The Experts below are selected from a list of 260124 Experts worldwide ranked by ideXlab platform
Michael Borre - One of the best experts on this subject based on the ideXlab platform.
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the mir 143 145 cluster regulates plasminogen activator inhibitor 1 in bladder cancer
British Journal of Cancer, 2012Co-Authors: Sune B. Villadsen, Erik D Wiklund, Jesper B. Bramsen, Thomas B. Hansen, Shan Gao, Marie Stampe Ostenfeld, Michael Borre, Niels Fristrup, Trine I Jensen, Torben F OrntoftAbstract:The enzyme plasminogen activator inhibitor-1 (PAI-1; encoded by the SERPINE1 locus) is an important member of the plasminogen activator system, and is involved in various processes including thrombosis, wound healing, angiogenesis and degradation of extracellular matrix components (reviewed by Lijnen (2005)). Plasminogen activator inhibitor-1 protein levels are commonly elevated in cancers, where it is secreted into the extracellular microenvironment by tumour cells, stromal fibroblasts and tumour-associated endothelial cells (McMahon and Kwaan, 2008; Kwaan and McMahon, 2009). High PAI-1 levels in tumours usually coincide with poor prognosis, and serve as an important prognostic marker in many cancer types. Moreover, PAI-1 is known to promote cancer cell proliferation and angiogenesis by inhibiting apoptosis in cell culture systems (Kwaan et al, 2000; Chen et al, 2004). Thus, PAI-1 acts broadly as an oncogene, and further insight into its regulation will be important for future diagnostic and therapeutic developments. MicroRNAs (miRNAs) are a class of ca. 22 nt non-coding RNAs that regulate gene expression at the level of mRNA stability and translation (Bartel, 2004). It has been estimated that miRNAs regulate the expression of 30% of protein-coding genes, and it is generally accepted that they are at some level involved in practically all cellular processes (Lewis et al, 2005). Many miRNAs are highly tissue specific and important for cell development and differentiation, and aberrant miRNA expression can lead to cellular dedifferentiation, oncogenesis, cancer metastasis and tumour invasion (Esquela-Kerscher and Slack, 2006). As such, widespread miRNA deregulation is a common hallmark of cancer (Wang and Lee, 2009), making miRNAs interesting as diagnostic and therapeutic targets. MicroRNA-directed deregulation of cancer-associated genes constitutes a rapidly growing research field, and decoding the underlying regulatory pathways is essential for the understanding of cancer aetiology and progression. Both MiR-143 and miR-145 are frequently downregulated in a broad range of cancer cell lines and tumours deriving from the haematopoietic system, breast, lung, colon, prostate, the gastrointestinal system, ovary, cervix, head and neck, and bladder tissue (Volinia et al, 2006; Dyrskjot et al, 2009; Wang and Lee, 2009). These miRNAs are transcribed from a putative cluster on chromosome 5, and they are coordinately expressed in a variety of cell types and tissues (Iio et al, 2010). Both MiR-143 and -145 are important in maintaining the differentiated state of smooth muscle cells (SMCs), and loss of expression in SMCs correlates with vascular disease (Cordes et al, 2009; Elia et al, 2009). Moreover, ectopic expression of miR-143 and -145 in a variety of cancer cell lines leads to decreased viability (Borralho et al, 2009; Chiyomaru et al, 2010; Ostenfeld et al, 2010; Spizzo et al, 2010; Zhang et al, 2010a; Noguchi et al, 2011). Accordingly, miR-143 and miR-145 are considered to act as broad tumour suppressors, and their deregulation has been reported as an early event in transformation (Michael et al, 2003; Sempere et al, 2007). In this study, we investigated putative miRNA regulation of mRNAs in a panel of normal bladder urothelial biopsies, superficial Ta bladder tumours and invasive T1-T4 tumours. Previously, we profiled miRNA expression in clinical bladder cancer specimens and found miR-145 to be the most downregulated miRNA in bladder tumours compared with normal urothelium (Dyrskjot et al, 2009). Here, we report that miR-143 and miR-145 are coordinately downregulated as an early neoplastic event in bladder cancer, which is inversely correlated with PAI-1 expression. Conversely, ectopic miR-143/-145 administration in bladder cell lines represses PAI-1 expression by directly targeting complementary miR-143 and miR-145 sequences in the PAI-1 3′UTR. The clinical significance of PAI-1 and miR-145 expression was investigated in non-muscle-invasive tumours using immunohistochemical and in situ hybridisation analyses on tissue microarrays (TMAs). Accordingly, both were usable markers with elevated levels correlating with poor and good prognosis, respectively. This is the first report of PAI-1 as a direct target of miR-143 and -145, and, to our knowledge, the first demonstration of a cluster of non-family miRNAs targeting the same mRNA.
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coordinated epigenetic repression of the mir 200 family and mir 205 in invasive bladder cancer
International Journal of Cancer, 2011Co-Authors: Erik D Wiklund, Jesper B. Bramsen, Toby Hulf, Lars Dyrskjøt, Ramshanker Ramanathan, Thomas B. Hansen, Sune B. Villadsen, Shan Gao, Marie Stampe Ostenfeld, Michael BorreAbstract:MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The Mir-200 family (Mir-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress Mir-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the Mir-200 family and miR-205. Recently, Mir-200 silencing was also reported in cancer stem cells, implying that Mir-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents Mir-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the Mir-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the Mir-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that Mir-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose Mir-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and Mir-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the Mir-200 and miR-205 promoters, and may act as a repressor of Mir-200 and miR-205 expression.
Carolyn M Klinge - One of the best experts on this subject based on the ideXlab platform.
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reduced expression of mir 200 family members contributes to antiestrogen resistance in ly2 human breast cancer cells
PLOS ONE, 2013Co-Authors: Tissa T Manavalan, Yun Teng, Lacey M Litchfield, Penn Muluhngwi, Numan Alrayyan, Carolyn M KlingeAbstract:Introduction The role of miRNAs in acquired endocrine-resistant breast cancer is not fully understood. One hallmark of tumor progression is epithelial-to-mesenchymal transition (EMT), characterized by a loss of cell adhesion resulting from reduced E-cadherin and increased cell mobility. Mir-200 family members regulate EMT by suppressing expression of transcriptional repressors ZEB1/2. Previously we reported that the expression of Mir-200a, Mir-200b, and Mir-200c was lower in LY2 endocrine-resistant, mesenchymal breast cancer cells compared to parental, endocrine sensitive, epithelial MCF-7 breast cancer cells. Here we investigated the regulation of Mir-200 family members and their role in endocrine-sensitivity in breast cancer cells. Results Mir-200 family expression was progressively reduced in a breast cancer cell line model of advancing endocrine/tamoxifen (TAM) resistance. Concomitant with Mir-200 decrease, there was an increase in ZEB1 mRNA expression. Overexpression of Mir-200b or Mir-200c in LY2 cells altered cell morphology to a more epithelial appearance and inhibited cell migration. Further, Mir-200b and Mir-200c overexpression sensitized LY2 cells to growth inhibition by estrogen receptor (ER) antagonists TAM and fulvestrant. Knockdown of ZEB1 in LY2 cells recapitulated the effect of Mir-200b and Mir-200c overexpression resulting in inhibition of LY2 cell proliferation by TAM and fulvestrant, but not the aromatase inhibitor exemestane. Demethylating agent 5-aza-2′-deoxycytidine (5-aza-dC) in combination with histone deacetylase inhibitor trichostatin A (TSA) increased Mir-200b and Mir-200c in LY2 cells. Concomitant with the increase in Mir-200b and Mir-200c, ZEB1 expression was decreased and cells appeared more epithelial in morphology and were sensitized to TAM and fulvestrant inhibition. Likewise, knockdown of ZEB1 increased antiestrogen sensitivity of LY2 cells resulting in inhibition of cell proliferation. Conclusions Our data indicate that reduced miRNA-200b and Mir-200c expression contributes to endocrine resistance in breast cancer cells and that the reduced expression of these Mir-200 family members in endocrine-resistant cells can be reversed by 5-aza-dC+TSA.
Ming Te Huang - One of the best experts on this subject based on the ideXlab platform.
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microrna 200a b influenced the therapeutic effects of curcumin in hepatocellular carcinoma hcc cells
Tumor Biology, 2013Co-Authors: Hung Hua Liang, Po Li Wei, Chin Sheng Hung, Weu Wang, Ming Te HuangAbstract:MicroRNAs (miRNAs) play an essential role in regulating gene expression in normal and malignant cells. Expression of the microRNA-200 (Mir-200) family has been correlated with malignancy in cancers. However, whether Mir-200a/b plays a role in curcumin-mediated treatment of hepatocellular carcinoma (HCC) is unknown. We performed miRNA array analyses in two different HCC cell lines (HepG2 and HepJ5). The expression patterns of Mir-200 family members were assessed with real-time PCR. We overexpressed Mir-200 family members using a lentiviral system and selected stably transduced clones with antibiotics. The anticancer effects of curcumin on J5-200a, J5-200b, and J5-control cells were assessed by MTT assay, flow cytometry cell cycle analysis, and TUNEL assay. We found that HepG2 cells, which were more resistant to curcumin treatment than HepJ5 cells, expressed higher levels of Mir-200a/b. The MTT assay revealed that the overexpression of Mir-200a/b in HepJ5 cells conferred enhanced resistance to curcumin treatment compared with the control cells. By cell cycle analysis and TUNEL assay, we found that apoptosis was increased dramatically in J5-control cells compared with J5-200a and J5-200b cells after curcumin treatment. Finally, we evaluated the levels of Bcl-2, Bax, and Bad, and found a decrease of Bcl-2 levels and increase of Bad levels in the J5-control cells treated with curcumin. The expression levels of Mir-200a/b might determine the therapeutic efficacy of curcumin on HCC cells.
David H Engelsvold - One of the best experts on this subject based on the ideXlab platform.
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mirna and mrna expression profiling identifies members of the mir 200 family as potential regulators of epithelial mesenchymal transition in pterygium
Experimental Eye Research, 2013Co-Authors: David H Engelsvold, Ole Kristoffer Olstad, Jon Roger Eidet, Annemarie Siebke Troseid, Tor Paaske Utheim, Pedro Gonzalez, Torstein Lyberg, Darlene A DarttAbstract:Abstract The current study investigates whether microRNA (miRNA) regulators of epithelial–mesenchymal transition (EMT), tissue fibrosis, and angiogenesis are differentially expressed in human primary pterygium. Genome-wide miRNA and mRNA expression profiling of paired pterygium and normal conjunctiva was performed in the context of conventional excision of pterygium with autotransplantation of conjunctiva (n = 8). Quantitative real time polymerase chain reaction (qRT-PCR) was used to validate the expression of key molecules previously detected by microarray. In pterygium, 25 miRNAs and 31 mRNAs were significantly differentially expressed by more than two-fold compared to normal conjunctiva. 14 miRNAs were up-regulated (miR-1246, -486, -451, -3172, -3175, -1308, -1972, -143, -211, -665, -1973, -18a, 143, and -663b), whereas 11 were down-regulated (miR-675, -200b-star, -200a-star, -29b, -200b, -210, -141, -31, -200a, -934, and -375). Unsupervised hierarchical cluster analysis demonstrated that members of the Mir-200 family were coexpressed and down-regulated in pterygium. The molecular and cellular functions that were most significant to the miRNA data sets were cellular development, cellular growth and proliferation, and cellular movement. qRT-PCR confirmed the expression of 15 of the 16 genes tested and revealed that miR-429 was down-regulated by more than two-fold in pterygium. The concerted down-regulation of four members from both clusters of the Mir-200 family (Mir-200a/-200b/-429 and Mir-200c/-141), which are known to regulate EMT, and up-regulation of the predicted target and mesenchymal marker fibronectin (FN1), suggest that EMT could potentially play a role in the pathogenesis of pterygium and might constitute promising new targets for therapeutic intervention in pterygium.
Erik D Wiklund - One of the best experts on this subject based on the ideXlab platform.
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the mir 143 145 cluster regulates plasminogen activator inhibitor 1 in bladder cancer
British Journal of Cancer, 2012Co-Authors: Sune B. Villadsen, Erik D Wiklund, Jesper B. Bramsen, Thomas B. Hansen, Shan Gao, Marie Stampe Ostenfeld, Michael Borre, Niels Fristrup, Trine I Jensen, Torben F OrntoftAbstract:The enzyme plasminogen activator inhibitor-1 (PAI-1; encoded by the SERPINE1 locus) is an important member of the plasminogen activator system, and is involved in various processes including thrombosis, wound healing, angiogenesis and degradation of extracellular matrix components (reviewed by Lijnen (2005)). Plasminogen activator inhibitor-1 protein levels are commonly elevated in cancers, where it is secreted into the extracellular microenvironment by tumour cells, stromal fibroblasts and tumour-associated endothelial cells (McMahon and Kwaan, 2008; Kwaan and McMahon, 2009). High PAI-1 levels in tumours usually coincide with poor prognosis, and serve as an important prognostic marker in many cancer types. Moreover, PAI-1 is known to promote cancer cell proliferation and angiogenesis by inhibiting apoptosis in cell culture systems (Kwaan et al, 2000; Chen et al, 2004). Thus, PAI-1 acts broadly as an oncogene, and further insight into its regulation will be important for future diagnostic and therapeutic developments. MicroRNAs (miRNAs) are a class of ca. 22 nt non-coding RNAs that regulate gene expression at the level of mRNA stability and translation (Bartel, 2004). It has been estimated that miRNAs regulate the expression of 30% of protein-coding genes, and it is generally accepted that they are at some level involved in practically all cellular processes (Lewis et al, 2005). Many miRNAs are highly tissue specific and important for cell development and differentiation, and aberrant miRNA expression can lead to cellular dedifferentiation, oncogenesis, cancer metastasis and tumour invasion (Esquela-Kerscher and Slack, 2006). As such, widespread miRNA deregulation is a common hallmark of cancer (Wang and Lee, 2009), making miRNAs interesting as diagnostic and therapeutic targets. MicroRNA-directed deregulation of cancer-associated genes constitutes a rapidly growing research field, and decoding the underlying regulatory pathways is essential for the understanding of cancer aetiology and progression. Both MiR-143 and miR-145 are frequently downregulated in a broad range of cancer cell lines and tumours deriving from the haematopoietic system, breast, lung, colon, prostate, the gastrointestinal system, ovary, cervix, head and neck, and bladder tissue (Volinia et al, 2006; Dyrskjot et al, 2009; Wang and Lee, 2009). These miRNAs are transcribed from a putative cluster on chromosome 5, and they are coordinately expressed in a variety of cell types and tissues (Iio et al, 2010). Both MiR-143 and -145 are important in maintaining the differentiated state of smooth muscle cells (SMCs), and loss of expression in SMCs correlates with vascular disease (Cordes et al, 2009; Elia et al, 2009). Moreover, ectopic expression of miR-143 and -145 in a variety of cancer cell lines leads to decreased viability (Borralho et al, 2009; Chiyomaru et al, 2010; Ostenfeld et al, 2010; Spizzo et al, 2010; Zhang et al, 2010a; Noguchi et al, 2011). Accordingly, miR-143 and miR-145 are considered to act as broad tumour suppressors, and their deregulation has been reported as an early event in transformation (Michael et al, 2003; Sempere et al, 2007). In this study, we investigated putative miRNA regulation of mRNAs in a panel of normal bladder urothelial biopsies, superficial Ta bladder tumours and invasive T1-T4 tumours. Previously, we profiled miRNA expression in clinical bladder cancer specimens and found miR-145 to be the most downregulated miRNA in bladder tumours compared with normal urothelium (Dyrskjot et al, 2009). Here, we report that miR-143 and miR-145 are coordinately downregulated as an early neoplastic event in bladder cancer, which is inversely correlated with PAI-1 expression. Conversely, ectopic miR-143/-145 administration in bladder cell lines represses PAI-1 expression by directly targeting complementary miR-143 and miR-145 sequences in the PAI-1 3′UTR. The clinical significance of PAI-1 and miR-145 expression was investigated in non-muscle-invasive tumours using immunohistochemical and in situ hybridisation analyses on tissue microarrays (TMAs). Accordingly, both were usable markers with elevated levels correlating with poor and good prognosis, respectively. This is the first report of PAI-1 as a direct target of miR-143 and -145, and, to our knowledge, the first demonstration of a cluster of non-family miRNAs targeting the same mRNA.
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coordinated epigenetic repression of the mir 200 family and mir 205 in invasive bladder cancer
International Journal of Cancer, 2011Co-Authors: Erik D Wiklund, Jesper B. Bramsen, Toby Hulf, Lars Dyrskjøt, Ramshanker Ramanathan, Thomas B. Hansen, Sune B. Villadsen, Shan Gao, Marie Stampe Ostenfeld, Michael BorreAbstract:MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The Mir-200 family (Mir-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress Mir-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the Mir-200 family and miR-205. Recently, Mir-200 silencing was also reported in cancer stem cells, implying that Mir-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents Mir-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the Mir-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the Mir-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that Mir-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose Mir-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and Mir-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the Mir-200 and miR-205 promoters, and may act as a repressor of Mir-200 and miR-205 expression.