Highly Coordinated Gene Regulation in Mouse Skeletal Muscle Regeneration

Mammalian skeletal muscles are capable of regeneration after injury. Quiescent satellite cells are activated to reenter the cell cycle and to differentiate for repair, recapitulating features of myogenesis during embryonic development. To understand better the molecular mechanism involved in this process in vivo, we employed high density cDNA microarrays for gene expression profiling in mouse tibialis anterior muscles after a cardiotoxin injection. Among 16,267 gene elements surveyed, 3,532 elements showed at least a 2.5-fold change at one or more time points during a 14-day time course. Hierarchical cluster analysis and semiquantitative reverse transcription-PCR showed induction of genes important for cell cycle control and DNA replication during the early phase of muscle regeneration. Subsequently, genes for myogenic regulatory factors, a group of imprinted genes and genes with functions to inhibit cell cycle progression and promote myogenic differentiation, were induced when myogenic stem cells started to differentiate. Induction of a majority of these genes, including E2f1 and E2f2, was abolished in muscles lacking satellite cell activity after gamma radiation. Regeneration was severely compromised in E2f1 null mice but not affected in E2f2 null mice. This study identifies novel genes potentially important for muscle regeneration and reveals highly coordinated myogenic cell proliferation and differentiation programs in adult skeletal muscle regeneration in vivo

MicroRNA expression distinguishes SCLC from NSCLC lung tumor cells and suggests a possible pathological relationship between SCLCs and NSCLCs

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown that microRNAs (miRNAs) play roles in tumorigenesis and are reliable classifiers of certain cancer types and subtypes. However, the role of miRNAs in the pathogenesis and diagnosis of small cell carcinoma (SCLC), the majority of which represent the most aggressive lung tumors, has not been investigated.</p> <p>Methods</p> <p>In order to explore miRNA involvement in the pathogenesis of small cell lung carcinoma (SCLC) and the potential role of miRNAs in SCLC diagnosis, we compared the miRNA expression profile of a set of SCLC cell lines to that of a set of non-small cell lung cancer (NSCLC) cell lines and normal immortalized human bronchial epithelial cells (HBECs) using microarray analysis.</p> <p>Results</p> <p>Our results show that miRNA profiles reliably distinguish SCLC cell lines from NSCLC and HBEC cell lines. Further analysis of the miRNA expression profile of the two subtypes of lung cancer cell lines indicates that the expression levels of the majority of the miRNAs that are differentially expressed in SCLC cells relative to NSCLC cells and HBECs show a progressive trend from HBECs to NSCLC cells to SCLC cells.</p> <p>Conclusions</p> <p>The distinctive miRNA expression signature of SCLCs relative to NSCLCs and HBECs suggests that miRNA profiles have the potential to serve as a diagnostic marker of SCLC lung tumors. The progressive trend of miRNA profile changes from HBECs to NSCLCs to SCLCs suggests a possible pathological relationship between SCLCs and NSCLCs, and suggests that the increasing dysregulation of miRNA expression may play a role in lung tumor progression. The specific role of these miRNAs in lung tumor pathogenesis and differentiation need to be investigated further in future studies.</p

miR-93, miR-98, and miR-197 Regulate Expression of Tumor Suppressor Gene FUS1

FUS1 is a tumor suppressor gene located on human chromosome 3p21, and expression of Fus1 protein is highly regulated at various levels, leading to lost or greatly diminished tumor suppressor function in many lung cancers. Here we show that selected microRNAs (miRNAs) interact with the 3’ untranslated region (3’ UTR) of FUS1, leading to down-regulation of protein expression. Using computational methods, we first predicted that FUS1 is a target of three miRNAs, miR-93, miR-98 and miR-197, and then showed that exogenous over-expression of these miRNAs inhibited Fus1 protein expression. We then confirmed that the three miRNAs target the 3’UTR region of the FUS1 transcript, and that individual deletion of the three miRNA target sites in the FUS1 3’UTR restores the expression level of Fus1 protein. We further found that miR-93 and miR-98 are expressed at higher levels in small cell lung cancer cell lines (SCLC) than in non-small cell lung cancer cell lines (NSCLC) and immortalized human bronchial epithelial cells (HBECs), and that miR-197 is expressed at higher levels in both SCLC and NSCLC than in HBECs. Finally, we found that elevated miR-93 and miR-197 expression is correlated with reduced Fus1 expression in NSCLC tumor specimens. These results suggest that the three miRNAs are negative regulators of Fus1 expression in lung cancers

Collaborating to Compete: Blood Profiling Atlas in Cancer (BloodPAC) Consortium

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136731/1/cpt666.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136731/2/cpt666_am.pd

miR-337-3p and Its Targets STAT3 and RAP1A Modulate Taxane Sensitivity in Non-Small Cell Lung Cancers

NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC