miR‐200/375 control epithelial plasticity‐associated alternative splicing by repressing the
            <scp>RNA</scp>
            ‐binding protein Quaking

Pillman, Katherine A.; Phillips, C.; Roslan, Suraya; Toubia, John; Dredge, B Kate; Bert, Andrew G.; Lumb, Rachael; Neumann, Daniel; Li, Xiaochun; Conn, Simon J.; Liu, Dawei; Bracken, Cameron P.; Lawrence, David; Stylianou, Nataly; Schreiber, Andreas W.; Tilley, Wayne D.; Hollier, Brett G.; Khew‐Goodall, Yeesim; Selth, Luke A.; Goodall, Gregory J.; Gregory, Philip A.

doi:10.15252/embj.201899016

Cited by 91 publications

(137 citation statements)

References 95 publications

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“…After QKI knock‐down, 1,627 genes were upregulated and 662 genes were downregulated (fold change >1.5, q < 0.05). Gene set enrichment analyses revealed that RNA splicing (normalized enrichment score, NES = ‐10.36) gene signature was depleted in QKI knock‐down cells, as expected; however, gene signatures including cytokine production (NES = 8.57), interferon gamma response (NES = 7.71) and inflammatory response (NES = 5.70) were enriched (Figs. a and b ).…”

Section: Resultssupporting

confidence: 69%

QKI, a miR‐200 target gene, suppresses epithelial‐to‐mesenchymal transition and tumor growth

Kim

Lee

et al. 2019

Intl Journal of Cancer

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The microRNA-200 (miR-200) family plays a major role in specifying epithelial phenotype by preventing expression of the transcription repressors ZEB1 and ZEB2, which are well-known regulators of the epithelial-to-mesenchymal transition (EMT) in epithelial tumors including oral squamous cell carcinoma (OSCC). Here, we elucidated whether miR-200 family members control RNA-binding protein quaking (QKI), a newly identified tumor suppressor that is regulated during EMT. We predicted that miR-200a and miR-200b could recognize QKI 3 0 -UTR by analyzing TargetScan and The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) dataset. Forced expression of miR-200b/a/429 inhibited expression of ZEB1/2 and decreased cell migration in OSCC cell lines CAL27 and HSC3. QKI expression was also suppressed by miR-200 overexpression, and the 3 0 -UTR of QKI mRNA was directly targeted by miR-200 in luciferase reporter assays. Interestingly, shRNA-mediated knockdown of QKI led to pronounced EMT and protumor effects in both in vitro and in vivo studies of OSCC. Furthermore, high expression of QKI protein is associated with favorable prognosis in surgically resected HNSCC and lung adenocarcinoma. In conclusion, QKI increases during EMT and is targeted by miR-200; while, it suppresses EMT and tumorigenesis. We suggest that QKI and miR-200 form a negative feedback loop to maintain homeostatic responses to EMT-inducing signals.

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Section: Resultssupporting

confidence: 69%

QKI, a miR‐200 target gene, suppresses epithelial‐to‐mesenchymal transition and tumor growth

Kim

Lee

et al. 2019

Intl Journal of Cancer

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“…Additionally, the reduction of QKI is important for CRC development and the stemness maintenance of both normal stem cells and CSCs [95,96]. Moreover, QKI-5 is involved in EMT regulation as well [97]. miR-221 attenuates the suppressive effect of QKI-5 on CSCs to facilitate enlargement of the CSC population and tumorigenesis.…”

Section: Mir-221mentioning

confidence: 99%

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

Jiao

Qian

et al. 2019

Cells

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Cancer ranks as the second leading cause of death worldwide, causing a large social and economic burden. However, most anti-cancer treatments face the problems of tumor recurrence and metastasis. Therefore, finding an effective cure for cancer needs to be solved urgently. Recently, the discovery of cancer stem cells (CSCs) provides a new orientation for cancer research and therapy. CSCs share main characteristics with stem cells and are able to generate an entire tumor. Besides, CSCs usually escape from current anti-cancer therapies, which is partly responsible for tumor recurrence and poor prognosis. microRNAs (miRNAs) belong to small noncoding RNA and regulate gene post-transcriptional expression. The dysregulation of miRNAs leads to plenty of diseases, including cancer. The aberrant miRNA expression in CSCs enhances stemness maintenance. In this review, we summarize the role of miRNAs on CSCs in the eight most common cancers, hoping to bridge the research of miRNAs and CSCs with clinical applications. We found that miRNAs can act as tumor promoter or suppressor. The dysregulation of miRNAs enhances cell stemness and contributes to tumor metastasis and therapeutic resistance via the formation of feedback loops and constitutive activation of carcinogenic signaling pathways. More importantly, some miRNAs may be potential targets for diagnosis, prognosis, and cancer treatments.

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“…pos-1 contains several predicted miRNA binding sites in its 3′UTR (Table S1), and based on our GFP reporter validation study is strongly expressed in the body muscle (Figure S4). We also find the KH domain containing protein gld-1 , the homolog of the human gene QKI , which is targeted by miR-214 (Wu et al 2017), miR-200c and miR-375 (Pillman et al 2018).…”

Section: Resultsmentioning

confidence: 90%

miRNA activity contributes to accurate RNA splicing inC. elegansintestine and body muscle tissues

Kotagama

Schorr

Steber

et al. 2018

Preprint

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MicroRNAs (miRNAs) are known to modulate gene expression, but their activity at the tissue-specific level remains largely uncharacterized. In order to study their contribution to tissue-specific gene expression, we developed novel tools to profile miRNA targets in the C. elegans intestine and body muscle.We validated many previously described interactions, and identified ~3,500 novel targets. Many of the miRNA targets curated are known to modulate the functions of their respective tissues. Within our datasets we observed a disparity in the use of miRNA-based gene regulation between the intestine and body muscle. The intestine contained significantly more miRNA targets than the body muscle highlighting its transcriptional complexity. We detected an unexpected enrichment of RNA binding proteins targeted by miRNA in both tissues, with a notable abundance of RNA splicing factors.We developed in vivo genetic tools to validate and further study three RNA splicing factors identified as miRNA targets in our study (asd-2, hrp-2 and smu-2), and show that these factors indeed contain functional miRNA regulatory elements in their 3’UTRs that are able to repress their expression in the intestine. In addition, the alternative splicing pattern of their respective downstream targets (unc-60, unc-52, lin-10 and ret-1) is dysregulated when the miRNA pathway is disrupted.A re-annotation of the transcriptome data in C. elegans strains that are deficient in the miRNA pathway from past studies supports and expands on our results. This study highlights an unexpected role for miRNAs in modulating tissue-specific gene isoforms, where post-transcriptional regulation of RNA splicing factors associates with tissue-specific alternative splicing.

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miR‐200/375 control epithelial plasticity‐associated alternative splicing by repressing the RNA ‐binding protein Quaking

Cited by 91 publications

References 95 publications

QKI, a miR‐200 target gene, suppresses epithelial‐to‐mesenchymal transition and tumor growth

QKI, a miR‐200 target gene, suppresses epithelial‐to‐mesenchymal transition and tumor growth

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

miRNA activity contributes to accurate RNA splicing inC. elegansintestine and body muscle tissues

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