ΔNp63α and microRNAs: leveraging the epithelial-mesenchymal transition

Stacy, Andrew J.; Craig, Michael P.; Sakaram, Suraj; Kadakia, Madhavi

doi:10.18632/oncotarget.13797

Cited by 23 publications

(14 citation statements)

References 135 publications

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“…We previously showed that TP63 controls the expression of high-molecular weight keratins (KRT5, KRT6, and KRT14) and suppresses EMT (Choi et al, 2014b; Tran et al, 2013). The central role of p63 in the maintenance of epithelial phenotype and EMT was confirmed in several variants of solid tumors (Soares and Zhou, 2018; Stacy et al, 2017; Tanaka et al, 2018). We therefore performed additional analyses to further characterize the role of EMT in SARC.…”

Section: Resultsmentioning

confidence: 88%

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

et al. 2019

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SUMMARY Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle- invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

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Section: Resultsmentioning

confidence: 88%

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

et al. 2019

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“…NSC and sip63 samples clustered together with up- or down-regulation of a majority of miRNA correlating with sample type. This list of miRNA was compared to a previously published dataset of p63-regulated miRNAs summarized in our previous study 21 . Eight of the currently identified miRNA were previously shown to be regulated by ΔNp63α and served as positive controls (miR-185–5p, miR-205-5p, miR-130b-3p, miR-203a-5p, and miR-429) 10 , 22 – 24 .…”

Section: Resultsmentioning

confidence: 99%

Identification of novel ΔNp63α-regulated miRNAs using an optimized small RNA-Seq analysis pipeline

Sakaram

Craig

Hill

et al. 2018

Sci Rep

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Advances in high-throughput sequencing have enabled profiling of microRNAs (miRNAs), however, a consensus pipeline for sequencing of small RNAs has not been established. We built and optimized an analysis pipeline using Partek Flow, circumventing the need for analyzing data via scripting languages. Our analysis assessed the effect of alignment reference, normalization method, and statistical model choice on biological data. The pipeline was evaluated using sequencing data from HaCaT cells transfected with either a non-silencing control or siRNA against ΔNp63α, a p53 family member protein which is highly expressed in non-melanoma skin cancer and shown to regulate a number of miRNAs. We posit that 1) alignment and quantification to the miRBase reference provides the most robust quantitation of miRNAs, 2) normalizing sample reads via Trimmed Mean of M-values is the most robust method for accurate downstream analyses, and 3) use of the lognormal with shrinkage statistical model effectively identifies differentially expressed miRNAs. Using our pipeline, we identified previously unrecognized regulation of miRs-149-5p, 18a-5p, 19b-1-5p, 20a-5p, 590-5p, 744-5p and 93-5p by ΔNp63α. Regulation of these miRNAs was validated by RT-qPCR, substantiating our small RNA-Seq pipeline. Further analysis of these miRNAs may provide insight into ΔNp63α’s role in cancer progression. By defining the optimal alignment reference, normalization method, and statistical model for analysis of miRNA sequencing data, we have established an analysis pipeline that may be carried out in Partek Flow or at the command line. In this manner, our pipeline circumvents some of the major hurdles encountered during small RNA-Seq analysis.

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“…Accumulating evidence has indicated that miR-373 participates in tumor metastasis (32), and the role of human miR-373 in metastasis is dependent the tissue and organ type. miR-373 was first identified to be a metastasis-promoting miRNA in breast cancer (30).…”

Section: Discussionmentioning

confidence: 99%

miR-373 suppresses gastric cancer metastasis by downregulating vimentin

Shi

Zhang

et al. 2017

Mol Med Report

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MicroRNA-373 (miR-373) has been reported to be an oncogene in a number of solid human tumors. However, the role of miR‑373 in gastric cancer has not been completely elucidated and the mechanisms remain unclear. In the present study, we compared miR‑373 expression between clinical gastric cancer tissues and paired non‑tumorous tissues by reverse transcription‑quantitative polymerase chain reaction. The impact of miR‑373 on proliferation, migration and invasion in gastric cancer cells was additionally investigated. Hsa‑miR‑373 mimics were applied to mimic the function of endogenous miR‑373. A colony formation assay and flow cytometry were performed to analyze the proliferation of gastric cancer cells. Wound healing and Transwell invasion assays were employed to detect the migratory and invasive abilities of gastric cancer cells. Western blotting was used to test the expression of epithelial‑mesenchymal transition‑associated proteins. The results demonstrated that the level of miR‑373 in gastric cancer was upregulated compared with paired non‑tumorous tissues. It was confirmed that miR‑373 inhibited the migration and invasion of the gastric cancer cell lines SGC‑7901 and HGC‑27 by downregulating vimentin expression. The results of the present study demonstrated an oncogenic role of miR‑373 in the metastasis of human gastric cancer, and may provide a novel therapeutic strategy for gastric cancer.

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ΔNp63α and microRNAs: leveraging the epithelial-mesenchymal transition

Cited by 23 publications

References 135 publications

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Identification of novel ΔNp63α-regulated miRNAs using an optimized small RNA-Seq analysis pipeline

miR-373 suppresses gastric cancer metastasis by downregulating vimentin

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