN4 product protein is associated with disease progress and metastatic processes in variety of neoplasms due to its crucial involvement in cell adhesion and motility mechanisms. Elevated α-actinin 4 in neoplastic tissue is usually negative predictor of disease prognosis although there are reports proposing suppressive effects on tumor cells growth and malignant phenotype. In some cancer types ACTN4 is candidate oncogene. |
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Entity | Pancreatic cancer |
Note | Increased level of α-actinin 4 has been determined as independent prognostic factor associated with most unfavorable prognosis in a group of 173 patients with invasive ductal carcinoma of the pancreas (Kikuchi et al., 2008). Amplification of chromosome 19q13.1-q13.2 has been reported in pancreatic cancer-derived cell lines and pancreatic cancer tissue. ACTN4 is one of the putative oncogenes in that locus (Miwa et al., 1996; Höglund et al., 1998). |
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Entity | Breast cancer |
Note | α-Actinin 4 is detected in many histological subtypes of breast cancer and subcellular localization of the molecule (nucleus vs. cytosol) is related to disease outcome. Cytosolic localization has been found in the types of cancer with more malignant histological subtype, metastasis, and worse survival (Honda et al., 1998). Proliferation of MCF-7 breast cancer cells is promoted by α-actinin 4 although the precise mechanism was not identified (Khurana et al., 2011). |
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Entity | Colorectal cancer |
Note | Specimens from 26 patients with colorectal cancer were immunostained to visualize the expression of α-actinin 4. In 19 preparations (73.1%) the expression was increased especially in the malignant cells in the "focal dedifferentiation" areas. In the cell line DLD1 (derived from colorectal adenocarcinoma) stable expression of ACTN4 protein dramatically changed cell morphology and increased motility. When those cells are injected into the spleens of the mice with severe combined immunodeficiency metastasis developed in the surrounding lymph nodes. On the other hand, injection of original DLD1 cells did not induce metastatic disease (Honda et al., 2005). These findings suggest involvement of ACTN4 in progression of colorectal carcinoma. |
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Entity | Lung cancer |
Note | ACTN4 gene product has been reported to exert multiple effects on human lung cancer cell biology and disease prognosis. Moreover, the available data so far has shown that α-actinin 4 is able to promote as well as suppress the malignant development reflecting probably the diversity of mechanisms involved in oncogenesis of lung cancer. Several mutations and splice variants in ACTN4 that influence the lung cancer cell phenotype have been described. Using highly specific monoclonal antibody, alternatively spliced variant of ACTN4 has been identified exclusively in high-grade neuroendocrine lung tumors compared to non-neuroendocrine lung cancers, 96 of 176 (55%) versus 3 of 378 (0.8%) of investigated patients, respectively. Statistical analysis revealed that variant α-actinin 4 is independent negative prognostic factor. The protein binds F-actin with higher avidity (Miyanaga et al., 2013). Analysis of gene expression by microarray technology proved α-actinin 4 as a marker of worse disease development in non-small cell lung cancer. Higher expression of α-actinin 4 has been correlated to significantly lower survival (Yamagata et al., 2003). Small cell lung cancer (SCLC) cell lines and tissue from the patient biopsies express ACTN4 alternatively spliced variant, normally found in the testis. Variant α-actinin 4 binds F-actin with higher affinity. This splice variant was proposed as diagnostic marker in SCLC (Honda et al., 2004). Immune response against the mutated ACTN4 in the patient with large cell lung cancer has been involved in the clinical evolution of the disease. Furthermore, after extraction of the primary tumor the cytotoxic T lymphocyte clone targeting mutated α-actinin 4 persisted many years in the patient's blood (Echchakir et al., 2001). In the subsequent study, it has been shown that the above point mutation removes antiproliferative effect of ACTN4 protein in the cancer cell line and supports the notion that ACTN4 may be both tumor suppressor as well as tumor promoter gene (Menez et al., 2004). |
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Entity | Nervous system neoplasms |
Note | Similar to various carcinomas, increase of ACTN4 protein levels also appears to be involved in progression of certain brain tumors. In human astrocytoma contrasted to normal human brain tissue, Western blot densitometric quantification demonstrated ~2 times higher levels of α-actinin 4 in the tumor samples; furthermore, in higher grades astrocytomas (III-IV) α-actinin 4 has additional 1.9 fold increase compared to low grades astrocytomas (I-II). In vitro downregulation of α-actinin 4 (RNAi) in human astrocytoma cell lines U-373, U-87, and A172 reduced cell adhesion and motility, cortical actin localization, and RhoA mRNA and protein. In U-373 cells only α-actinin 4 promoted cell growth (Quick and Skalli, 2010). However, some experimental data support the opposite concept: a number of cytoskeleton-associated proteins show reduced expression in cancer cells and recovering their levels (e.g., in vitro transfection) transform the cells phenotype to less malignant (Glück et al., 1993). Human neuroblastoma cell lines with high malignant phenotype express lower level of α-actinin 4 compared to more differentiated and less malignant neuroblastoma cell lines. Transfection with ACTN4 has suppressed tumorigenicity and has converted neuroblasts from high to low malignant phenotype. The effect persisted until the level of α-actinin 4 in transfected cells was maintained and initial high malignancy phenotype recovered when α-actinin 4 declined (Nikolopoulos et al, 2000). |
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Entity | Esophageal cancer |
Note | In a Chinese cohort of 12 patients suffering esophageal squamous cell carcinoma, α-actinin 4 overexpression has been detected in tumor tissue and proposed as a marker for prognostic evaluation of the disease (Fu et al., 2007). |
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Entity | Prostate cancer |
Note | Involvement of α-actinin 4 in tumor pathophysiology is undoubtedly mediated by various mechanisms because of the large number of binding partner molecules that have been identified. In human prostate cancer cell lines (22RV1, PC-3, LNCaP) ACTN4 protein product was less abundant than in normal human prostate epithelial cells, an observation that is conflicting with the findings in the most reports investigating relationship ACTN4-cancer development. Increasing the level of α-actinin 4 in those prostate cancer cells markedly suppressed cell-growth (Hara et al., 2007). In the same report the authors propose disturbance in clathrin-mediated endocytosis as the main mechanism associated with α-actinin 4 mediated cellular effects. |
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Entity | Bladder cancer |
Note | The promoting effect of ACTN4 gene product on cancer invasion has also been found in the bladder cancer cell lines (T24, J82) and tissue from superficial and invasive bladder cancers. ACTN4 mRNA and protein levels are higher in malignant cell lines and the tissues from the patients versus disease-free state. RNAi silencing of ACTN4 resulted in decreased cell invasion as measured by in vitro assay but did not affect the cell growth (Koizumi et al., 2010). |
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Entity | Ovarian cancer |
Note | Increased expression of α-actinin 4 and 19q12-13 genetic locus amplification has been detected in 21% of 136 cases of advanced-stage ovarian cancer. Statistical analysis associated higher copy number of ACTN4 as negative prognostic factor in the patients with ovarian cancer (Yamamoto et al., 2007). ACTN4 is a candidate oncogene in epithelial ovarian cancer. In subset of patients it has been found that the chromosome 19q12-q13 region is amplified correlating with higher expression of α-actinin 4 protein (Yamamoto et al., 2009). |
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Entity | Glomerular kidney disease - Focal segmental glomerulosclerosis (FSGS) |
Note | Autosomal dominant point mutations in ACTN4 are associated with inherited form of FSGS. Aberrant α-actinin 4 disrupts glomerular podocytes especially their foot processes, which are essential in blood-urine barrier function. Clinically the disease causes proteinuria and deteriorating renal function. Mutant α-actinin 4 aggregates in the cytosol of podocytes and degrades faster than the normal molecule (Yao et al., 2004). |
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Entity | Autoimmune diseases - Systemic lupus erythematodes (SLE) |
Note | Autoantibodies against double stranded DNA cross-reacting with α-actinin in the renal structures are associated with the development lupus nephritis (Mostoslavsky et al., 2001). Lupus-prone mouse strain overexpresses α-actinin 1 and 4 in glomerular mesangial cells (Zhao et al., 2006). In patients with lupus nephritis clinical studies have suggested the link between anti-α-actinin autoantibodies and kidney involvement (Becker-Merok et al., 2006), however in the reports there is no discrimination between the 2 "non-muscle" α-actinin isoforms. Given the fact that α-actinin 4 is highly expressed in the affected renal structures in SLE nephritis, the involvement of isoform 4 is probable. |
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Entity | Autoimmune hepatitis type I |
Note | Autoantibodies against α-actinin are proposed as markers for severity and activity of autoimmune hepatitis type I (Gueguen et al., 2006). However, there is no report so far describing the exact α-actinin isoform as a target antigen. |
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