TPM1

Gene Summary

Gene:TPM1; tropomyosin 1 (alpha)
Aliases: CMH3, TMSA, CMD1Y, LVNC9, C15orf13, HEL-S-265, HTM-alpha
Location:15q22.2
Summary:This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tropomyosin alpha-1 chain
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: TPM1 (cancer-related)

Petrović N
miR-21 Might be Involved in Breast Cancer Promotion and Invasion Rather than in Initial Events of Breast Cancer Development.
Mol Diagn Ther. 2016; 20(2):97-110 [PubMed] Related Publications
Breast cancer (BC) is a heterogeneous disease that develops into a large number of varied phenotypes. One of the features used in its classification and therapy selection is invasiveness. MicroRNA-21 (miR-21) is considered to be an important element of BC invasiveness, and miR-21 levels are frequently increased in different tumor types compared with normal tissue, including the breast. Experimental and literature research has highlighted that miR-21 was always significantly elevated in every study that included invasive breast carcinomas compared with healthy breast tissue. The main goal of this research was to specify the predominant role of miR-21 in the different phases of BC pathogenesis, i.e. whether it was involved in the early (initiation), later (promotion), or late (propagation, progression) phases. Our second goal was to explain the roles of miR-21 targets in BC by an in silico approach and literature review, and to associate the importance of miR-21 with particular phases of BC pathogenesis through the action of its target genes. Analysis has shown that changes in miR-21 levels might be important for the later and/or late phases of breast cancerogenesis rather than for the initial early phases. Targets of miR-21 (TIMP3, PDCD4, PTEN, TPM1 and RECK) are also primarily involved in BC promotion and progression, especially invasion, angiogenesis and metastasis. miR-21 expression levels could perhaps be used in conjunction with the standard diagnostic parameters as an indicator of BC presence, and to indicate a phenotype likely to show early invasion/metastasis detection and poor prognosis.

Huang QX, Cui JY, Ma H, et al.
Screening of potential biomarkers for cholangiocarcinoma by integrated analysis of microarray data sets.
Cancer Gene Ther. 2016 Feb-Mar; 23(2-3):48-53 [PubMed] Related Publications
Cholangiocarcinoma (CCA) continues to harbor a difficult prognosis and it is difficult to diagnose in its early stages. The molecular mechanisms of CCA oncogenesis and progression are poorly understood. This study aimed to identify candidate biomarkers for CCA. Integrated analysis of microarray data sets was performed to identify differentially expressed genes (DEGs) between CCA and normal tissues. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to identify the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. The expressions of DEGs were validated in human CCA tissues by qRT-PCR. A set of 712 DEGs were identified in CCA compared with normal tissues, including 306 upregulated and 406 downregulated DEGs. It can be shown from the KEGG pathway analysis that some pathways may have important roles in pathology of CCA, including peroxisome proliferator-activated receptor signaling pathway, bile secretion, cell cycle, fat digestion and absorption. PPI network indicated that the significant hub proteins were PKM, SPP1 and TPM1. The abnormally overexpression PKM, SPP1 and TPM1 were closely related to oncogenesis and progression of CCA. PKM, SPP1, TPM1, COL1A1 and COL1A2 may serve as candidate biomarkers for diagnosis and prognosis of CCA.

Du HQ, Wang Y, Jiang Y, et al.
Silencing of the TPM1 gene induces radioresistance of glioma U251 cells.
Oncol Rep. 2015; 33(6):2807-14 [PubMed] Related Publications
The present study was designed to investigate the relationship between tropomyosin 1 (TPM1) and radioresistance in human U251 cells. Radioresistant U251 (RR-U251) cells were established by repeated small irradiating injury. TPM1 levels in the U251 and RR-U251 cells were inhibited by transfection with TPM1-short hairpin RNA (shRNA) while overexpression was induced by treatment with pcDNA3.1‑TPM1. The radiosensitivity of the U251 and RR-U251 cells and the plasmid-transfected cells was evaluated by cell viability, migration and invasion assays. Cell apoptosis was also examined in vitro. The radiosensitivity of U251 xenografts was observed by tumor growth curve after radiotherapy in an in vivo experiment. Western blotting and immunohistochemistry were used to detect the level of TPM1 in vivo. The expression of TPM1 was significantly decreased in the RR-U251 cells, which may be correlated with the radioresistance of the glioma U251 cells. In the TPM1-silenced RR-U251 and TPM1-silenced U251 cells, cell viability, migration and invasion ability were significantly increased, and the rate of cell apoptosis was decreased. Consistent with these results, in the TPM1-overexpressing U251 and RR-U251 cells, cell viability, migration and invasion abilities were markedly decreased, and increased apoptosis was noted when compared to the control group. Tumor growth of the U251 xenografts was significantly inhibited following treatment with pcDNA3.1‑TPM1 combined with radiotherapy. Taken together, these results indicate that TPM1 may be one mechanism underlying radiation resistance, and TPM1 may be a potential target for overcoming the radiation resistance in glioma.

Wang J, Guan J, Lu Z, et al.
Clinical and tumor significance of tropomyosin-1 expression levels in renal cell carcinoma.
Oncol Rep. 2015; 33(3):1326-34 [PubMed] Related Publications
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and has been described as one of the deadliest of cancers affecting the genitourinary tract. Tropomyosin is a two-stranded α-helical coiled coil protein found in cell cytoskeletons. One of its isoforms, tropomyosin-1 (TPM1) has been reported as a novel tumor-suppressor gene and is downregulated in many solid tumors. However the expression level and function of TPM1 in RCC have not yet been determined. In the present study, we evaluated the TPM1-4 mRNA and TPM1 protein levels in RCC tissue samples. TPM1-overexpressing OSRC-2 and 786-O cell lines were also used to investigate the impact of TPM1 on RCC cells. We found that TPM1 was significantly and specifically downregulated in the RCC tissues. TPM1 expression was associated with tumor size, smoking status, Fuhrman grade and the prognosis of RCC patients. After TPM1 transfection, the migratory and invasive abilities of the OSRC-2 and 786-O cell lines were both reduced when compared to the control groups. Meanwhile, apoptosis was also enhanced in these two RCC cell lines following TPM1 transfection. Taken together, TPM1 exhibits characteristics of a tumor-suppressor gene while being overexpressed in RCC cell lines.

Wang Y, Gao X, Wei F, et al.
Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis.
Gene. 2014; 533(1):389-97 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) have been reported to be aberrantly expressed in patients with cancer. Many studies have shown that circulating miRNAs could play potential roles as diagnostic and prognostic biomarkers of cancers. The aim of this meta-analysis is to summarize the role of circulating miR-21 as a biomarker in patients with a variety of carcinomas.
MATERIAL AND METHODS: Eligible studies were identified and assessed for quality through multiple search strategies. For diagnostic meta-analysis, the sensitivity, specificity, and other measures of miR-21 in the diagnosis of cancer were pooled using bivariate random-effects approach models. For prognostic meta-analysis, pooled hazard ratios (HRs) of circulating miR-21 for survival were calculated.
RESULTS: A total of 36 studies dealing with various carcinomas were included for the systemic review. Among them, 23 studies were finally enrolled in the global meta-analysis (17 studies for diagnosis and 6 studies for prognosis). For diagnostic meta-analysis, the overall pooled results for sensitivity, specificity, positive likelihood ratio (LRP), negative likelihood ratios (LRN) and diagnostic odds ratio (DOR) were 75.7% (95% CI: 67.1%-82.6%), 79.3% (95% CI: 74.2%-83.5%), 3.65 (95% CI: 2.83-4.70), 0.31 (95% CI: 0.22-0.43), and 11.88 (95% CI: 6.99-20.19), respectively. For prognostic meta-analysis, the pooled HR of higher miR-21 expression in circulation was 2.37 (95% CI: 1.83-3.06, P<0.001), which could significantly predict poorer survival in general carcinomas. Importantly, subgroup analysis suggested that higher expression of miR-21 correlated with worse overall survival (OS) significantly in carcinomas of digestion system (HR, 5.77 [95% CI: 2.65-12.52]).
CONCLUSIONS: Our findings suggest that circulating miR-21 may not suitable to be a diagnostic biomarker, but it has a prognostic value in patients with cancer.

Hu J, Ho AL, Yuan L, et al.
From the Cover: Neutralization of terminal differentiation in gliomagenesis.
Proc Natl Acad Sci U S A. 2013; 110(36):14520-7 [PubMed] Free Access to Full Article Related Publications
An immature state of cellular differentiation--characterized by stem cell-like tendencies and impaired differentiation--is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.

Tang HY, Beer LA, Tanyi JL, et al.
Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer.
J Proteomics. 2013; 89:165-78 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: New serological biomarkers for early detection and clinical management of ovarian cancer are urgently needed, and many candidates have been reported. A major challenge frequently encountered when validating candidates in patients is establishing quantitative assays that distinguish between highly homologous proteins. The current study tested whether multiple members of two recently discovered ovarian cancer biomarker protein families, chloride intracellular channel (CLIC) proteins and tropomyosins (TPM), were detectable in ovarian cancer patient sera. A multiplexed, label-free multiple reaction monitoring (MRM) assay was established to target peptides specific to all detected CLIC and TPM family members, and their serum levels were quantitated for ovarian cancer patients and non-cancer controls. In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. Some of the additional biomarkers identified in this homolog-centric verification and validation approach may be superior to the previously identified biomarkers at discriminating between ovarian cancer and non-cancer patients. This demonstrates the importance of considering all potential protein homologs and using quantitative assays for cancer biomarker validation with well-defined isoform specificity.
BIOLOGICAL SIGNIFICANCE: This manuscript addresses the importance of distinguishing between protein homologs and isoforms when identifying and validating cancer biomarkers in plasma or serum. Specifically, it describes the use of targeted in-depth LC-MS/MS analysis to determine the members of two protein families, chloride intracellular channel (CLIC) and tropomyosin (TPM) proteins that are detectable in sera of ovarian cancer patients. It then establishes a multiplexed isoform- and homology-specific MRM assay to quantify all observed gene products in these two protein families as well as many of the closely related tropomyosin isoforms. Using this assay, levels of all detected CLICs and TPMs were quantified in ovarian cancer patient and control subject sera. These results demonstrate that in addition to the previously known CLIC1, multiple tropomyosins and CLIC4 are promising new ovarian cancer biomarkers. Based on these initial validation studies, these new ovarian cancer biomarkers appear to be superior to most previously known ovarian cancer biomarkers.

Lv L, Huang F, Mao H, et al.
MicroRNA-21 is overexpressed in renal cell carcinoma.
Int J Biol Markers. 2013; 28(2):201-7 [PubMed] Related Publications
OBJECTIVE: To identify microRNAs (miRNAs) that are overexpressed in renal cell carcinoma (RCC) and characterize the functional role of miR-21.
MATERIALS AND METHODS: The miRNA expression profiles between RCC tissue and adjacent normal tissue were compared using microarray analysis. The differential expression of miR-21 was validated by real-time polymerase chain reaction (RT-PCR). 786-O RCC cells were transfected with miR-21 mimic, miR-21 inhibitor, or negative controls and cell proliferation, apoptosis and cell cycle were examined by MTT assay and flow cytometry. The expression of programmed cell death 4 (PDCD4) and tropomyosin 1 (TPM1) was detected by RT-PCR and Western blot analysis.
RESULTS: Compared to adjacent normal tissue, 10 human miRNAs were significantly upregulated and 7 were downregulated in RCC tissue. RT-PCR confirmed that miR-21 was significantly overexpressed in RCC tissue. In vitro expression of miR-21 mimic promoted the growth of 786-O cells, whereas miR-21 inhibitor inhibited cell growth by inducing apoptosis and cell cycle arrest at S phase. Furthermore, miR-21 mimic or inhibitor significantly reduced or increased the expression of PDCD4 and TPM1.
CONCLUSIONS: MiR-21 is overexpressed in RCC tissue and modulates the growth, apoptosis and cell cycle progression of RCC cells and regulates the expression of PDCD4 and TPM1.

Yang W, Wang X, Zheng W, et al.
Genetic and epigenetic alterations are involved in the regulation of TPM1 in cholangiocarcinoma.
Int J Oncol. 2013; 42(2):690-8 [PubMed] Related Publications
Cholangiocarcinoma is a malignant tumor originating from biliary epithelial cells. The tumor suppressor gene tropomyosin 1 (TPM1) is downregulated in several human cancer types; however, its expression status in cholangiocarcinoma is still unknown. We elucidated TPM1 expression and its regulation mechanism in cholangiocarcinoma. Real-time (RT)-PCR, western blot analysis and immunohistochemistry were performed to examine TPM1 expression levels in cholangiocarcinoma cell lines and tumor tissues. Cell lines were treated with lentiviral vector containing the miR-21 knockdown and inhibitors of genetic and epigenetic mechanisms (manumycin A, LY294002, U0126, DAC and TSA), and the TPM1 expression change was observed by RT-PCR and western blot analyses. Cell proliferation, apoptosis and migration were evaluated by water-soluble tetrazolium salt (WST-1) assay, flow cytometry and wound healing experiments, respectively. TPM1 was downregulated in the intrahepatic cholangiocarcinoma cells (HuCCT1) and upregulated in the extrahepatic cholangiocarcinoma cells (QBC939) compared with normal intrahepatic biliary epithelial cells (HIBEC). TPM1 stained negative in the intrahepatic cholangiocarcinoma tissues, as revealed by immunohistochemistry, although there was no significant difference in staining of the intrahepatic cholangiocarcinoma tissues and adjacent non-cancer tissues. RAS and two important downstream signaling pathways (RAS/PI3K/AKT and RAS/MEK/ERK) were involved in TPM1 regulation and inhibition of the epigenetic mechanisms such as DNA methylation, histone deacetylation and miR-21 upregulation upregulated TPM1 expression. Inhibitors of genetic and epigenetic mechanisms (manumycin A, LY294002, U0126, DAC and TSA) inhibited cell proliferation and migration and induced apoptosis. These data indicated that TPM1 is downregulated in HuCCT1 cells and that the Ras signaling pathway as well as DNA methylation, histone deacetylation and miR-21 upregulation play important roles in the suppression of TPM1 expression in HuCCT1 cells. Thus, compounds that inhibit genetic and epigenetic mechanisms may be promising agents in treating cholangiocarcinoma.

Zare M, Jazii FR, Soheili ZS, Moghanibashi MM
Downregulation of tropomyosin-1 in squamous cell carcinoma of esophagus, the role of Ras signaling and methylation.
Mol Carcinog. 2012; 51(10):796-806 [PubMed] Related Publications
Tropomyosins (TMs) are a family of cytoskeletal proteins that bind to and stabilize actin microfilaments. Non-muscle cells express multiple isoforms of TMs including three high molecular weight (HMW) isoforms: TM1, TM2, and TM3. While reports have indicated downregulation of TMs in transformed cells and several human cancers, nevertheless, little is known about the underlying mechanism of TMs suppression. In present study the expression of HMW TMs was investigated in squamous cell carcinoma of esophagus (SCCE), relative to primary cell cultures of normal esophagus by western blotting and real-time RT-PCR. Our results showed that TM1, TM2, and TM3 were significantly downregulated in cell line of SCCE. Moreover, mRNA level of TPM1 and TPM2 were markedly decreased by 93% and 96%, in tumor cell line relative to esophagus normal epithelial cells. Therefore, downregulation of TMs could play an important role in tumorigenesis of esophageal cancer. To asses the mechanism of TM downregulation in esophageal cancer, the role of Ras dependent signaling and promoter hypermethylation were investigated. We found that inhibition of two Ras effectory downstream pathways; MEK/ERK and PI3K/Akt leads to significant increased expression of TM1 protein and both TPM1 and TPM2 mRNAs. In addition, methyltransferase inhibition significantly upregulated TM1, suggesting the prominent contribution of promoter hypermethylation in TM1 downregulation in esophageal cancer. These data indicate that downregulation of HMW TMs occurs basically in SCCE and the activation of MEK/ERK and PI3K/Akt pathways as well as the epigenetic mechanism of promoter hypermethylation play important role in TM1 suppression in SCCE.

Dong CG, Wu WK, Feng SY, et al.
Co-inhibition of microRNA-10b and microRNA-21 exerts synergistic inhibition on the proliferation and invasion of human glioma cells.
Int J Oncol. 2012; 41(3):1005-12 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs that function as negative gene regulators. Alterations in the expression of miRNAs have been implicated in the pathogenesis and development of most human malignancies. Recent data indicate that microRNA-21 and microRNA-10b are significantly elevated in glioblastoma multiforme (GBM) suggesting their role in the regulation of multiple genes associated with cancer. In this study, U87MG human glioblastoma cells were treated with miRNA inhibitors targeting miR-10b and miR-21, alone or in combination. The results showed that the miR-21 inhibitor additively interacted with miR-10b inhibitor on U87MG cells. The 50% inhibitory concentration values were dramatically decreased in cells treated with the combination of miR-10b and miR-21 inhibitors. Furthermore, inhibitors synergistically combined, enhanced apoptosis significantly and reduced invasion ability assessed by flow cytometry and Transwell migration assay. Thus, the miR-21 inhibitor may interrupt the activity of EGFR pathways, increasing PDCD4 and TPM1 expression and reducing MMP activities, independently of PTEN status. Meanwhile, miR-10b inhibitor reduced by Twist proceeds to inhibit translation of the mRNA encoding HOXD10 leading to the increase of the expression of the well-characterized pro-metastatic gene RHOC. Taken together, these data strongly suggest that a combination of miR-21 inhibitor and miR-10b inhibitor could be an effective therapeutic strategy for controlling the growth of GBM by inhibiting oncogene expression and overexpressing tumor suppressor genes. Moreover, a regulatory strategy based on the combination of miRNA inhibitors may provide insights into the mechanisms of the modulation of signaling genes involved in tumor cell apoptosis and invasiveness.

Liao SJ, Zhou YH, Yuan Y, et al.
Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvβ3-mediated adhesion and invasive migration.
Breast Cancer Res Treat. 2012; 133(3):853-63 [PubMed] Related Publications
Triggering of Toll-like receptor 4 (TLR4) on tumor cells has been found to promote tumor progression by promoting tumor cell proliferation and survival. So far, however, the effect of TLR4 signaling on tumor metastasis has not been well elucidated. Here, we report that triggering of TLR4 on metastatic breast cancer cells could reciprocally regulate the expression of αvβ3 and the expressions of TPM1 and maspin, and promote αvβ3-mediated adhesion and invasive migration of the cells. In metastatic breast cancer cells, TLR4 signaling increased the expression of integrin αvβ3 by activating NF-κB, resulting in the increased adhesion capacity of tumor cells to the ligand for αvβ3, and the increased polymerization of actin and production of MMP-9 in tumor cells in response to ECM. HoxD3 was required for the up-regulation of αv and β3 expressions by NF-κB. Moreover, TLR4 signaling increased the expression of miR-21 in breast cancer cells by activating NF-κB. Accordingly, the expressions of TPM1 and maspin were decreased at protein level, whereas the transcription activity of these genes was not influenced. Consistent with the promoting effect on αvβ3-mediated adhesion and invasive migration, TLR4 signaling promoted the arrest of metastatic breast cancer cells in circulation and following invasion. The effect of TLR4 signaling could be abrogated by inhibiting NF-κB. These findings suggest that metastatic breast cancer cells could acquire higher metastatic potential due to triggering of TLR4 and activation of NF-κB in the cells, and that both TLR4 and NF-κB could be therapeutic targets for preventing metastasis of breast cancer cells.

Langer W, Sohler F, Leder G, et al.
Exon array analysis using re-defined probe sets results in reliable identification of alternatively spliced genes in non-small cell lung cancer.
BMC Genomics. 2010; 11:676 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Treatment of non-small cell lung cancer with novel targeted therapies is a major unmet clinical need. Alternative splicing is a mechanism which generates diverse protein products and is of functional relevance in cancer.
RESULTS: In this study, a genome-wide analysis of the alteration of splicing patterns between lung cancer and normal lung tissue was performed. We generated an exon array data set derived from matched pairs of lung cancer and normal lung tissue including both the adenocarcinoma and the squamous cell carcinoma subtypes. An enhanced workflow was developed to reliably detect differential splicing in an exon array data set. In total, 330 genes were found to be differentially spliced in non-small cell lung cancer compared to normal lung tissue. Microarray findings were validated with independent laboratory methods for CLSTN1, FN1, KIAA1217, MYO18A, NCOR2, NUMB, SLK, SYNE2, TPM1, (in total, 10 events) and ADD3, which was analysed in depth. We achieved a high validation rate of 69%. Evidence was found that the activity of FOX2, the splicing factor shown to cause cancer-specific splicing patterns in breast and ovarian cancer, is not altered at the transcript level in several cancer types including lung cancer.
CONCLUSIONS: This study demonstrates how alternatively spliced genes can reliably be identified in a cancer data set. Our findings underline that key processes of cancer progression in NSCLC are affected by alternative splicing, which can be exploited in the search for novel targeted therapies.

Ku BM, Ryu HW, Lee YK, et al.
4'-Acetoamido-4-hydroxychalcone, a chalcone derivative, inhibits glioma growth and invasion through regulation of the tropomyosin 1 gene.
Biochem Biophys Res Commun. 2010; 402(3):525-30 [PubMed] Related Publications
Chalcones are precursors of flavonoids and have been shown to have anti-cancer activity. Here, we identify the synthetic chalcone derivative 4'-acetoamido-4-hydroxychalcone (AHC) as a potential therapeutic agent for the treatment of glioma. Treatment with AHC reduced glioma cell invasion, migration, and colony formation in a concentration-dependent manner. In addition, AHC inhibited vascular endothelial growth factor-induced migration, invasion, and tube formation in HUVECs. To determine the mechanism underlying the inhibitory effect of AHC on glioma cell invasion and migration, we investigated the effect of AHC on the gene expression change and found that AHC affects actin dynamics in U87MG glioma cells. In actin cytoskeleton regulating system, AHC increased tropomyosin expression and stress fiber formation, probably through activation of PKA. Suppression of tropomyosin expression by siRNA or treatment with the PKA inhibitor H89 reduced the inhibitory effects of AHC on glioma cell invasion and migration. In vivo experiments also showed that AHC inhibited tumor growth in a xenograft mouse tumor model. Together, these data suggest that the synthetic chalcone derivative AHC has potent anti-cancer activity through inhibition of glioma proliferation, invasion, and angiogenesis and is therefore a potential chemotherapeutic candidate for the treatment of glioma.

Fix LN, Shah M, Efferth T, et al.
MicroRNA expression profile of MCF-7 human breast cancer cells and the effect of green tea polyphenon-60.
Cancer Genomics Proteomics. 2010 Sep-Oct; 7(5):261-77 [PubMed] Related Publications
This study reports for the first time the microRNA expression profile of human breast cancer MCF-7 cells and the effect of green tea. Although hundreds of miRNAs have been identified in humans, only a small proportion (25.6%) of miRNAs are expressed in MCF-7 cells. Low concentration treatment with Polyphenon-60 significantly alters the miRNA expression profile in MCF-7 cells. Twenty three miRNAs have been identified with differential expression after a 48 h treatment with 10 μg/ml Polyphenon-60 (green tea extract). These miRNAs include miR-21 and miR-27 that were found to be down-regulated following treatment with green tea. These two miRNAs have previously been identified as being overexpressed in MCF-7 breast cancer cells, with miR-21 specifically implicated in down-regulating the tumor suppressor gene, tropomyosin-1. This data supports the hypothesis that Polyphenon-60-induced modification of the breast cancer miRNA expression profile contributes to the efficacy of green tea treatment. The resulting decrease in carcinogenesis is further supported by the altered miRNA regulation of potential oncogenes and tumor-suppressor genes.

Mlakar V, Berginc G, Volavsek M, et al.
Presence of activating KRAS mutations correlates significantly with expression of tumour suppressor genes DCN and TPM1 in colorectal cancer.
BMC Cancer. 2009; 9:282 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite identification of the major genes and pathways involved in the development of colorectal cancer (CRC), it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC. Therefore we wanted to improve our understanding of the genetic mechanisms of CRC development.
METHODS: We used microarrays to identify novel genes involved in the development of CRC. Real time PCR was used for mRNA expression as well as to search for chromosomal abnormalities within candidate genes. The correlation between the expression obtained by real time PCR and the presence of the KRAS mutation was investigated.
RESULTS: We detected significant previously undescribed underexpression in CRC for genes SLC26A3, TPM1 and DCN, with a suggested tumour suppressor role. We also describe the correlation between TPM1 and DCN expression and the presence of KRAS mutations in CRC. When searching for chromosomal abnormalities, we found deletion of the TPM1 gene in one case of CRC, but no deletions of DCN and SLC26A3 were found.
CONCLUSION: Our study provides further evidence of decreased mRNA expression of three important tumour suppressor genes in cases of CRC, thus implicating them in the development of this type of cancer. Moreover, we found underexpression of the TPM1 gene in a case of CRCs without KRAS mutations, showing that TPM1 might serve as an alternative path of development of CRC. This downregulation could in some cases be mediated by deletion of the TPM1 gene. On the other hand, the correlation of DCN underexpression with the presence of KRAS mutations suggests that DCN expression is affected by the presence of activating KRAS mutations, lowering the amount of the important tumour suppressor protein decorin.

Li J, Huang H, Sun L, et al.
MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor.
Clin Cancer Res. 2009; 15(12):3998-4008 [PubMed] Related Publications
PURPOSE: We aim to examine miR-21 expression in tongue squamous cell carcinomas (TSCC) and correlate it with patient clinical status, and to investigate its contribution to TSCC cell growth, apoptosis, and tumorigenesis.
EXPERIMENTAL DESIGN: MicroRNA profiling was done in 10 cases of TSCC with microarray. MiR-21 overexpression was quantitated with quantitative reverse transcription-PCR in 103 patients, and correlated to the pathoclinical status of the patients. Immunohistochemistry was used to examine the expression of TPM1 and PTEN, and terminal deoxynucleotidyl transferase-mediated dUTP labeling to evaluate apoptosis. Moreover, miR-21 antisense oligonucleotide (ASO) was transfected in SCC-15 and CAL27 cell lines, and tumor cell growth was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, adherent colony formation, and soft agar assay, whereas apoptosis was determined by Annexin V assay, cytochrome c release, and caspase 3 assay. Tumorigenesis was evaluated by xenografting SCC-15 cells in nude mice.
RESULTS: MiR-21 is overexpressed in TSCC relative to adjacent normal tissues. The level of miR-21 is reversely correlated with TPM1 and PTEN expression and apoptosis of cancer cells. Multivariate analysis showed that miR-21 expression is an independent prognostic factor indicating poor survival. Inhibiting miR-21 with ASO in TSCC cell lines reduces survival and anchorage-independent growth, and induces apoptosis in TSCC cell lines. Simultaneous silencing of TPM1 with siRNA only partially recapitulates the effect of miR-21 ASO. Furthermore, repeated injection of miR-21 ASO suppresses tumor formation in nude mice by reducing cell proliferation and inducing apoptosis.
CONCLUSIONS: miR-21 is an independent prognostic indicator for TSCC, and may play a role in TSCC development by inhibiting cancer cell apoptosis partly via TPM1 silencing.

Qi L, Bart J, Tan LP, et al.
Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma.
BMC Cancer. 2009; 9:163 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal breast cancer (IDC) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA.
METHODS: We performed miRNA in-situ hybridization (ISH) on 15 cases with simultaneous presence of normal breast tissue, FEA and/or DCIS and 17 additional cases with IDC. Expression of the miR-21 targets PDCD4, TM1 and PTEN was investigated by immunohistochemistry.
RESULTS: Two out of fifteen cases showed positive staining for miR-21 in normal breast ductal epithelium, seven out of fifteen cases were positive in the FEA component and nine out of twelve cases were positive in the DCIS component. A positive staining of miR-21 was observed in 15 of 17 IDC cases. In 12 cases all three components were present in one tissue block and an increase of miR-21 from normal breast to FEA and to DCIS was observed in five cases. In three cases the FEA component was negative, whereas the DCIS component was positive for miR-21. In three other cases, normal, FEA and DCIS components were negative for miR-21 and in the last case all three components were positive. Overall we observed a gradual increase in percentage of miR-21 positive cases from normal, to FEA, DCIS and IDC. Immunohistochemical staining for PTEN revealed no obvious changes in staining intensities in normal, FEA, DCIS and IDC. Cytoplasmic staining of PDCD4 increased from normal to IDC, whereas, the nuclear staining decreased. TM1 staining decreased from positive in normal breast to negative in most DCIS and IDC cases. In FEA, the staining pattern for TM1 was similar to normal breast tissue.
CONCLUSION: Upregulation of miR-21 from normal ductal epithelial cells of the breast to FEA, DCIS and IDC parallels morphologically defined carcinogenesis. No clear relation was observed between the staining pattern of miR-21 and its previously reported target genes.

Li T, Li D, Sha J, et al.
MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells.
Biochem Biophys Res Commun. 2009; 383(3):280-5 [PubMed] Related Publications
Prostate cancer is one of the most common malignant cancers in men. Recent studies have shown that microRNA-21 (miR-21) is overexpressed in various types of cancers including prostate cancer. Studies on glioma, colon cancer cells, hepatocellular cancer cells and breast cancer cells have indicated that miR-21 is involved in tumor growth, invasion and metastasis. However, the roles of miR-21 in prostate cancer are poorly understood. In this study, the effects of miR-21 on prostate cancer cell proliferation, apoptosis, and invasion were examined. In addition, the targets of miR-21 were identified by a reported RISC-coimmunoprecipitation-based biochemical method. Inactivation of miR-21 by antisense oligonucleotides in androgen-independent prostate cancer cell lines DU145 and PC-3 resulted in sensitivity to apoptosis and inhibition of cell motility and invasion, whereas cell proliferation were not affected. We identified myristoylated alanine-rich protein kinase c substrate (MARCKS), which plays key roles in cell motility, as a new target in prostate cancer cells. Our data suggested that miR-21 could promote apoptosis resistance, motility, and invasion in prostate cancer cells and these effects of miR-21 may be partly due to its regulation of PDCD4, TPM1, and MARCKS. Gene therapy using miR-21 inhibition strategy may therefore be useful as a prostate cancer therapy.

Liu S, Ren S, Howell P, et al.
Identification of novel epigenetically modified genes in human melanoma via promoter methylation gene profiling.
Pigment Cell Melanoma Res. 2008; 21(5):545-58 [PubMed] Related Publications
The inactivation of tumor-related genes through the aberrant methylation of promoter CpG islands is thought to contribute to tumor initiation and progression. We therefore investigated promoter methylation events involved in cutaneous melanoma by screening 30 genes of interest for evidence of promoter hypermethylation, examining 20 melanoma cell lines and 40 freshly procured melanoma samples. Utilizing quantitative methylation-specific PCR, we identified five genes (SOCS1, SOCS2, RAR-beta 2, TNFSF10C, and TNFSF10D) with hypermethylation frequencies ranging from 50% to 80% in melanoma cell lines as well as freshly procured tissue samples. Eighteen genes (LOX, RASSF1A, WFDC1, TM, APC, TFPI2, TNFSF10A, CDKN2A, MGMT, TIMP3, ASC, TPM1, IRF8, CIITA-PIV, CDH1, SYK, HOXB13, and DAPK1) were methylated at lower frequencies (2-30%). Two genes (CDKN1B and PTEN), previously reported as methylated in melanoma, and five other genes (RECK, IRF7, PAWR, TNFSF10B, and Rb) were not methylated in the samples screened here. Daughter melanoma cell lines showed identical methylation patterns when compared with original samples from which they were derived, as did synchronous metastatic lesions from the same patient. We identified four genes (TNFSF10C, TNFSF10D, LOX, and TPM1) that have never before been identified as hypermethylated in melanoma, with an overall methylation frequency of 60, 80, 50, and 10%, respectively, hypothesizing that these genes may play an important role in melanoma progression.

Thorsen K, Sørensen KD, Brems-Eskildsen AS, et al.
Alternative splicing in colon, bladder, and prostate cancer identified by exon array analysis.
Mol Cell Proteomics. 2008; 7(7):1214-24 [PubMed] Related Publications
Alternative splicing enhances proteome diversity and modulates cancer-associated proteins. To identify tissue- and tumor-specific alternative splicing, we used the GeneChip Human Exon 1.0 ST Array to measure whole-genome exon expression in 102 normal and cancer tissue samples of different stages from colon, urinary bladder, and prostate. We identified 2069 candidate alternative splicing events between normal tissue samples from colon, bladder, and prostate and selected 15 splicing events for RT-PCR validation, 10 of which were successfully validated by RT-PCR and sequencing. Furthermore 23, 19, and 18 candidate tumor-specific splicing alterations in colon, bladder, and prostate, respectively, were selected for RT-PCR validation on an independent set of 81 normal and tumor tissue samples. In total, seven genes with tumor-specific splice variants were identified (ACTN1, CALD1, COL6A3, LRRFIP2, PIK4CB, TPM1, and VCL). The validated tumor-specific splicing alterations were highly consistent, enabling clear separation of normal and cancer samples and in some cases even of different tumor stages. A subset of the tumor-specific splicing alterations (ACTN1, CALD1, and VCL) was found in all three organs and may represent general cancer-related splicing events. In silico protein predictions suggest that the identified cancer-specific splice variants encode proteins with potentially altered functions, indicating that they may be involved in pathogenesis and hence represent novel therapeutic targets. In conclusion, we identified and validated alternative splicing between normal tissue samples from colon, bladder, and prostate in addition to cancer-specific splicing events in colon, bladder, and prostate cancer that may have diagnostic and prognostic implications.

Zhu S, Wu H, Wu F, et al.
MicroRNA-21 targets tumor suppressor genes in invasion and metastasis.
Cell Res. 2008; 18(3):350-9 [PubMed] Related Publications
MicroRNAs (miRNAs) are a class of naturally occurring small non-coding RNAs that target protein-coding mRNAs at the post-transcriptional level. Our previous studies suggest that mir-21 functions as an oncogene and has a role in tumorigenesis, in part through regulation of the tumor suppressor gene tropomyosin 1 (TPM1). Given that TPM1 has been implicated in cell migration, in this study we further investigated the role of mir-21 in cell invasion and tumor metastasis. We found that suppression of mir-21 in metastatic breast cancer MDA-MB-231 cells significantly reduced invasion and lung metastasis. Consistent with this, ectopic expression of TPM1 remarkably reduced cell invasion. Furthermore, we identified two additional direct mir-21 targets, programmed cell death 4 (PDCD4) and maspin, both of which have been implicated in invasion and metastasis. Like TPM1, PDCD4 and maspin also reduced invasiveness of MDA-MB-231 cells. Finally, the expression of PDCD4 and maspin inversely correlated with mir-21 expression in human breast tumor specimens, indicating the potential regulation of PDCD4 and maspin by mir-21 in these tumors. Taken together, the results suggest that, as an oncogenic miRNA, mir-21 has a role not only in tumor growth but also in invasion and tumor metastasis by targeting multiple tumor/metastasis suppressor genes. Therefore, suppression of mir-21 may provide a novel approach for the treatment of advanced cancers.

Zhu S, Si ML, Wu H, Mo YY
MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).
J Biol Chem. 2007; 282(19):14328-36 [PubMed] Related Publications
MicroRNAs are small noncoding RNA molecules that control expression of target genes. Our previous studies show that mir-21 is overexpressed in tumor tissues compared with the matched normal tissues. Moreover, suppression of mir-21 by antisense oligonucleotides inhibits tumor cell growth both in vitro and in vivo. However, it remains largely unclear as to how mir-21 affects tumor growth, because our understanding of mir-21 targets is limited. In this study, we performed two-dimensional differentiation in-gel electrophoresis of tumors treated with anti-mir-21 and identified the tumor suppressor tropomyosin 1 (TPM1) as a potential mir-21 target. In agreement with this, there is a putative mir-21 binding site at the 3'-untranslated region (3'-UTR) of TPM1 variants V1 and V5. Thus, we cloned the 3'-UTR of TPM1 into a luciferase reporter and found that although mir-21 down-regulated the luciferase activity, anti-mir-21 up-regulated it. Moreover, deletion of the mir-21 binding site abolished the effect of mir-21 on the luciferase activity, suggesting that this mir-21 binding site is critical. Western blot with the cloned TPM1-V1 plus the 3'-UTR indicated that TPM1 protein level was also regulated by mir-21, whereas real-time quantitative reverse transcription-PCR revealed no difference at the mRNA level, suggesting translational regulation. Finally, overexpression of TPM1 in breast cancer MCF-7 cells suppressed anchorage-independent growth. Thus, down-regulation of TPM1 by mir-21 may explain, at least in part, why suppression of mir-21 can inhibit tumor growth, further supporting the notion that mir-21 functions as an oncogene.

Gardina PJ, Clark TA, Shimada B, et al.
Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array.
BMC Genomics. 2006; 7:325 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST) that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression.
RESULTS: We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported) transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic predictions of alternative splicing in cancer.
CONCLUSION: Differential expression of high confidence transcripts correlated extremely well with known cancer genes and pathways, suggesting that the more speculative transcripts, largely based solely on computational prediction and mostly with no previous annotation, might be novel targets in colon cancer. Five of the identified splicing events affect mediators of cytoskeletal organization (ACTN1, VCL, CALD1, CTTN, TPM1), two affect extracellular matrix proteins (FN1, COL6A3) and another participates in integrin signaling (SLC3A2). Altogether they form a pattern of colon-cancer specific alterations that may particularly impact cell motility.

Okamura M, Unami A, Moto M, et al.
The possible mechanism of enhanced carcinogenesis induced by genotoxic carcinogens in rasH2 mice.
Cancer Lett. 2007; 245(1-2):321-30 [PubMed] Related Publications
Microarray and RT-PCR analyses were performed for the transgene and Ras-related genes in forestomach squamous cell carcinomas (SCCs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rasH2 mice; these results were compared with our previous molecular data of N-ethyl-N-nitrosourea-induced forestomach SCCs and urethane-induced lung adenomas in rasH2 mice. Overexpression of the transgene was detected in the DMBA-induced SCCs, suggesting that the transgene plays an important role in enhanced carcinogenesis in rasH2 mice. In addition, the mouse endogenous ras genes were up-regulated in the DMBA-induced SCCs, and are probably involved in the tumorigenesis of forestomach SCCs. Genes such as osteopontin, Cks1b, Tpm1, Reck, gelsolin, and amphiregulin that were commonly altered in these three different carcinogen-induced tumors may contribute to the development of tumors in rasH2 mice.

Qi Y, Chiu JF, Wang L, et al.
Comparative proteomic analysis of esophageal squamous cell carcinoma.
Proteomics. 2005; 5(11):2960-71 [PubMed] Related Publications
Ranking as the fourth commonest cancer, esophageal squamous cell carcinoma (ESCC) represents one of the leading causes of cancer death in China. One of the main reasons for the low survival rate is that neoplasms in esophagus are not detected until they have invaded into surrounding tissues or spread throughout the body at advanced stages. A better understanding of the malignant mechanism and early diagnosis are important for fighting ESCC. In this study, we used proteomics to analyze ESCC tissues, aiming at defining the proteomic features implicated in the multistage progression of esophageal carcinogenesis. Proteins that exhibited significantly different expressions were identified by peptide mass fingerprinting and validated by Western blotting and reverse transcriptase-polymerase chain reaction. The protein changes were then correlated to the different grades of disease differentiation. Compared to those in adjacent normal epitheliums, the expression of 15 proteins including enolase, elongation factor Tu, isocitrate dehydrogenase, tubulin alpha-1 chain, tubulin beta-5 chain, actin (cytoplasmic 1), glyceraldehyde-3 phosphate dehydrogenase, tropomyosin isoform 4 (TPM4), prohibitin, peroxiredoxin 1 (PRX1), manganese-containing superoxide dismutase (MnSOD), neuronal protein, and transgelin was up-regulated; and the expression of five proteins including TPM1, squamous cell carcinoma antigen 1 (SCCA1), stratifin, peroxiredoxin 2 isoform a, and alpha B crystalline was down-regulated in cancer tissues with a statistical significance (p < 0.05). In addition, the differential expression of SCCA1, PRX1, MnSOD, TPM4, and prohibitin can be observed in precancerous lesions of ESCC. The expression of stratifin, prohibitin, and SCCA1 dropped with increasing dedifferentiation of ESCC. These data may suggest that these proteins contribute to the multistage process of carcinogenesis, tumor progression, and invasiveness of ESCC.

Varga AE, Stourman NV, Zheng Q, et al.
Silencing of the Tropomyosin-1 gene by DNA methylation alters tumor suppressor function of TGF-beta.
Oncogene. 2005; 24(32):5043-52 [PubMed] Related Publications
Loss of actin stress fibers has been associated with cell transformation and metastasis. TGF-beta induction of stress fibers in epithelial cells requires high molecular weight tropomyosins encoded by TPM1 and TPM2 genes. Here, we investigated the mechanism underlying the failure of TGF-beta to induce stress fibers and inhibit cell migration in metastatic cells. RT-PCR analysis in carcinoma cell lines revealed a significant reduction in TPM1 transcripts in metastatic MDA-MB-231, MDA-MB-435 and SW620 cell lines. Treatment of these cells with demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) increased mRNA levels of TPM1 with no effect on TPM2. Importantly, 5-aza-dC treatment of MDA-MB-231 cells restored TGF-beta induction of TPM1 and formation of stress fibers. Forced expression of TPM1 by using Tet-Off system increased stress fibers in MDA-MB-231 cells and reduced cell migration. A potential CpG island spanning the TPM1 proximal promoter, exon 1, and the beginning of intron 1 was identified. Bisulfite sequencing showed significant cytosine methylation in metastatic cell lines that correlated with a reduced expression of TPM1. Together these results suggest that epigenetic suppression of TPM1 may alter TGF-beta tumor suppressor function and contribute to metastatic properties of tumor cells.

Ruiz C, Huang W, Hegi ME, et al.
Growth promoting signaling by tenascin-C [corrected].
Cancer Res. 2004; 64(20):7377-85 [PubMed] Related Publications
Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of beta-catenin and stimulated the expression of the beta-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.

Raval GN, Bharadwaj S, Levine EA, et al.
Loss of expression of tropomyosin-1, a novel class II tumor suppressor that induces anoikis, in primary breast tumors.
Oncogene. 2003; 22(40):6194-203 [PubMed] Related Publications
Suppression of tropomyosins (TMs), a family of actin-binding, microfilament-associated proteins, is a prominent feature of many transformed cells. Yet it is unclear whether downregulation of TMs occur in human tumors. We have investigated the expression of tropomyosin-1 (TM1) in human breast carcinoma tissues by in situ hybridization and immunofluorescence. TM1 mRNA and protein are readily detectable in normal mammary tissue. In contrast, TM1 expression is abolished in the primary human breast tumors. Expression of other TM isoforms, however, is variable among the tumors. The consistent and profound downregulation of TM1 suggests that TM1 may be a novel and useful biomarker of mammary neoplasms. These data also support the hypothesis that suppression of TM1 expression during the malignant conversion of mammary epithelium as a contributing factor of breast cancer. In support of this hypothesis, we show that the ability to suppress malignant growth properties of breast cancer cells is specific to TM1 isoform. Investigations into the mechanisms of TM1-induced tumor suppression reveal that TM1 induces anoikis (detachment induced apoptosis) in breast cancer cells. Downregulation of TM1 in breast tumors may destabilize microfilament architecture and confer resistance to anoikis, which facilitates survival of neoplastic cells outside the normal microenvironment and promote malignant growth.

Bharadwaj S, Prasad GL
Tropomyosin-1, a novel suppressor of cellular transformation is downregulated by promoter methylation in cancer cells.
Cancer Lett. 2002; 183(2):205-13 [PubMed] Related Publications
Tropomyosins (TMs) are a family of microfilament binding proteins, which are suppressed in the transformed cells. We have investigated the mechanism of suppression of TMs, in particular that of tropomyosin-1 (TM1), in breast cancer cells. Inhibition of DNA methyl transferase with 5-aza-2'-deoxycytidine (AZA) alone did not induce TM1 expression. However, combined treatment of trichostatin A (TSA) and AZA resulted in readily detectable expression of TM1, but not that of other TM isoforms. Upregulation of TM1 expression paralleled with the reemergence of TM1 containing microfilaments, and in abolition of anchorage-independent growth. The synergistic action of AZA and TSA in reactivation of TM1 gene was also evident in ras-transformed fibroblasts. These data, for the first time, show that hypermethylation of TM1 gene and chromatin remodeling are the predominant mechanisms by which TM1 expression is downregulated in breast cancer cells.

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