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Carlo M Croce - One of the best experts on this subject based on the ideXlab platform.
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microrna dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency
Oncotarget, 2016Co-Authors: Louise Y Y Fong, Hansjuerg Alder, Cristian Taccioli, Yubao Jiang, Karl J Smalley, Paolo Fadda, John L Farber, Ruiyan Jing, Carlo M CroceAbstract:// Louise Y. Fong 1,2 , Cristian Taccioli 3 , Ruiyan Jing 1 , Karl J. Smalley 2 , Hansjuerg Alder 4 , Yubao Jiang 1 , Paolo Fadda 4 , John L. Farber 1 and Carlo M. Croce 4 1 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA 2 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 3 Animal Medicine, Production and Health Department, University of Padua, Padua, Italy 4 Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA Correspondence to: Louise Y. Fong, email: // Keywords : microRNA expression profiling, esophageal squamous cell carcinoma, dietary zinc deficiency dose-response, Mir-223, miR-21 Received : December 16, 2015 Accepted : February 08, 2016 Published : February 21, 2016 Abstract Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC), and marginal ZD is prevalent in humans. In rats, marked-ZD (3 mg Zn/kg diet) induces a proliferative esophagus with a 5-microRNA signature (miR-31, -223, -21, -146b, -146a) and promotes ESCC. Here we report that moderate and mild-ZD (6 and 12 mg Zn/kg diet) also induced esophageal hyperplasia, albeit less pronounced than induced by marked-ZD, with a 2-microRNA signature (miR-31, -146a). On exposure to an environmental carcinogen, ~16% of moderate/mild-ZD rats developed ESCC, a cancer incidence significantly greater than for Zn-sufficient rats (0%) ( P ≤ 0.05), but lower than marked-ZD rats (68%) ( P < 0.001). Importantly, the high ESCC, marked-ZD esophagus had a 15-microRNA signature, resembling the human ESCC miRNAome, with Mir-223, miR-21, and miR-31 as the top-up-regulated species. This signature discriminated it from the low ESCC, moderate/mild-ZD esophagus, with a 2-microRNA signature (miR-31, Mir-223). Additionally, Fbxw7, Pdcd4, and Stk40 (tumor-suppressor targets of Mir-223, -21, and -31) were downregulated in marked-ZD cohort. Bioinformatics analysis predicted functional relationships of the 3 tumor-suppressors with other cancer-related genes. Thus, microRNA dysregulation and ESCC progression depend on the extent of dietary Zn deficiency. Our findings suggest that even moderate ZD may promote esophageal cancer and dietary Zn has preventive properties against ESCC. Additionally, the deficiency-associated Mir-223, miR-21, and miR-31 may be useful therapeutic targets in ESCC.
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mir 221 overexpression contributes to liver tumorigenesis
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Pascal Pineau, Carlo M Croce, Stefano Volinia, Katherine Mcjunkin, Agnes Marchio, Carlo Battiston, Benoit Terris, Vincenzo Mazzaferro, Scott W Lowe, Anne DejeanAbstract:MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, Mir-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. Mir-221/222, the most up-regulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for Mir-221. In addition, we show, using a mouse model of liver cancer, that Mir-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of Mir-221. Taken together, these data reveal an important contribution for Mir-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of Mir-221 may prove to be a promising approach to liver cancer treatment.
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role of microrna 155 at early stages of hepatocarcinogenesis induced by choline deficient and amino acid defined diet in c57bl 6 mice
Hepatology, 2009Co-Authors: Bo Wang, Carlo M Croce, Stefano Volinia, Sarmila Majumder, Gerard J Nuovo, Huban Kutay, Tushar Patel, Thomas D Schmittgen, Kalpana Ghoshal, Samson T JacobAbstract:MicroRNAs are conserved, small (20–25 nucleotide) noncoding RNAs that negatively regulate expression of mRNAs at the post-transcriptional level. Aberrant expression of certain microRNAs plays a causal role in tumorigenesis. Here, we report identification of hepatic microRNAs that are dysregulated at early stages of feeding C57BL/6 mice choline deficient and amino acid defined (CDAA) diet that is known to promote nonalcoholic steatohepatitis (NASH)-induced hepatocarcinogenesis after 84 weeks. Microarray analysis identified 30 hepatic microRNAs that are significantly (P≤0.01) altered in mice fed CDAA diet for 6, 18, 32 and 65 weeks compared to those fed choline sufficient and amino acid defined diet. Real-time RT-PCR analysis demonstrated upregulation of oncogenic miR-155, Mir-221/222 and miR-21 and downregulation of the most abundant liver specific miR-122 at early stages of hepatocarcinogenesis. Western blot analysis showed reduced expression of hepatic PTEN and C/EBPβ respective targets of miR-21 and miR-155, in these mice at early stages. DNA binding activity of NF-kB that transactivates miR-155 gene was significantly (P=0.002) elevated in the liver nuclear extract of mice fed CDAA diet. Further, the expression of miR-155, as measured by in situ hybridization and real-time RT-PCR, correlated with diet-induced histopathological changes in the liver. Ectopic expression of miR-155 promoted growth of HCC cells whereas its depletion inhibited cell growth. Notably, miR-155 was significantly (P=0.0004) upregulated in primary human HCCs with concomitant decrease (P=0.02) in C/EBPβ level compared to matching liver tissues. Conclusion Temporal changes in microRNA profile occur at early stages of CDAA diet-induced hepatocarcinogenesis. Reciprocal regulation of specific oncomirs and their tumor suppressor targets implicate their role in NASH-induced hepatocarcinogenesis and suggest their use in the diagnosis, prognosis and therapy of liver cancer.
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abstract 4723 microrna 221 222 confer breast cancer resistance to fulvestrant by targeting multiple oncogenic activities
Cancer Research, 2009Co-Authors: Xi Rao, Carlo M Croce, Gianpiero Di Leva, Fang Fang, Curtis Balch, John P Thomson, Scott M Hammond, Corinna Hartmanfrey, Yunlong Liu, Kenneth P NephewAbstract:Breast cancer is the leading cause of female death worldwide and will afflict 1 of 8 U.S. women in their lifetime. One commonly used breast cancer therapy, fulvestrant, has potent activity against hormone-sensitive breast cancers. However, almost all patients eventually develop resistance to fulvestrant, and the underlying mechanism(s) of loss of drug response remains unknown. We had previously generated a fulvestrant-resistant cell line (MCF7-F) highly characteristic of this clinical phenomenon (Cancer Res, 66, 2006). MicroRNAs, 19-22-nucleotide non-coding regulatory RNAs, have recently been implicated in breast cancer, and we subjected MCF7-F cells to microRNA expression analysis using a 612-feature custom microarray. From those analyses, we determined that two specific microRNAs, Mir-221 and Mir-222, were significantly upregulated by 9-fold and 6-fold respectively in MCF7-F cells (as compared to the parental MCF7 cell line). To further assess the role of Mir-221/222 in MCF7-F cells, we downregulated Mir-221/222 by using chemically stable, antisense oligoribonucleotides (\#8220;antagomirs\#8221;) against those specific microRNA sequences, demonstrating that Mir-221/222 antagomir treatment significantly decreased cell proliferation by 40%. In addition, the cyclin-dependent kinase inhibitor (and tumor suppressor) p27(Kip1) (CDKN1B, a known target protein for Mir-221/222), which is downregulated in MCF7-F, was upregulated after antagomir treatment, with cell cycle analyses demonstrating G1 cell cycle arrest. Based on this evidence, we hypothesize that Mir-221/222 upregulation contributes to the development of fulvestrant resistance, leading to loss of p27(Kip1), which subsequently facilitates estrogen-independent cell cycle progression. However, as any single microRNA likely targets numerous genes to influence the overall malignant phenotype, we sought to identify additional Mir-221/222 targets in MCF7-F cells. MCF7-F cells were treated with Mir-221/222 antagomirs, and then subjected to Affymetrix gene expression profiling and pathway enrichment analysis. Several well known signaling pathways appeared to be regulated by Mir-221/222, including p53, TGF-beta, Notch and MAPK. We are currently validating the regulatory role of Mir-221/222 in these pathways and investigating their role in the development of fulvestrant resistance. Overall, the findings indicate that Mir-221 and Mir-222 may represent promising therapeutic targets for fulvestrant resensitization in patients with advanced breast cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4723.
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micrornas mir 221 and mir 222 both overexpressed in human thyroid papillary carcinomas regulate p27kip1 protein levels and cell cycle
Endocrine-related Cancer, 2007Co-Authors: Rosa Visone, Hansjuerg Alder, Lucia Russo, Pierlorenzo Pallante, Ivana De Martino, Angelo Ferraro, Vincenza Leone, Eleonora Borbone, Fabio Petrocca, Carlo M CroceAbstract:We have recently reported that MicroRNAs (miR)-221 and Mir-222 were up-regulated in human thyroid papillary carcinomas in comparison with the normal thyroid tissue. Bioinformatic analysis proposed the p27(Kip1) protein, a key regulator of cell cycle, as a candidate target for the Mir-221/222 cluster. Here, we report that the enforced expression of Mir-221 and Mir-222 was able to reduce p27(Kip1) protein levels in thyroid carcinoma and HeLa cells in the absence of significant changes in specific p27(Kip1) mRNA levels. This effect is direct as Mir-221 and Mir-222 negatively regulate the expression of the 3'-untranslated region-based reporter construct from the p27(Kip1) gene, and is dependent on two target sites in this region. Consistent with these results, an enforced expression of the Mir-221 and Mir-222 induced the thyroid papillary carcinoma cell line (TPC-1) to progress to the S phase of the cell cycle. It is likely that the negative regulation of p27(Kip1) by Mir-221 and Mir-222 might also have a role in vivo since we report an inverse correlation between Mir-221 and Mir-222 up-regulation and down-regulation of the p27(Kip1) protein levels in human thyroid papillary carcinomas. Therefore, the data reported here demonstrate that Mir-221 and Mir-222 are endogenous regulators of p27(Kip1) protein expression, and thereby, the cell cycle.
Yungui Gong - One of the best experts on this subject based on the ideXlab platform.
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kinetic temperature of massive star forming molecular clumps measured with formaldehyde iii the orion molecular cloud 1
Astronomy and Astrophysics, 2018Co-Authors: Xin Di Tang, C Henkel, K M Menten, F Wyrowski, N Brinkmann, X W Zheng, Yungui GongAbstract:We mapped the kinetic temperature structure of the Orion molecular cloud 1 (OMC-1) with para-H2CO(J(KaKc) = 3(03)- 2(02), 3(22)- 2(21), and 3(21)-2(20)) using the APEX 12m telescope. This is compared with the temperatures derived from the ratio of the NH3 (2, 2)/(1, 1) inversion lines and the dust emission. Using the RADEX non-LTE model, we derive the gas kinetic temperature modeling the measured averaged line ratios of para-H(2)CO3(22)-2(21)/3(03)-2(02) and 3(21)-2(20)/3(03)-2(02). The gas kinetic temperatures derived from the para-H(2)COline ratios are warm, ranging from 30 to > 200K with an average of 62 +/- 2K at a spatial density of 105 cm(-3). These temperatures are higher than those obtained from NH3 (2, 2) /(1, 1) and CH3CCH(6-5) in the OMC-1 region. The gas kinetic temperatures derived from para-H2CO agree with those obtained from warm dust components measured in the mid infrared (MIR), which indicates that the para-H2CO(3-2) ratios trace dense and warm gas. The cold dust components measured in the far infrared (FIR) are consistent with those measured with NH3 (2, 2) /(1, 1) and the CH3CCH(6-5) line series. With dust at MIR wavelengths and para-H2CO(3-2) on one side, and dust at FIR wavelengths, NH3 (2, 2) /(1, 1), and CH3CCH(6-5) on the other, dust and gas temperatures appear to be equivalent in the dense gas (n(H-2) greater than or similar to 104 cm 3) of the OMC-1 region, but provide a bimodal distribution, one more directly related to star formation than the other. The non-thermal velocity dispersions of para-H2CO are positively correlated with the gas kinetic temperatures in regions of strong non-thermal motion (Mach number > greater than or similar to 2 : 5) of the OMC-1, implying that the higher temperature traced by para-H2CO is related to turbulence on a similar to 0.06 pc scale. Combining the temperature measurements with para-H2CO and NH3 (2, 2) /(1, 1) line ratios, we find direct evidence for the dense gas along the northern part of the OMC-1 10 km s(-1) filament heated by radiation from the central Orion nebula.
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kinetic temperature of massive star forming molecular clumps measured with formaldehyde iii the orion molecular cloud 1
arXiv: Astrophysics of Galaxies, 2017Co-Authors: C Henkel, K M Menten, F Wyrowski, N Brinkmann, Yungui Gong, X D Tang, Xingwu ZhengAbstract:We mapped the kinetic temperature structure of the Orion molecular cloud 1 with para-H2CO(303-202, 322-221, and 321-220) using the APEX 12m telescope. This is compared with the temperatures derived from the ratio of the NH3(2,2)/(1,1) inversion lines and the dust emission. Using the RADEX non-LTE model, we derive the gas kinetic temperature modeling the measured averaged line ratios of para-H2CO 322-221/303-202 and 321-220/303-202. The gas kinetic temperatures derived from the para-H2CO line ratios are warm, ranging from 30 to >200 K with an average of 62 K at a spatial density of 10$^5$ cm$^{-3}$. These temperatures are higher than those obtained from NH3(2,2)/(1,1) and CH3CCH(6-5) in the OMC-1 region. The gas kinetic temperatures derived from para-H2CO agree with those obtained from warm dust components measured in the mid infrared (MIR), which indicates that the para-H2CO(3-2) ratios trace dense and warm gas. The cold dust components measured in the far infrared (FIR) are consistent with those measured with NH3(2,2)/(1,1) and the CH3CCH(6-5) line series. With dust at MIR wavelengths and para-H2CO(3-2) on one side and dust at FIR wavelengths, NH3(2,2)/(1,1), and CH3CCH(6-5) on the other, dust and gas temperatures appear to be equivalent in the dense gas of the OMC-1 region, but provide a bimodal distribution, one more directly related to star formation than the other. The non-thermal velocity dispersions of para-H2CO are positively correlated with the gas kinetic temperatures in regions of strong non-thermal motion (Mach number >2.5) of the OMC-1, implying that the higher temperature traced by para-H2CO is related to turbulence on a 0.06 pc scale. Combining the temperature measurements with para-H2CO and NH3(2,2)/(1,1) line ratios, we find direct evidence for the dense gas along the northern part of the OMC-1 10 km s$^{-1}$ filament heated by radiation from the central Orion nebula.
Qingzhong Xiao - One of the best experts on this subject based on the ideXlab platform.
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mir 22 is a novel mediator of vascular smooth muscle cell phenotypic modulation and neointima formation
Circulation, 2017Co-Authors: Feng Yang, Qishan Chen, Mei Yang, Eithne Margaret Maguire, Tayyab Adeel Afzal, Le Anh Luong, Li Zhang, Qingzhong XiaoAbstract:Background —MicroRNA-22 (Mir-22) has recently been reported to play a regulatory role during vascular smooth muscle cell (VSMC) differentiation from stem cells, but little is known about its target genes and related pathways in mature VSMC phenotypic modulation or its clinical implication in neointima formation following vascular injury. Methods —We applied wire-injury mouse model as well as local delivery of AgoMir-22 or Mir-22 inhibitor to explore the therapeutic potential of Mir-22 in vascular diseases. Furthermore, normal and diseased human femoral arteries were harvested and various in vivo , ex vivo , and in vitro models of VSMC phenotype switching were conducted to examine Mir-22 expression during VSMC phenotype switching. Results —Expression of Mir-22 was closely regulated during VSMC phenotypic modulation. Mir-22 over-expression significantly increased expression of VSMC marker genes and inhibited VSMC proliferation and migration, whilst the opposite effect was observed when endogenous Mir-22 was knocked down. As expected, two previously reported Mir-22 target genes, methyl-CpG binding protein 2 (MECP2) and histone deacetylase 4 (HDAC4), exhibited a regulatory role in VSMC phenotypic modulation. A transcriptional regulator and oncoprotein, Ecotropic Virus Integration Site 1 Protein Homolog (EVI1), has been identified as a novel Mir-22 target gene in VSMC phenotypic modulation. Of note, overexpression of Mir-22 in the injured vessels significantly reduced the expression of its target genes; decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries, whilst the opposite effect was observed with local application of a Mir-22 inhibitor to injured arteries. We next examined the clinical relevance of Mir-22 expression and its target genes in human femoral arteries. We found that Mir-22 expression was significantly reduced, while MECP2 and EVI1 expression levels were dramatically increased, in diseased compared to healthy femoral human arteries. This inverse relationship between Mir-22 and MECP2 and/or EVI1 was evident in both healthy and diseased human femoral arteries. Conclusions —Our data demonstrates that Mir-22 and EVI1 are novel regulators of VSMC function specifically during neointima hyperplasia, offering a novel therapeutic opportunity for treating vascular diseases.
Chunxiang Zhang - One of the best experts on this subject based on the ideXlab platform.
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a necessary role of mir 221 and mir 222 in vascular smooth muscle cell proliferation and neointimal hyperplasia
Circulation Research, 2009Co-Authors: Xiaojun Liu, Jian Yang, Yunhui Cheng, Shuo Zhang, Ying Lin, Chunxiang ZhangAbstract:MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression. Functionally, an individual miRNA is as important as a transcription factor because it is able to regulate the expression of its multiple target genes. Recently, Mir-221 and Mir-222 have been found to play a critical role in cancer cell proliferation. However, their roles in vascular smooth muscle cell (VSMC) biology are currently unknown. In the present study, the time course changes and cellular distribution of Mir-221 and Mir-222 expression were identified in rat carotid arteries after angioplasty, in which their expression was upregulated and localized in VSMCs in the injured vascular walls. In cultured VSMCs, Mir-221 and Mir-222 expression was increased by growth stimulators. Knockdown of Mir-221 and Mir-222 resulted in decreased VSMC proliferation in vitro. Using both gain-of-function and loss-of-function approaches, we found that p27(Kip1) and p57(Kip2) were 2 target genes that were involved in Mir-221– and Mir-222–mediated effect on VSMC growth. Finally, knockdown of Mir-221 and Mir-222 in rat carotid arteries suppressed VSMC proliferation in vivo and neointimal lesion formation after angioplasty. The results indicate that Mir-221 and Mir-222 are novel regulators for VSMC proliferation and neointimal hyperplasia. These findings may also represent promising therapeutic targets in proliferative vascular diseases.
Feng Yang - One of the best experts on this subject based on the ideXlab platform.
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mir 22 is a novel mediator of vascular smooth muscle cell phenotypic modulation and neointima formation
Circulation, 2017Co-Authors: Feng Yang, Qishan Chen, Mei Yang, Eithne Margaret Maguire, Tayyab Adeel Afzal, Le Anh Luong, Li Zhang, Qingzhong XiaoAbstract:Background —MicroRNA-22 (Mir-22) has recently been reported to play a regulatory role during vascular smooth muscle cell (VSMC) differentiation from stem cells, but little is known about its target genes and related pathways in mature VSMC phenotypic modulation or its clinical implication in neointima formation following vascular injury. Methods —We applied wire-injury mouse model as well as local delivery of AgoMir-22 or Mir-22 inhibitor to explore the therapeutic potential of Mir-22 in vascular diseases. Furthermore, normal and diseased human femoral arteries were harvested and various in vivo , ex vivo , and in vitro models of VSMC phenotype switching were conducted to examine Mir-22 expression during VSMC phenotype switching. Results —Expression of Mir-22 was closely regulated during VSMC phenotypic modulation. Mir-22 over-expression significantly increased expression of VSMC marker genes and inhibited VSMC proliferation and migration, whilst the opposite effect was observed when endogenous Mir-22 was knocked down. As expected, two previously reported Mir-22 target genes, methyl-CpG binding protein 2 (MECP2) and histone deacetylase 4 (HDAC4), exhibited a regulatory role in VSMC phenotypic modulation. A transcriptional regulator and oncoprotein, Ecotropic Virus Integration Site 1 Protein Homolog (EVI1), has been identified as a novel Mir-22 target gene in VSMC phenotypic modulation. Of note, overexpression of Mir-22 in the injured vessels significantly reduced the expression of its target genes; decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries, whilst the opposite effect was observed with local application of a Mir-22 inhibitor to injured arteries. We next examined the clinical relevance of Mir-22 expression and its target genes in human femoral arteries. We found that Mir-22 expression was significantly reduced, while MECP2 and EVI1 expression levels were dramatically increased, in diseased compared to healthy femoral human arteries. This inverse relationship between Mir-22 and MECP2 and/or EVI1 was evident in both healthy and diseased human femoral arteries. Conclusions —Our data demonstrates that Mir-22 and EVI1 are novel regulators of VSMC function specifically during neointima hyperplasia, offering a novel therapeutic opportunity for treating vascular diseases.