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ABSTRACT: Evaluation of: Lubezky N, Loewenstein S, Ben-Haim M et al. MicroRNA expression signatures in intraductal papillary mucinous neoplasm of the pancreas. Surgery doi:10.1016/j.surg.2012.11.016 (2013) (Epub ahead of print). Pancreatic cysts are now being detected more frequently owing to increased recognition and the liberal use of cross-sectional imaging. There is a spectrum of pancreatic cystic lesions ranging from the completely benign inflammatory to the highly malignant. Pancreatic cystic tumors, especially those with a mucinous epithelial lining such as the intraductal papillary mucinous neoplasms (IPMNs), have the potential to become malignant. The evaluated paper provides further evidence for miRNAs as diagnostic biomarkers for detecting dysplastic and malignant change in IPMNs, which may be useful for future clinical decision making. IPMNs of varying degrees of dysplasia, as well as IPMN with carcinoma, pancreatic ductal adenocarcinoma and normal pancreas samples were examined by microarray. Upregulation of miR-21, miR-155 and miR-708 was found to occur during IPMN malignant transformation. Here, the authors evaluate the published miRNA profiles of premalignant pancreatic lesions in order to consolidate these data.
Expert Review of Molecular Diagnostics 05/2013; 13(4):325-9. · 4.86 Impact Factor
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Loredana Pellegrino,
Justin Stebbing,
Vania M Braga,
Adam E Frampton,
Jimmy Jacob,
Lakjaya Buluwela,
Long R Jiao,
Manikandan Periyasamy,
Chris D Madsen,
Matthew P Caley,
Silvia Ottaviani,
Laura Roca-Alonso,
Mona El-Bahrawy,
R Charles Coombes,
Jonathan Krell, Leandro Castellano
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ABSTRACT: Uncontrolled cell proliferation and cytoskeletal remodeling are responsible for tumor development and ultimately metastasis. A number of studies have implicated microRNAs in the regulation of cancer cell invasion and migration. Here, we show that miR-23b regulates focal adhesion, cell spreading, cell-cell junctions and the formation of lamellipodia in breast cancer (BC), implicating a central role for it in cytoskeletal dynamics. Inhibition of miR-23b, using a specific sponge construct, leads to an increase of cell migration and metastatic spread in vivo, indicating it as a metastatic suppressor microRNA. Clinically, low miR-23b expression correlates with the development of metastases in BC patients. Mechanistically, miR-23b is able to directly inhibit a number of genes implicated in cytoskeletal remodeling in BC cells. Through intracellular signal transduction, growth factors activate the transcription factor AP-1, and we show that this in turn reduces miR-23b levels by direct binding to its promoter, releasing the pro-invasive genes from translational inhibition. In aggregate, miR-23b expression invokes a sophisticated interaction network that co-ordinates a wide range of cellular responses required to alter the cytoskeleton during cancer cell motility.
Nucleic Acids Research 04/2013; · 8.03 Impact Factor
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ABSTRACT: Evaluation of: Kanaan Z, Rai SN, Eichenberger MR et al. Plasma MiR-21: a potential diagnostic marker of colorectal cancer. Ann. Surg. 256(3), 544-551 (2012). Few studies have assessed circulating miRNAs in the blood of colorectal cancer (CRC) patients. In the evaluated article, Kanaan et al. demonstrated that miR-21 may be a promising diagnostic plasma biomarker for CRC. They assessed miRNAs dysregulated in both tissue and blood samples from patients with CRC. A high-throughput microarray was used to first detect miRNAs deregulated in CRC compared with adjacent normal tissue. The three most upregulated and downregulated miRNAs were then measured in blood samples. Plasma miR-21 was able to correctly identify CRC with 90% specificity and sensitivity. In this article, we have considered the use of miRNAs as blood-based biomarkers for CRC.
Expert Review of Molecular Diagnostics 03/2013; 13(2):141-5. · 4.86 Impact Factor
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Future Oncology 02/2013; 9(2):141-4. · 3.16 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression. They are characterized by specific maturation processes defined by canonical and non-canonical biogenic pathways. Analysis of ∼0.5 billion sequences from mouse data sets derived from different tissues, developmental stages and cell types, partly characterized by either ablation or mutation of the main proteins belonging to miRNA processor complexes, reveals 66 high-confidence new genomic loci coding for miRNAs that could be processed in a canonical or non-canonical manner. A proportion of the newly discovered miRNAs comprises mirtrons, for which we define a new sub-class. Notably, some of these newly discovered miRNAs are generated from untranslated and open reading frames of coding genes, and we experimentally validate these. We also show that many annotated miRNAs do not present miRNA-like features, as they are neither processed by known processing complexes nor loaded on AGO2; this indicates that the current miRNA miRBase database list should be refined and re-defined. Accordingly, a group of them map on ribosomal RNA molecules, whereas others cannot undergo genuine miRNA biogenesis. Notably, a group of annotated miRNAs are Dgcr8 independent and DICER dependent endogenous small interfering RNAs that derive from a unique hairpin formed from a short interspersed nuclear element.
Nucleic Acids Research 01/2013; · 8.03 Impact Factor
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ABSTRACT: Evaluation of: Ali S, Saleh H, Sethi S, Sarkar FH, Philip PA. MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer. Br. J. Cancer 107(8), 1354-1360 (2012). Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, despite advances in imaging, surgery and a greater understanding of its molecular biology. Patient outcomes remain poor due to an inability to detect disease early and resistance to anticancer treatments. miRNAs are promised to become ideal cancer biomarkers, as they are tumor and tissue specific and also incredibly stable molecules. So far, large profiling studies of the PDAC miRNome have identified the 'usual suspects' known to be deregulated in solid tumors, such as oncomiR-21, as well as others that could be more robust for differentiating malignant from benign pancreatic disease. However, many of these are yet to be validated clinically. The paper under evaluation provides further evidence for the use of miRNAs as diagnostic biomarkers for PDAC. We have reviewed the use of miRNAs as diagnostic analytes for detecting PDAC in biopsies.
Expert Review of Molecular Diagnostics 01/2013; 13(1):31-4. · 4.86 Impact Factor
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ABSTRACT: Evaluation of: Jafarnejad SM, Ardekani GS, Ghaffari M, Martinka M, Li G. Sox4-mediated Dicer expression is critical for suppression of melanoma cell invasion. Oncogene doi:10.1038/onc.2012.239 (2012) (Epub ahead of print). Several studies have implicated miRNAs in the initiation and progression of human cancers. Examining the biogenesis pathways that generate these important regulatory molecules has revealed new mechanisms for tumor development. Altered expression of the endoribonuclease Dicer in many tumors has given new hope to unraveling the complex relationship between miRNA processing and cancer. This may provide further insight into mechanisms for targeting multiple genes that are critical for the malignant phenotype of several cancers. The evaluated article demonstrates that Dicer is transcriptionally regulated by Sox4 and reduced levels of this transcription factor consequently leads to a reduction in expression, and therefore deregulation of cancer-related miRNAs in melanoma. Reduced Dicer expression in malignant melanoma is an independent predictor of poor survival. In this review, we assess the prognostic significance of Dicer expression in different tumor types.
Expert Review of Anti-infective Therapy 01/2013; 13(1):21-7. · 2.65 Impact Factor
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ABSTRACT: There has been very little progress in improving outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) over the past few decades. High-throughput array profiling has made it possible to discover new assays to diagnose or prognose PDAC more accurately based on the genetic profile of an individual tumor. To improve patient survival, there is a need to extract the most practical data to define tumor subgroups and personalize anticancer therapy. In the evaluated study, a multiplatform, survival-based analysis of molecular changes was performed for PDAC to discover clinically useful biomarkers. A composite score predictive for survival was calculated for individual genes, taking into account the DNA copy-number and any regulation by miRNAs. Several genes involved in the PI3K/AKT and SRC signaling pathways were identified and further investigated.
Expert Review of Anti-infective Therapy 10/2012; 12(10):1275-8. · 2.65 Impact Factor
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ABSTRACT: Cardiotoxicity associated with breast cancer treatment is an important concern in the oncology clinic. Different types of anti-cancer therapies have recorded high rates of cardiac dysfunction in treated patients. Cardiac dysfunction linked to anthracyclines - one of the most common conventional chemotherapies - has extensively been described and several mechanisms have been proposed, although their mode of action is not fully understood even in cancer cells. The mediation of cardiac damage by reactive oxygen species stress is a recent hypothesis that has attracted a lot of interest, since it might explain the tissue-specific toxic effects of anthracyclines in the heart. Regarding molecular targeted tyrosine kinase inhibitors used in patients with human epidermal growth factor receptor type 2+ tumours (e.g., trastuzumab, lapatinib), it is the blockage of survival pathways required for a normal heart development and function that seems to lead to cardiac pathology. Both types of breast cancer treatment appear to trigger cardiotoxicity synergically, being patients under adjuvant therapy closely monitored. Given the complex nature of heart failure and of the pathways altered by anti-cancer drugs, global gene expression regulation is key in the heart disease process. MicroRNAs have been demonstrated to be small molecules with big roles as essential gene expression modulators. The great potential of microRNAs as biomarkers in the cardio-oncology field needs to be further explored before new microRNA-based diagnostic and therapeutic tools can be developed.
Cardiology 08/2012; 122(4):253-9. · 1.71 Impact Factor
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ABSTRACT: The tumor-suppressor miRNA 126 (miR-126) is downregulated in many tumors and has recently been placed at the heart of complex metastatic pathways. Hamada and colleagues have identified miR-126 as being downregulated in pancreatic ductal adenocarcinoma (PDAC) patient samples and cell lines. The protein ADAM9 has been implicated in the progression of various solid tumors including PDAC. ADAM9 is overexpressed in PDAC and also a direct target of miR-126. The miR-126/ADAM9 axis was subsequently established to control migration and invasion in PDAC, as well as reversal of epithelial-to-mesenchymal transition. miR-126 is also known to target other crucial oncogenes in PDAC such as KRAS and CRK. Replacing miR-126 in PDAC patients may be a novel strategy for preventing progression and metastasis.
Expert Review of Anti-infective Therapy 07/2012; 12(7):881-4. · 2.65 Impact Factor
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Surgery 06/2012; 152(5):936-8. · 3.10 Impact Factor
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ABSTRACT: The pathogenesis of thyroid-associated orbitopathy (TAO) remains unclear. The aim of this study is to elucidate the gene expression profile of orbital fat from patients with active, but untreated, TAO.
A case-control gene expression study was conducted using test samples of orbital fat from TAO patients and control orbital fat specimens; apart from drugs to control thyrotoxicosis, the TAO patients had received no treatment for orbital disease. cDNA expression analysis was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 platform and validated using quantitative PCR.
The highest-ranked differentially expressed genes were dominated by IGF-1 signalling genes. These include IGF-1, IGF-1 receptor binding/signalling genes, such as SOCS3 and IRS2, and downstream signalling and transcriptional regulators, such as SGK (PDK/Akt signalling) and c-JUN. Our microarray data also demonstrate dysregulation of wingless-type MMTV (Wnt) signalling gene expression, including Wnt5a, sFRPs and DKK.
Altered Wnt signalling confirms previous array findings. Further investigation of the role of Wnt signalling in TAO pathogenesis is warranted. These data also provide the first evidence of dysregulation of IGF-1 pathway genes in TAO tissue, further strengthening the evidence for the role of IGF-1 signalling in the pathogenesis and potential treatment of TAO.
Journal of clinical pathology 05/2012; 65(7):608-13. · 2.43 Impact Factor
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ABSTRACT: Retinoblastoma protein (RB) is one of the most important tumor suppressors and functions in multiple biological pathways that are deregulated during tumor initiation and progression. Epithelial-to-mesenchymal transition (EMT) is a reversible embryonic process by which epithelial cells lose cell-cell contact and polarity, and its aberrant activation can trigger tumor progression and metastasis. Previously, it has been shown that depletion of RB initiates EMT by downregulating the adhesion molecule E-cadherin. The evaluated article suggests that RB inactivation contributes to loss of cell cycle control and also leads to downregulation of the miR-200 family, thereby causing upregulation of ZEB expression and consequently EMT by downregulation of E-cadherin. RB inactivation could be a key event underlying the mesenchymal and aggressive phenotype of triple-negative breast cancer. Furthermore, exploring links between RB inactivation and EMT might reveal new therapeutic targets for triple-negative breast cancer.
Expert Review of Anti-infective Therapy 05/2012; 12(5):581-4. · 2.65 Impact Factor
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Jonathan Krell,
Adam E Frampton,
Jimmy Jacob,
Loredana Pellegrino,
Laura Roca-Alonso,
Daniel Zeloof,
Costi Alifrangis,
Jacqueline S Lewis,
Long R Jiao,
Justin Stebbing, Leandro Castellano
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ABSTRACT: MicroRNAs (miRNAs) may function as suppressors or promoters of tumor metastasis according to their messenger RNA targets. Previous studies have suggested that miR-9 and miR-151-5p are associated with metastasis in breast cancer and hepatocellular carcinoma, respectively. We aimed to further establish the potential roles of miR-9 and miR-151-5p in tumor invasion and metastasis and investigate their use as biomarkers.
We used quantitative real-time PCR (qRT-PCR) to measure differences in miR-9 and miR-151-5p expression between primary breast tumors and their lymph-node metastases in 194 paired tumor samples from 97 patients. We also correlated expression levels with histologic data to investigate their utility as biomarkers.
There were no significant differences in miR-9 expression between the primary tumors and lymph nodes; however, miR-151-5p expression was significantly lower in the lymph-node metastases than in their corresponding tumors (p < 0.05). miR-9 levels were elevated in primary breast tumors from patients diagnosed with higher-grade tumors (p < 0.05); however, no differences were observed in miR-151-5p levels between different grades of tumor. Interestingly, miR-9 levels were elevated in invasive lobular carcinomas (ILC) compared with invasive ductal carcinomas (IDC; p < 0.01).
In aggregate, these data suggest that miR-151-5p upregulation may suppress metastasis in primary breast tumors. Both miRNAs may serve as useful biomarkers in future clinical trials in breast cancer.
Molecular diagnosis & therapy 04/2012; 16(3):167-72. · 1.71 Impact Factor
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ABSTRACT: Over the past decade, major advances in our comprehension of breast cancer biology have led to improved diagnostic and prognostic techniques and the development of novel targeted therapies. However, the efficacy of new treatments remains limited by a combination of drug toxicity, resistance and persisting insufficiencies in our understanding of tumor-signaling pathways; furthermore, the reliability of identified biomarkers is contentious. Following their recent discovery, miRNAs have been established as critical regulators of gene expression, and their putative roles as oncogenes and tumor-suppressor genes has provided a potential new dimension to our clinical approach to breast cancer diagnosis and treatment. Their role as biomarkers and therapeutic targets is appealing; however, several barriers have limited our ability to translate this potential into a clinical reality. This review focuses on the currently accepted roles of miRNAs in breast cancer pathogenesis, and highlights the clinical challenges and breakthroughs in this field to date.
Pharmacogenomics 04/2012; 13(6):709-19. · 3.97 Impact Factor
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ABSTRACT: miRNAs play a role in post-transcriptional gene regulation by translational repression and/or mRNA degradation in a very tissue-specific manner. In order to understand the function of a miRNA, it is best to identify the genes that it regulates. Putative mRNA targets of miRNAs identified from seed sequence matches are available using computational algorithms in various web-based databases. However, these tend to have high false-positive rates and, owing to a whole-genome approach, cannot identify tissue/tumor specificity of regulation. The evaluated article presents a large amount of data analyzing global RNA expression in breast cancer and examines whether miRNAs are prognostic due to their effects on mRNA targets. This valuable and important resource of combined miRNA and mRNA expression in breast cancer and its subtypes has been summarized. Many studies have now investigated the integrated analysis of miRNA:mRNA profiles in human malignancies, the goal as always being to identify novel biomarkers and therapeutic targets for each tumor.
Expert Review of Anti-infective Therapy 03/2012; 12(3):323-30. · 2.65 Impact Factor
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Long R Jiao,
Adam E Frampton,
Jimmy Jacob,
Loredana Pellegrino,
Jonathan Krell,
Georgios Giamas,
Nicole Tsim,
Panagiotis Vlavianos,
Patrizia Cohen,
Raida Ahmad,
Andreas Keller,
Nagy A Habib,
Justin Stebbing, Leandro Castellano
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ABSTRACT: MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated.
Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets.
Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change.
Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers.
PLoS ONE 01/2012; 7(2):e32068. · 4.09 Impact Factor
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ABSTRACT: microRNAs (miRs) are a recently recognized class of noncoding short RNAs, 17-25 nucleotides in length, that play a role in post-transcriptional gene regulation by translational repression and/or mRNA degradation. Various miRs have been highlighted in pancreatic cancer development and metastasis, and as potential clinical diagnostic/prognostic biomarkers. Recently, studies have indicated that miRs are responsible for resistance to chemotherapeutic agents. The miR-10b has been identified as a 'metastamiR' in various tumor types, notably breast cancer, but data surrounding its relevance in pancreatic ductal adenocarcinoma has been sparse. The evaluated article presents data indicating that miR-10b is upregulated in pancreatic ductal adenocarcinoma and can be used as a diagnostic marker in endoscopic ultrasound-guided fine-needle aspiration biopsies of suspicious pancreatic lesions. In addition, miR-10b may be able to guide neoadjuvant gemcitabine-based chemoradiotherapy and predict metastatic-free survival and overall survival.
Expert Review of Anti-infective Therapy 12/2011; 11(12):1837-42. · 2.65 Impact Factor
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ABSTRACT: The metastatic transformation of epithelial tumors progresses through various steps leading to the generation of circulating tumor cells (CTCs). Measurement of CTCs in the peripheral blood is being increasingly recognized as a promising tool in breast oncology. Several studies have evaluated the prognostic significance of CTCs in newly diagnosed metastatic breast cancer (MBC) patients. The IC 2006-04 was a high-powered, prospective, multicenter, observational study conceived to assess CTC changes in women with MBC treated with first-line chemotherapy. Levels ≥ 5 CTCs/7.5 ml blood at baseline and before the second cycle of treatment were independent prognostic factors associated with shorter progression-free and overall survival. This study provides further level II evidence for the clinical and prognostic value of CTCs in MBC, confirming data from earlier small studies. It also provides proof that CTCs should be investigated in ongoing interventional trials to see if better patient outcomes can be attained by altering treatment based on CTC levels.
Expert Review of Anti-infective Therapy 09/2011; 11(9):1345-50. · 2.65 Impact Factor
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Georgios Giamas,
Aleksandra Filipović,
Jimmy Jacob,
Walter Messier,
Hua Zhang,
Dongyun Yang,
Wu Zhang,
Belul Assefa Shifa,
Andrew Photiou,
Cathy Tralau-Stewart, Leandro Castellano,
Andrew R Green,
R Charles Coombes,
Ian O Ellis,
Simak Ali,
Heinz-Josef Lenz,
Justin Stebbing
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ABSTRACT: Therapies targeting estrogen receptor α (ERα, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERα pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERα activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERα activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERα+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERα+ but not ERα- cells, indicative of its role in ERα activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target.
Nature medicine 06/2011; 17(6):715-9. · 27.14 Impact Factor
