Differential microRNA expression profiling of mesothelioma and expression analysis of miR-1 and miR-214 in mesothelioma

Amatya, Vishwa Jeet; Mawas, Amany Sayed; Kushitani, Kei; El-Din, Mouchira M. Mohi; Takeshima, Yukio

doi:10.3892/ijo.2016.3358

Cited by 31 publications

(31 citation statements)

References 41 publications

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“…However, information related to human studies is still largely lacking due to difficulty identifying LGR5 + cells in human intestine; this is probably due to the lack of appropriate antibodies and the low expression of LGR5. Alternate approaches, such as the use of SmartFlare RNA-based technology, are now being developed (54). To test the hypothesis that Lgr5 + stem cells are responsible for epithelial regeneration, several mouse models were developed to determine if an alternative stem cell population can replenish the intestinal epithelial under conditions in which Lgr5 + stem cells are ablated or damaged.…”

Section: Human Mini-intestines In the Study Of Intestinal Physiologymentioning

confidence: 99%

The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology

Hasan

et al. 2017

Annu. Rev. Physiol.

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The lack of accessibility to normal and diseased human intestine and the inability to separate the different functional compartments of the intestine even when tissue could be obtained have held back the understanding of human intestinal physiology. Clevers and his associates identified intestinal stem cells and established conditions to grow “mini-intestines” ex vivo in differentiated and undifferentiated conditions. This pioneering work has made a new model of the human intestine available and has begun making contributions to the understanding of human intestinal transport in normal physiologic conditions and the pathophysiology of intestinal diseases. However, this model is reductionist and lacks many of the complexities of normal intestine. Consequently, it is not yet possible to predict how great the advances using this model will be for understanding human physiology and pathophysiology, nor how the model will be modified to include multiple other intestinal cell types and physical forces necessary to more closely approximate normal intestine. This review describes recent studies using mini-intestines, which have readdressed previously established models of normal intestinal transport physiology and newly examined intestinal pathophysiology. The emphasis is on studies with human enteroids grown either as three-dimensional spheroids or two-dimensional monolayers. In addition, comments are provided on mouse studies in cases when human studies have not yet been described.

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Section: Human Mini-intestines In the Study Of Intestinal Physiologymentioning

confidence: 99%

The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology

Hasan

et al. 2017

Annu. Rev. Physiol.

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“…Interestingly, miR‐99a was found at lower levels in MPM samples compared with normal pleura (Andersen et al ., ) and differentially expressed between epithelioid and sarcomatoid tumors (Pass et al ., ). Similarly, miR‐214 was shown to be downregulated in MPM samples compared with controls in two independent studies (Amatya et al ., ; Balatti et al ., ). In addition, we found that FGF signaling suppressed the expression of miR‐23a and miR‐223, both of which are altered in MPM and predicted to target components of the FGF axis (Birnie et al ., ; Cheng et al ., ).…”

Section: Discussionmentioning

confidence: 98%

A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma

et al. 2017

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Malignant pleural mesothelioma (MPM) is an aggressive malignancy with very limited therapeutic options. Fibroblast growth factor (FGF) signals play important roles in mesothelioma cell growth. Several FGFs and FGF receptors (FGFRs) are predicted targets of the miR‐15/16 family, which is downregulated in MPM. The aim of this study was to explore the link between the miR‐15/16 family and the FGF axis in MPM. Expression analyses via RT‐qPCR showed downregulation of the FGF axis after transfection with miR‐15/16 mimics. Direct interaction was confirmed by luciferase reporter assays. Restoration of miR‐15/16 led to dose‐dependent growth inhibition in MPM cell lines, which significantly correlated with their sensitivity to FGFR inhibition. Treatment with recombinant FGF2 prevented growth inhibition and further reduced the levels of FGF/R‐targeting microRNAs, indicating a vicious cycle between miR‐15/16 down‐ and FGF/FGFR signaling upregulation. Combined inhibition of two independent miR‐15/16 targets, the FGF axis and Bcl‐2, resulted in additive or synergistic activity. Our data indicate that post‐transcriptional repression of FGF‐mediated signals contributes to the tumor suppressor function of the microRNA‐15/16 family. Inhibiting hyperactivated FGF signals and Bcl‐2 might serve as a novel therapeutic combination strategy in MPM.

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“…S2). Two other studies in MM generating miR microarray profiles also suggest that miR‐18a is significantly upregulated in MM cell lines and MM tumor tissue compared to normal tissue (Amatya et al ., ; Ramirez‐Salazar et al ., ). Although none of these studies identified any key downstream targets of miR‐18a, they do support our idea that miR‐18a plays an important role in MM.…”

Section: Discussionmentioning

confidence: 99%

Post‐transcriptional regulation of PIAS3 expression by miR‐18a in malignant mesothelioma

et al. 2018

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Protein inhibitor of activated STAT3 (PIAS3) is an endogenous suppressor of signal transducer and activator of transcription 3 (STAT3) signaling. By directly interacting with phosphorylated STAT3, PIAS3 can block the downstream transcriptional activity of STAT3, which is hyper‐activated in various cancers. We previously reported that in malignant mesothelioma (MM), low PIAS3 expression is associated with increased STAT3 activation and correlates with poor patient survival, yet the regulatory mechanism(s) governing PIAS3 expression in MM remain unclear. Here, we demonstrate that PIAS3 protein expression does not correlate with its mRNA level in MM cell lines, indicating that PIAS3 expression is regulated at a post‐transcriptional level. Inhibition of proteasomal degradation with MG132 (10 μm) or bortezomib (1 μm), alone and in combination, did not increase PIAS3 protein levels; furthermore, inhibition of protein synthesis by cycloheximide treatment did not decrease PIAS3 levels within 48 h, suggesting that PIAS3 expression is not actively regulated at a post‐translational level. To determine whether miRNA (miRs) can translationally regulate PIAS3 expression, we combined miR microarray analysis with bioinformatic screening to identify candidate miRs, in MM cell lines with low PIAS3 expression, followed by luciferase reporter assays to validate miR regulation of the PIAS3 3′UTR. We identified miR‐18a as a suppressor of PIAS3 expression that is upregulated in MM cells and whose inhibition can increase PIAS3 expression and suppress STAT3 activity. Moreover, we showed that miR‐18a inhibition can decrease MM cell viability and that its expression is negatively correlated with MM patient survival. Taken together, these results suggest that targeting miR‐18a may have therapeutic benefit in MM.

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Differential microRNA expression profiling of mesothelioma and expression analysis of miR-1 and miR-214 in mesothelioma

Cited by 31 publications

References 41 publications

The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology

The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology

A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma

Post‐transcriptional regulation of PIAS3 expression by miR‐18a in malignant mesothelioma

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