MicroRNA signatures associated with basal cell carcinoma subtypes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE245676 | GEO | 2024/01/01
REPOSITORIES: GEO
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Project description:Basal cell carcinomas (BCCs) are the most common cancers in the US. Histologic appearance distinguishes several subtypes, each of which can have a different biologic behavior. In this study global miRNA expression was quantified by high throughput sequencing in nodular BCCs, a subtype that is slow growing, and infiltrative BCCs, aggressive tumors that extend through the dermis and invade structures such as cutaneous nerves. Principal components analysis correctly classified seven out of eight infiltrative tumors on the basis of miRNA expression. The remaining tumor, on pathology review, contained a mixture of nodular and infiltrative elements. Nodular tumors did not cluster tightly, likely reflecting broader histopathologic diversity in this class, but trended toward forming a group separate from infiltrative BCCs. qPCR assays were developed for six of the miRNAs that showed significant differences between the BCC subtypes, and five of these six were validated in a replication set of four infiltrative and three nodular tumors. The expression level of miR-183, a miRNA that inhibits invasion and metastasis in several types of malignancies, was consistently lower in infiltrative than nodular tumors and could be one element underlying the difference in invasiveness. These results represent the first miRNA profiling study in BCCs and demonstrate that miRNA gene expression may be involved in tumor pathogenesis and particularly in determining the aggressiveness of these malignancies. Total RNA was extracted from eight nodular and eight infiltrative basal cell carcinomas. miRNA was then processed into libraries using the Illumina Small RNA Ver 1.5 protocol. Samples were then sequenced on the Illumina GAII system
2012-02-01 | E-GEOD-33665 | biostudies-arrayexpress
Project description:Basal cell carcinomas (BCCs) are the most common cancers in the US. Histologic appearance distinguishes several subtypes, each of which can have a different biologic behavior. In this study global miRNA expression was quantified by high throughput sequencing in nodular BCCs, a subtype that is slow growing, and infiltrative BCCs, aggressive tumors that extend through the dermis and invade structures such as cutaneous nerves. Principal components analysis correctly classified seven out of eight infiltrative tumors on the basis of miRNA expression. The remaining tumor, on pathology review, contained a mixture of nodular and infiltrative elements. Nodular tumors did not cluster tightly, likely reflecting broader histopathologic diversity in this class, but trended toward forming a group separate from infiltrative BCCs. qPCR assays were developed for six of the miRNAs that showed significant differences between the BCC subtypes, and five of these six were validated in a replication set of four infiltrative and three nodular tumors. The expression level of miR-183, a miRNA that inhibits invasion and metastasis in several types of malignancies, was consistently lower in infiltrative than nodular tumors and could be one element underlying the difference in invasiveness. These results represent the first miRNA profiling study in BCCs and demonstrate that miRNA gene expression may be involved in tumor pathogenesis and particularly in determining the aggressiveness of these malignancies.
2012-02-01 | GSE33665 | GEO
Project description:Little is known regarding the differences between BCC subtypes, despite clearly distinct phenotypes and clinical outcomes. In particular, what distinguishes the aggressive infiltrative BCC subtype. We determine that infiltrative BCC do not contain an obviously distinct genomic variant profile however show clear molecular signalling differences compared to less aggressive subtypes. RNA sequencing enabled identification of candidate regulators of infiltrative subtype development such as Wnt and Integrin signalling, and suggested that infiltrative BCC have a strong relationship with their surrounding environment. In particular, WISP1 and Periostin gene expression is associated with the infiltrating subtype and represent candidate regulators of subtype differences in human BCC.
2021-04-19 | GSE156171 | GEO
Project description:Background; Basal cell carcinoma (BCC) is the most common cancer in humans. The pathogenesis of BCC is associated with the sonic hedgehog (SHH) signaling pathway. Vismodegib, a smoothened inhibitor, that targets this pathway is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. Methods; We studied gene expression profiling of BCC tumour tissue coupled with laser capture microdissection to identify tumor specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. The expression of selected molecules was confirmed by quantitative RT-PCR (qRT-PCR) and by immunohistochemistry. The action of kinase inhibitors was examined on primary normal human epidermal keratinocytes. Results; We found a >250 fold change increase (false discovery rate <10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger staining of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Additionally, Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met, another receptor tyrosine kinase, inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 mRNA by approximately 60% and 20%, respectively (p<0.05). Conclusions; Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promotes keratinocyte proliferation. Furthermore, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients. Laser capture microdissection was performed on 5 cases of nodular/superficial BCC, 5 cases of infiltrative BCC.
2013-01-30 | E-GEOD-42109 | biostudies-arrayexpress
Project description:Patients with advanced colorectal cancer (CRC) are commonly treated with systemic combination therapy but suffer eventually from drug resistance. MicroRNAs (miRNAs) are suggested to play a role in treatment resistance of CRC. We studied whether restoring downregulated miR-195-5p and 497-5p sensitize CRC cells to currently used chemotherapeutics 5-fluorouracil, oxaliplatin and irinotecan. Sensitivity to 5-FU, oxaliplatin and irinotecan before and after transfection with miR-195-5p and miR-497-5p mimics was analyzed in CRC cell lines HCT116, RKO, DLD-1 and SW480. Mass spectrometry based proteomic analysis of transfected and wild-type cells was used to identify targets involved in sensitivity to chemotherapy. Proteomic analysis revealed 181 proteins with significantly altered expression after transfection with miR-195-5p mimic in HCT116 and RKO, including 118 downregulated and 63 upregulated proteins. After transfection with miR-497-5p mimic, 130 proteins were significantly downregulated and 102 were upregulated in HCT116 and RKO (P<0.05 and FC<-3 or FC>3). CHUK and LUZP1 were coinciding downregulated proteins in sensitized CRC cells after transfection with either mimic. Resistance mechanisms of these two proteins may be related to nuclear factor kappa-B signaling and G1 cell cycle arrest, respectively. Restoring miR-195-5p and miR-497-5p expression enhanced sensitivity to chemotherapy, mainly oxaliplatin, in CRC cells and could be a promising treatment strategy for patients with mCRC. Proteomics revealed potential targets of these miRNAs involved in sensitivity to chemotherapy.
2019-09-27 | PXD015369 | Pride
Project description:Hibernating American black bears have significantly different clotting parameters than their active summer counterparts, affording them innate protection against venous thromboembolism (VTE) despite prolonged periods of immobility. Physiologic changes that occur during hibernation are thought to result from differential gene expression, rather than novel genes, and there is increasing evidence miRNAs may play an important role this regulation. We propose that significant differences exist in miRNA expression in the plasma of hibernating black bears compared to their active counter parts (summer), which lead to critical gene regulation responsible for auto-anticoagulation during hibernation. Methods: Blood was collected from 21 American black bears in the Northern Michigan Peninsula in summer 2017 and winter 2018 (11 active, 10 hibernating). Plasma was extracted Results: Fifteen miRNAs were differentially expressed in the plasma of hibernating black bears. Nine miRNAs were significantly downregulated (miR10b-3p, miR-136-3p, miR-181c-5p , miR-200a-3p, miR-200b-5p, miR-200c-3p, miR-320b, miR-320c and miR-320d) and six miRNAs were significantly upregulated (miR-15a-5p, miR-15b-3p, miR-15b-5p, miR-16-5p, miR-92a-3p, miR-150-5p) during hibernation. Twelve miRNAs had no identifiable targets, but miR-200a-3p, miR-200b-5p and miR-200c-3p found to be targets of SERPINC1, the gene responsible for the production of antithrombin (AT). Conclusions: Several miRNAs were differentially expressed in hibernating bears (12). Most importantly miR-200a-3p, miR-200b-5p and miR-200c-3p were all downregulated in hibernation and associated with increased expression of SERPINC1 and production of AT. AT is a powerful anticoagulant and this finding may explain the hibernating black bears ability to achieve auto-anticoagulation and protection from VTE.
2020-09-01 | GSE124398 | GEO
Project description:BACKGROUND: Basal cell carcinoma (BCC) is the most common form of human cancer. Though the genetic mutation and subsequent aberrant signaling role of the Hedgehog pathway in BCC development is understood, little is known about the downstream genetic mechanisms underlying BCC growth. The characterization of molecular events would improve our understanding of carcinogenesis and may define new therapeutic intervention opportunities. OBJECTIVE: To identify differential gene expression associated with tumorigenesis promotion and to define common signaling pathways significant in BCC survival and growth. METHODS: Microarray analysis, using a 21K expanded sequence verified cDNA set was performed on tissues obtained from previously untreated patients undergoing Mohs surgical resection (8 superficial BCC, 8 nodular BCC, 7 morphea form, 8 normal skin). Significantly differentially expressed genes were identified by analysis of microarray results in various data sets and subsequently screened for signaling pathway involvement. Selected genes were validated using real-time PCR analysis using an expanded set of 31 BCC samples. RESULTS: The global gene expression profiles in BCCs and normal skin were distinguishable by unpaired T test. 2429 genes were at least 1.5 fold differentially expressed between BCC (all morphological types) and normal skin (p < 0.01). Multiple singaling pathways were activated, but the hedgehog, WNT, MAPK and calcium signal transduction pathways predominated. CONCLUSION: Our findings may have important implications for understanding the pathogenesis of BCC and suggest targeting of the WNT and MAPK pathways with therapeutic intervention. Keywords: disease state analysis
2006-12-15 | GSE6520 | GEO
Project description:Somatic and germline mutations in GATA2 were recently identified in patients diagnosed with monoMAC, the hallmarks of which include monocytopenia, B-cell and NK-cell lymphopenia, susceptibility to opportunistic infections (e.g. MAC), and a strong propensity to develop hypocellular MDS/AML or CMML. GATA2 mutations are thought to result in loss of function or haploinsufficiency, but the precise mechanism for the development of cytopenias, immunodeficiency, and susceptibility to MDS remains to be elucidated. MicroRNA (miR) represents a unique mechanism of post-transcriptional gene regulation. In this study we generated microRNA profiles of patient derived monoMAC cell lines followed by functional studies to identify aberrant miRs and their targets, which could potentially cooperate with GATA2 deficiency in generating cytopenias and hematologic disease. In our study, eight miRs were significantly differentially expressed (≥ 2-fold; p ≤ 0.05) as determined by microRNA microarray profiles; miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582-5p showed increased expression in monoMAC cell lines compared to controls, while miR-223 and miR-424-3p showed significantly decreased expression. Among the differentially expressed miRs that were validated by quantitative RT-PCR was miR-181c, which demonstrated a 2.2 fold increase in expression in monoMAC cell lines (p = 0.013). Among the target transcripts potentially regulated by miR-181c, MCL1 expression was significantly decreased (2 fold; p = 0.018) in monoMAC cell lines in comparison to control cell lines. Transient transfection of miR-181c in Ly8 cells resulted in 40% decrease of MCL1 mRNA level, suggesting that miR-181c negatively regulates MCL1 in MonoMAC. These findings indicate that monoMAC/GATA2 deficiency is associated with significantly decreased expression of MCL1 possibly through negative regulation involving miR-181c. Deletion of Mcl1 is known to cause apoptosis, loss of HSCs, and cytopenias in murine studies. Thus, down-regulation of MCL1 seen in monoMAC/GATA2 deficiency may similarly favor unregulated apoptosis and the depletion of hematopoietic progenitors resulting in cytopenias, immunodeficiency, and risk of MDS/AML.
2023-06-23 | GSE51132 | GEO
Project description:We found frequently down-regulation of microRNA-181c in human gastric cancer cases. To identify the potential target of miR-181c, we introduced miR-181c into a gastric cancer cell line KATO-III and analyzed significant changes of gene expression which was induced after introducing miR-181c. Keywords: dose response
2010-01-20 | GSE16239 | GEO
Project description:From a previous microarray study we developed a small chondrogenesis model. We performed qPCR and measured how knockdown of miR-199a-5p or miR-199b-5p could modulate chondrogenesis. Several experiments were used to determine the parameters of this model. We utilised parameter scan and manual sliding to refine the model. Within are two models - an initial model which only comprises of genes which we have data for, and an enhanced model which expands of the initial model to make more predictions - e.g. how miR-140-5p is indirectly regulated by miR-199a-5p and miR-199b-5p.
2023-06-06 | MODEL2305010001 | BioModels