MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

Li, Yan; Cao, Rui; Liu, YuanBo; Wang, Lian-Zhao; Pan, Bo; Lv, Xiaoyan; Jiao, Hu; Zhuang, Qiang; Sun, Xuefeng; Xiao, Ran

doi:10.1038/srep28281

Cited by 44 publications

(34 citation statements)

References 36 publications

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“…miR-21-5p is involved in the regulation of epithelial-mesenchymal transition and stem-like cells in keratinocytes, as well as the regulation of PTEN [18]. The results from the present study also show that circRNA-ACAP2 and Tiam1 were expressed at a high level, whereas miR-21-5p was expressed at a low level in colon cancer tissue and colon cancer SW480 cells (Fig.…”

Section: Discussionsupporting

confidence: 75%

The CircRNA-ACAP2/Hsa-miR-21-5p/ Tiam1 Regulatory Feedback Circuit Affects the Proliferation, Migration, and Invasion of Colon Cancer SW480 Cells

Han

et al. 2018

Cell Physiol Biochem

109

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Background/Aims: Circular RNAs (circRNAs), a type of RNA that is widely expressed in human cells, have essential roles in the development and progression of cancer. CircRNAs contain microRNA (miRNA) binding sites and can function as miRNA sponges to regulate gene expression by removing the inhibitory effect of an miRNA on its target gene. Methods: We used the bioinformatics software TargetScan and miRanda to predict circRNA-miRNA and miRNAi-Mrna interactions. Rate of inhibiting of proliferation was measured using a WST-8 cell proliferation assay. Clone formation ability was assessed with a clone formation inhibition test. Cell invasion and migration capacity was evaluated by performing a Transwell assay. Relative gene expression was assessed using quantitative real-time polymerase chain reaction and relative protein expression levels were determined with western blotting. circRNA and miRNA interaction was confirmed by dual-luciferase reporter and RNA-pull down assays. Results: In the present study, the miRNA hsa-miR-21-5p was a target of circRNA-ACAP2, and T lymphoma invasion and metastasis protein 1 (Tiam1) was identified as a target gene of hsa-miR-21-5p. CircRNA-ACAP2 and Tiam1 were shown to be highly expressed in colon cancer tissue and colon cancer SW480 cells, but miR-21-5p was expressed at a low level. SW480 cell proliferation was suppressed when the expression of circRNA-ACAP2 and Tiam1 was decreased and the expression of miR-21-5p was increased in vivo and in vitro. SW480 cell migration and invasion were also inhibited under the same circumstance. The circRNA-ACAP2 interaction regulated the expression of miR-21-5p, and miR-21-5p regulated the expression of Tiam1. Down-regulation of circRNA-ACAP2 promoted miR-21-5p expression, which further suppressed the transcription and translation of Tiam1. Conclusion: The present study shows that the circRNA-ACAP2/hsa-miR-21-5p/Tiam1 regulatory feedback circuit could affect the proliferation, migration, and invasion of colon cancer SW480 cells. This was probably due to the fact that circRNA-ACAP2 could act as a miRNA sponge to regulate Tiam1 expression by removing the inhibitory effect of miR-21-5p on Tiam1 expression. The results from this study have revealed new insights into the pathogenicity of colon cancer and may provide novel therapeutic targets for the treatment of colon cancer.

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Section: Discussionsupporting

confidence: 75%

The CircRNA-ACAP2/Hsa-miR-21-5p/ Tiam1 Regulatory Feedback Circuit Affects the Proliferation, Migration, and Invasion of Colon Cancer SW480 Cells

Han

et al. 2018

Cell Physiol Biochem

109

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“…In addition to miR-200a and miR-200c, TTK indirectly regulates the expression of miR-132 45 and miR-21 34 . MiR-21 is a downstream target of TGF-β that is transactivated to promote the mesenchymal cell status and considered an onco-miR 46 – 48 . TTK upregulates miR-21 34 , and we demonstrated in TNBC cells, TTK also upregulates miR-21 expression, as inhibition of TTK by siRNA or inhibitor decreased miR-21 expression, and restoration of miR-21 moderately prevented the effect of TTK on EMT marker expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

TTK promotes mesenchymal signaling via multiple mechanisms in triple negative breast cancer

King

Zhang

et al. 2018

Oncogenesis

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Abnormal expression of TTK kinase has been associated with the initiation, progression, and therapeutic resistance of breast and other cancers, but its roles remain to be clarified. In this study, we examined the role of TTK in triple negative breast cancer (TNBC), and found that higher TTK expression correlated with mesenchymal and proliferative phenotypes in TNBC cells. Pharmacologic inhibition and genomic silencing of TTK not only reversed the epithelial-to-mesenchymal transition (EMT) in TNBC cells, but also increased the expression of KLF5, an effector of TGF-β signaling and inhibitor of EMT. In addition, TTK inhibition decreased the expression of EMT-associated micro-RNA miR-21 but increased the expression of miR-200 family members and suppressed TGF-β signaling. To test if upregulation of KLF5 plays a role in TTK-induced EMT, TTK and KLF5 were silenced simultaneously, which reversed the decreased EMT caused by loss of TTK. Consistently, the decrease in miR-21 expression and increase in miR-200 expression caused by TTK silencing were rescued by loss of KLF5. Altogether, this study highlights a novel role and signaling pathway for TTK in regulating EMT of TN breast cancer cells through TGF-β and KLF5 signaling, highlighting targetable signaling pathways for TTK inhibitors in aggressive breast cancer.

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“…Several experimental evidences reported that the upregulation of Epithelial to Mesenchymal Transition (EMT)-related genes is associated with an increased motility and also keratinocytes, when switched to a mesenchymal phenotype, could invade the surrounding normal tissues. 29 For this reason, we investigated also the expression of vimentin, important mesenchymal marker, usually absent in epidermal keratinocytes. 30,31 In our in vitro model, vimentin did not appear either in presence of Prisma Ò Skin or of mesoglycan (data not shown).…”

Section: Prisma ò Skin and Mesoglycan Enhanced The Invasion Ability Omentioning

confidence: 99%

“…To migrate over the wound site, keratinocytes must disengage cell-cell junctions and reorganize their cytoskeleton increasing the contractility forces, which are essential for motility. 29 In this scenario, actin is typically considered a mechanical regulator of cell migration and, particularly, F-actin polymerization is essential for the protrusion of lamellipodia. 32 Therefore, we analyzed the HaCaT F-actin organization by phalloidin staining highlighting a cortical arrangement at the border of not-treated cells ( administration of mesoglycan and especially of Prisma Ò Skin, F-actin polymerization in stress fibers became evident also in cells which were localized in the middle area of the typical islets characterizing the growth manner of epithelial cells.…”

Section: Prisma ò Skin and Mesoglycan Enhanced The Invasion Ability Omentioning

confidence: 99%

Effects of Prisma® Skin dermal regeneration device containing glycosaminoglycans on human keratinocytes and fibroblasts

Belvedere

Bizzarro

Parente

et al. 2017

Cell Adhesion & Migration

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Prisma® Skin is a new pharmaceutical device developed by Mediolanum Farmaceutici S.p.a. It includes alginates, hyaluronic acid and mainly mesoglycan. The latter is a natural glycosaminoglycan preparation containing chondroitin sulfate, dermatan sulfate, heparan sulfate and heparin and it is used in the treatment of vascular disease. Glycosaminoglycans may contribute to the re-epithelialization in the skin wound healing, as components of the extracellular matrix. Here we describe, for the first time, the effects of Prisma® Skin in in vitro cultures of adult epidermal keratinocytes and dermal fibroblasts. Once confirmed the lack of cytotoxicity by mesoglycan and Prisma® Skin, we have shown the increase of S and G2 phases of fibroblasts cell cycle distribution. We further report the strong induction of cell migration rate and invasion capability on both cell lines, two key processes of wound repair. In support of these results, we found significant cytoskeletal reorganization, following the treatments with mesoglycan and Prisma® Skin, as confirmed by the formation of F-actin stress fibers. Additionally, together with a significant reduction of E-cadherin, keratinocytes showed an increase of CD44 expression and the translocation of ezrin to the plasma membrane, suggesting the involvement of CD44/ERM (ezrin-radixin-moesin) pathway in the induction of the analyzed processes. Furthermore, as showed by immunofluorescence assay, fibroblasts treated with mesoglycan and Prisma® Skin exhibited the increase of Fibroblast Activated Protein α and a remarkable change in shape and orientation, two common features of reactive stromal fibroblasts. In all experiments Prisma® Skin was slightly more potent than mesoglycan. In conclusion, based on these findings we suggest that Prisma® Skin may be able to accelerate the healing process in venous skin ulcers, principally enhancing re-epithelialization and granulation processes.

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MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

Cited by 44 publications

References 36 publications

The CircRNA-ACAP2/Hsa-miR-21-5p/ Tiam1 Regulatory Feedback Circuit Affects the Proliferation, Migration, and Invasion of Colon Cancer SW480 Cells

The CircRNA-ACAP2/Hsa-miR-21-5p/ Tiam1 Regulatory Feedback Circuit Affects the Proliferation, Migration, and Invasion of Colon Cancer SW480 Cells

TTK promotes mesenchymal signaling via multiple mechanisms in triple negative breast cancer

Effects of Prisma® Skin dermal regeneration device containing glycosaminoglycans on human keratinocytes and fibroblasts

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