Consequences Of Aberrant Expression Research Articles

Notch Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling.

Lung development is mediated by assorted signaling proteins and orchestrated by complex mesenchymal-epithelial interactions. Notch signaling is an evolutionarily conserved cell-cell communication mechanism that exhibits a pivotal role in lung development. Notably, both aberrant expression and loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, in particular, pulmonary fibrosis, lung cancer, pulmonary arterial hypertension, and asthmatic airway remodeling; implying that precise regulation of intensity and duration of Notch signaling is imperative for appropriate lung development. Moreover, evidence suggests that Notch signaling links embryonic lung development and asthmatic airway remodeling. Herein, we summarized all-recent advances associated with the mechanistic role of Notch signaling in lung development, consequences of aberrant expression or deletion of Notch signaling in linking early-impaired lung development and asthmatic airway remodeling, and all recently investigated potential therapeutic strategies to treat asthmatic airway remodeling.

Characterization of microRNA transcriptome in tumor, adjacent, and normal tissues of lung squamous cell carcinoma

ObjectivesMicroRNAs are a class of regulatory molecules involved in a wide variety of biological processes, including growth, development, and apoptosis. Given the widespread roles of microRNAs in biological processes, understanding their different expression profiles in normal, adjacent, and tumor tissues will provide insights into the consequences of aberrant expression. MethodsWith the use of next-generation deep sequencing technology, microRNA profiles in 3 pooled samples from normal, adjacent, and tumor tissues of 19 patients with lung squamous cell carcinoma were characterized comprehensively. Quantitative polymerase chain reaction was used to verify the primary findings in another 38 lung squamous cell carcinoma tumor samples. In situ hybridization also was performed for validation. ResultsA total of 368, 306, and 231 known microRNAs were identified from tumor, adjacent, and normal pooled samples, respectively, of which 40, 44, and 26 microRNAs displayed dysregulation with 2-fold or greater change in 3 compared groups of tumor versus normal, tumor versus adjacent, and adjacent versus normal, respectively. Sequencing data also showed that some coexpressed microRNAs displayed a pattern of progressive dysregulation. Some of the microRNAs exhibited consistent changes; among them, miR-425-5p and miR-218-5p were confirmed by quantitative polymerase chain reaction and in situ hybridization, and proved that the microRNA expression levels were closely related to tumor stages and sizes. It is suggested that some microRNAs, such as miR-425 and miR-183, might be a driver for tumor formation, growth, and progression to higher staging, whereas others, such as miR-218, might behave as a tumor suppressor in lung cancer. Functional annotation analysis indicated that the proteoglycan pathway in cancer and mitogen-activated protein kinase, Wnt, PI3K-Akt, and transforming growth factor-beta signaling pathways might be involved in the pathogenesis of lung squamous cell carcinoma. ConclusionsThis study describes the use of deep sequencing for comprehensive profiling of microRNAs in lung squamous cell carcinoma. The identified microRNA signatures may provide biomarkers for early detection, subclassification, and potential therapeutic targets of lung squamous cell carcinoma. This study also provides some insights into the molecular mechanism underlying the development and progression of lung squamous cell carcinoma, which may prove helpful for early diagnosis and treatment of the disease.

Robust global microRNA expression profiling using next-generation sequencing technologies

miRNAs are a class of regulatory molecules involved in a wide range of cellular functions, including growth, development and apoptosis. Given their widespread roles in biological processes, understanding their patterns of expression in normal and diseased states will provide insights into the consequences of aberrant expression. As such, global miRNA expression profiling of human malignancies is gaining popularity in both basic and clinically driven research. However, to date, the majority of such analyses have used microarrays and quantitative real-time PCR. With the introduction of digital count technologies, such as next-generation sequencing (NGS) and the NanoString nCounter System, we have at our disposal many more options. To make effective use of these different platforms, the strengths and pitfalls of several miRNA profiling technologies were assessed, including a microarray platform, NGS technologies and the NanoString nCounter System. Overall, NGS had the greatest detection sensitivity, largest dynamic range of detection and highest accuracy in differential expression analysis when compared with gold-standard quantitative real-time PCR. Its technical reproducibility was high, with intrasample correlations of at least 0.95 in all cases. Furthermore, miRNA analysis of formalin-fixed, paraffin-embedded (FFPE) tissue was also evaluated. Expression profiles between paired frozen and FFPE samples were similar, with Spearman's ρ>0.93. These results show the superior sensitivity, accuracy and robustness of NGS for the comprehensive profiling of miRNAs in both frozen and FFPE tissues.

MiR-181a regulates multiple pathways in hypopharyngeal squamous cell carcinoma

MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that play essential roles in a variety of biological processes including apoptosis, proliferation and differentiation. Altered expression of miRNAs in head and neck cancer has been reported, but the consequences of aberrant expression of specific miRNAs on cancer pathways remain vague. Therefore, it is important to identify and elucidate pathways that may be regulated by specific miRNAs in this disease. miR-181a was up-regulated in head and neck versus normal tissues, thus pathway analysis was performed to profile the changes in the activities of ten signaling pathways relevant to cancer influenced by down-regulation of miR-181a. Expression of four pathway reporters were significantly increased (p53/DNA damage, TGFβ, MAPK/ERK and MAPK/JNK), while expression of two pathway reporters were decreased (Wnt and NFkB) upon miR-181a down-regulation. Notch, Myc/Max, hypoxia and cell cycle/pRB-E2F pathways were not significantly affected by miR-181a down-regulation. This study provides insight into the understanding of miRNA regulation on major cancer pathways. Key words : MicroRNA, head and neck cancer, miR-181a, pathway analysis, luciferase assay, FaDu cell line, transfection, qRT-PCR.