MicroRNA‐15b represents an independent prognostic parameter and is correlated with tumor cell proliferation and apoptosis in malignant melanoma
TL;DR: MiR‐15b appears to represent a particular important miRNA in melanoma that is associated with poor prognosis and tumorigenesis and can provide independent prognostic informations.
Abstract: MicroRNAs (miRNAs) are small noncoding RNAs ( approximately 22 bp) that posttranscriptionally regulate gene expression. MiRNAs possess oncogenic or tumor suppressor activity in various tumors but little is known about miRNA expression pattern in malignant melanoma. We determined the expression level of 16 potentially relevant miRNAs (miR-15a, miR-15b, miR-16, miR-34a, miR-210, let-7I, miR-23a, miR-23b, miR-24, miR-27a, miR-27b, miR-100, miR-137, miR-222, miR-373-1, miR-373*) by real-time PCR in 6 preparations of normal melanocytes vs. 10 melanoma cell lines and in formalin fixed paraffin embedded tissue of 11 melanocytic nevi versus 16 melanomas. MiR-15b and miR-210 were significantly upregulated, miR-34a was significantly downregulated in melanomas compared with melanocytic nevi. These 3 miRNAs were analyzed in a total of 128 primary melanomas from patients with detailed clinical follow-up information. High expression of miR-15b (but not miR-210 upregulation and miR-34a downregulation) was significantly associated with poor recurrence free survival and overall survival by univariate Kaplan-Meier and multivariate Cox analyses. Downregulation of miR-15b in two melanoma cell lines with high miR-15b expression by transfection with anti-miR-15b siRNA was associated with reduced tumor cell proliferation, whereas apoptosis was increased. In summary, miRNA expression levels show distinct differences comparing benign and malignant melanocytic cell proliferations and can provide independent prognostic informations. MiR-15b appears to represent a particular important miRNA in melanoma that is associated with poor prognosis and tumorigenesis.
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TL;DR: The discovery, structure, and mode of function of miRNAs in mammalian cells are described, before elaborating on their roles and significance during development and pathogenesis in the various mammalian organs, while attempting to reconcile their functions with the existing knowledge of their targets.
Abstract: MicroRNAs (miRNAs) are a class of posttranscriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. There are currently over 10,000 miRNAs that have been identified in a range of species including metazoa, mycetozoa, viridiplantae, and viruses, of which 940, to date, are found in humans. It is estimated that more than 60% of human protein-coding genes harbor miRNA target sites in their 3′ untranslated region and, thus, are potentially regulated by these molecules in health and disease. This review will first briefly describe the discovery, structure, and mode of function of miRNAs in mammalian cells, before elaborating on their roles and significance during development and pathogenesis in the various mammalian organs, while attempting to reconcile their functions with our existing knowledge of their targets. Finally, we will summarize some of the advances made in utilizing miRNAs in therapeutics.
1,096 citations
Cites background from "MicroRNA‐15b represents an independ..."
...High levels of miR-15b were shown to correlate with poor recurrence-free and overall survival, possibly through promoting tumor survival (530)....
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TL;DR: The miR-15/107 group of microRNA genes is a fascinating topic of study for evolutionary biologists, miRNA biochemists, and clinically oriented translational researchers alike and the roles played by these miRNAs in human diseases are investigated.
345 citations
TL;DR: Recent findings on the mechanism of hypoxia regulation of miR-210 expression and its multifaceted biological functions in normal physiological and malignant conditions are summarized, and the challenges the team faces in elucidating the biological functions of mi R-210 and exploring its potential use for therapeutics are discussed.
336 citations
TL;DR: Reflecting the pleiotropic actions of HIF-α, miR-210 appears to function as a “master microRNA” relevant for the control of diverse functions in the hypoxic state.
Abstract: Inadequate oxygen availability or hypoxia induces a complex and still incompletely understood set of adaptations that influence cellular survival and function. Many of these adaptations are directly controlled by a master transcription factor, hypoxia inducible factor-alpha (HIF-α). In response to hypoxia, HIF-α levels increase and directly induce the transcription of >100 genes, influencing functions ranging from metabolism, survival, proliferation, migration, to angiogenesis, among others. Recently, it has been demonstrated that a specific set of microRNA molecules are upregulated by hypoxia, which we denote here as “hypoxamirs.” In particular, the HIF-responsive hypoxamir microRNA-210 (miR-210) is a unique microRNA that is evolutionarily conserved and ubiquitously expressed in hypoxic cell and tissue types. A number of direct targets of miR-210 have been identified by in silico, transcriptional and biochemical methods, a subset of which have been extensively validated. As a result, miR-210 has been mechanistically linked to the control of a wide range of cellular responses known to influence normal developmental physiology as well as a number of hypoxia-dependent disease states, including tissue ischemia, inflammation and tumorigenesis. Thus, reflecting the pleiotropic actions of HIF-α, miR-210 appears to function as a “master microRNA” relevant for the control of diverse functions in the hypoxic state.
327 citations
TL;DR: This paper presents miR‐210, the master hypoxamir, which has shown promise as a treatment for central giant cell granuloma and is currently under development as a potential drug for wound healing.
Abstract: MicroRNAs (miRs) are small non-coding RNAs implicated mainly in post-transcriptional gene silencing by interacting with the unstranslated region of the transcript. miR-210 represents a major hypoxia-inducible miRs, also known as hypoxamirs, which is ubiquitously expressed in a wide range of cells, serving versatile functions. This review article summarizes the current progress on biogenesis of miR-210 and its physiological roles including arrest of cell proliferation, repression of mitochondrial respiration, arrest of DNA repair, vascular biology, and angiogenesis. Given the fact that miR-210 is aberrantly expressed in a number of diseases such as tumor progression, myocardial infarction and cutaneous ischemic wounds, miR-210 could serve as an excellent candidate for prognostic purposes and therapeutic intervention. With the advancement of computational prediction, high-throughput target validation methodology, sequencing, proteomic analysis and microarray, it is anticipated that more down-stream targets of miR-210 and its-associated biological consequences under hypoxia will be unveiled establishing miR-210 as a major hub in the biology of hypoxia-response.
322 citations
Cites background from "MicroRNA‐15b represents an independ..."
...The expression of miR-210 is elevated in human solid tumors, including glioma [64], head and neck carcinoma [40], lung adenocarcinoma [16], late stage small cell lung cancer [77], malignant melanoma [83], and pancreatic ductal adenocarcinomas [32]....
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...-181a, -181b, -181c, -192, -195, -210, -213, -429, -498, -572, -563, -637 and -628 [25,41,45,83]...
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TL;DR: Detailed deletion and expression analysis shows that miR15 and miR16 are located within a 30-kb region of loss in CLL, and that both genes are deleted or down-regulated in the majority (≈68%) of CLL cases.
Abstract: Micro-RNAs (miR genes) are a large family of highly conserved noncoding genes thought to be involved in temporal and tissue-specific gene regulation MiRs are transcribed as short hairpin precursors (≈70 nt) and are processed into active 21- to 22-nt RNAs by Dicer, a ribonuclease that recognizes target mRNAs via base-pairing interactions Here we show that miR15 and miR16 are located at chromosome 13q14, a region deleted in more than half of B cell chronic lymphocytic leukemias (B-CLL) Detailed deletion and expression analysis shows that miR15 and miR16 are located within a 30-kb region of loss in CLL, and that both genes are deleted or down-regulated in the majority (≈68%) of CLL cases
5,113 citations
"MicroRNA‐15b represents an independ..." refers background in this paper
...chromosomal loci.(23,24) The reason for miR-15b upregulation remains speculative....
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TL;DR: Aberrant expression of miR-21 can contribute to HCC growth and spread by modulating PTEN expression and PTEN-dependent pathways involved in mediating phenotypic characteristics of cancer cells such as cell growth, migration, and invasion.
2,640 citations
TL;DR: This revision of the staging system for cutaneous melanoma will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.
Abstract: PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of sa...
2,623 citations
"MicroRNA‐15b represents an independ..." refers background in this paper
...Abbreviations: PM, primary melanoma; SLN (B), sentinel lymph node (biopsy); AJCC, American Joint Committee of Cancer.21 C an ce r C el l B io lo gy downregulation of miR-15b in WM35 and MEWO melanoma cells, miR-16 and miR-21 levels were measured before and after transfection and showed no significant differences (data not shown)....
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...Abbreviations: PM, primary melanoma; SLN (B), sentinel lymph node (biopsy); AJCC, American Joint Committee of Cancer.(21)...
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TL;DR: It is shown that the highly malignant human brain tumor, glioblastoma, strongly over-expresses a specific miRNA, miR-21, which may contribute to the malignant phenotype by blocking expression of critical apoptosis-related genes.
Abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by targeting the mRNA of protein-coding genes for either cleavage or repression of translation. The roles of miRNAs in lineage determination and proliferation as well as the location of several miRNA genes at sites of translocation breakpoints or deletions has led to the speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state. Here we show that the highly malignant human brain tumor, glioblastoma, strongly overexpresses a specific miRNA, miR-21. Our studies show markedly elevated miR-21 levels in human glioblastoma tumor tissues, early-passage glioblastoma cultures, and in six established glioblastoma cell lines (A172, U87, U373, LN229, LN428, and LN308) compared with nonneoplastic fetal and adult brain tissues and compared with cultured nonneoplastic glial cells. Knockdown of miR-21 in cultured glioblastoma cells triggers activation of caspases and leads to increased apoptotic cell death. Our data suggest that aberrantly expressed miR-21 may contribute to the malignant phenotype by blocking expression of critical apoptosis-related genes.
2,588 citations
TL;DR: A unique microRNA signature is associated with prognostic factors and disease progression in CLL, and a germ-line mutation in the miR-16-1-miR-15a primary precursor caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele.
Abstract: Background MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL. Methods We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgVH ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities. Results A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgVH from those with mutated IgVH . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a...
2,554 citations