Overexpression of microRNA-194 suppresses the epithelial–mesenchymal transition in targeting stem cell transcription factor Sox3 in endometrial carcinoma stem cells

AbstractEndogenous retroviruses (ERVs) are remnants of ancient retroviral infections that make up 8% of the human genome. Although these elements are mostly fragmented and inactive, many proviruses belonging to the HERV-K (HML-2) family, the youngest lineage in the human genome, have intact open reading frames, some encoding for accessory genes called np9 and rec that interact with oncogenic pathways. Many studies have established that ERVs are transiently expressed in both stem cells and cancer, resulting in aberrant self-renewal and uncontrolled proliferation. np9 and rec expression are significantly correlated with a range of cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) biomarkers, including cellular receptors, transcription factors, and histone modifiers. Surprisingly, these ERV genes are negatively correlated with genes known to promote pluripotency in embryonic stem cell lines, such as Oct4. These results indicate that HERV-K (HML-2) is part of the transcriptional landscape responsible for cancer cells undergoing the phenotypic switch that characterises EMT. The discovery of np9 and rec’s correlation with CSC and EMT biomarkers suggest a yet undescribed role affecting the transitional CSC-like state in EMT and the shift towards cancer malignancy.ImportanceIn this study, we find that human endogenous retrovirus HERV-K (HML-2)-encoded genes np9 and rec are correlated with the expression of many biomarkers associated with cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT). There has been a significant effort to develop novel treatments targeting CSC and EMT-specific signalling pathways and cell surface markers. This research describes HERV-K (HML-2) as interacting or being part of the regulatory network that make up reversible cell state switching in EMT. Our findings suggest these specific HERVs may be good candidate biomarkers in identifying the transitional CSC-like states that are present during the progression of EMT and cancer metastasis.

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The epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in cancer

10.1101/2020.11.04.368688 ◽

2020 ◽

Author(s):

H Wang ◽

E Chirshev ◽

N Hojo ◽

T Suzuki ◽

A Bertucci ◽

...

Keyword(s):

Ovarian Cancer ◽

Transcription Factor ◽

Stem Cell ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Tumor Burden ◽

Cell Phenotype ◽

Mesenchymal Transition

AbstractWe aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.Novelty and ImpactThis study provides new insight into molecular mechanisms by which EMT transcription factor SNAI1 exerts its pro-stemness effects in cancer cells, demonstrating its potential as a stem cell-directed target for therapy. In vitro and in vivo, mesoporous silica nanoparticle-mediated SNAI1 knockdown resulted in restoration of let-7 miRNA, inhibiting stemness and reducing tumor burden. Our studies validate in vivo nanoparticle-delivered RNAi targeting the SNAI1/let-7 axis as a clinically relevant approach.

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Evidence for circulating cancer stem-like cells and epithelial–mesenchymal transition phenotype in the pleurospheres derived from lung adenocarcinoma using liquid biopsy

Tumor Biology ◽

10.1177/1010428317695915 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769591 ◽

Cited By ~ 6

Author(s):

Sheefa Mirza ◽

Nayan Jain ◽

Rakesh Rawal

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Tumor Stem Cells ◽

Mesenchymal Transition ◽

Lung Cancer Stem Cells

Lung cancer stem cells are supposed to be the main drivers of tumor initiation, maintenance, drug resistance, and relapse of the disease. Hence, identification of the cellular and molecular aspects of these cells is a prerequisite for targeted therapy of lung cancer. Currently, analysis of circulating tumor cells has the potential to become the main diagnostic technique to monitor disease progression or therapeutic response as it is non-invasive. However, accurate detection of circulating tumor cells has remained a challenge, as epithelial cell markers used so far are not always trustworthy for detecting circulating tumor cells, especially during epithelial–mesenchymal transition. As cancer stem cells are the only culprit to initiate metastatic tumors, our aim was to isolate and characterize circulating tumor stem cells rather than circulating tumor cells from the peripheral blood of NSCLC adenocarcinoma as limited data are available addressing the gene expression profiling of lung cancer stem cells. Here, we reveal that CD44(+)/CD24(−) population in circulation not only exhibit stem cell–related genes but also possess epithelial–mesenchymal transition characteristics. In conclusion, the use of one or more cancer stem cell markers along with epithelial, mesenchymal and epithelial mesenchymal transition markers will prospectively provide the most precise assessment of the threat for recurrence and metastatic disease and has a great potential for forthcoming applications in harvesting circulating tumor stem cells and their downstream applications. Our results will aid in developing diagnostic and prognostic modalities and personalized treatment regimens like dendritic cell–based immunotherapy that can be utilized for targeting and eliminating circulating tumor stem cells, to significantly reduce the possibility of relapse and improve clinical outcomes.

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Paracrine Signaling between Carcinoma Cells and Mesenchymal Stem Cells Generates Cancer Stem Cell Niche via Epithelial–Mesenchymal Transition: Figure 1.

Cancer Discovery ◽

10.1158/2159-8290.cd-12-0312 ◽

2012 ◽

Vol 2 (9) ◽

pp. 775-777 ◽

Cited By ~ 15

Author(s):

Kati Räsänen ◽

Meenhard Herlyn

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Cancer Stem Cell ◽

Stem Cell Niche ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

Paracrine Signaling ◽

Mesenchymal Transition ◽

Cell Niche

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Disseminating cells in human tumours acquire an EMT stem cell state that is predictive of metastasis

10.1101/2020.04.07.029009 ◽

2020 ◽

Cited By ~ 2

Author(s):

Gehad Youssef ◽

Luke Gammon ◽

Leah Ambler ◽

Bethan Wicker ◽

Swatisha Patel ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Oral Cancer ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Tumour Cells ◽

Mesenchymal Transition ◽

Cell State ◽

Significant Enrichment ◽

Stem Cell State

AbstractCancer stem cells undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. Here, we identify an EMT stem cell state that retains EpCAM and CD24 after undergoing EMT and exhibits enhanced plasticity. This afforded the opportunity to investigate whether retention of EpCAM and CD24 alongside upregulation of the EMT marker Vimentin can identify disseminating EMT stem cells in human oral cancer specimens. Examining disseminating tumour cells in the stromal region of 3500 imaging fields from 24 human oral cancer specimens, evenly divided into metastatic and non-metastatic specimens, we see a significant enrichment of EpCAM, CD24 and Vimentin co-stained cells in metastatic specimens. Through training an artificial neural network on the EpCAM, CD24 and Vimentin co-staining, we predict metastasis with high accuracy (F1 0.91; AUC 0.87). We have observed, for the first time, disseminating EMT stem cells in patient histological specimens and demonstrated their utility for predicting metastatic disease.

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Human Umbilical Cord Mesenchymal Stem Cell-derived Exosomal miR-27b Attenuate Subretinal Fibrosis via Suppressing Epithelial-mesenchymal Transition by Targeting HOXC6

10.21203/rs.3.rs-99751/v1 ◽

2020 ◽

Author(s):

dongli Li ◽

Junxiu Zhang ◽

Zijia Liu ◽

Yuanyuan Gong ◽

Zhi Zheng

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Umbilical Cord ◽

Epithelial Mesenchymal Transition ◽

Human Umbilical Cord ◽

Mesenchymal Transition ◽

Rpe Cells ◽

Subretinal Fibrosis

Abstract Background and aimSubretinal fibrosis resulting from neovascular age-related macular degeneration (nAMD) is one of the major causes of serious and irreversible vision loss worldwide, and no definite and effective treatment exists currently. Retinal pigmented epithelium (RPE) cells are crucial in maintaining the visual function of normal eyes and its epithelial–mesenchymal transition (EMT) is associated with the pathogenesis of subretinal fibrosis. Stem cells-derived exosomes have been reported to play a crucial part in tissue fibrosis by transferring their molecular contents. This study aimed to explore the effects of human umbilical cordderived mesenchymal stem cell exosomes (hucMSC-Exo) on subretinal fibrosis in vivo and in vitro and to investigate the anti-fibrotic mechanism of hucMSC-Exo.Methods In this study, we successfully cultured and identified human umbilical cord-derived mesenchymal stem cells (hucMSC), and isolated exosomes from their supernatant by ultracentrifugation.Laser-induced (choroidal neovascularization) CNV and subretinal fibrosis model indicated that intravitreal administration of hucMSC-Exo effectively alleviated subretinal fibrosis in vivo. Furthermore, we found that hucMSC-Exo could efficaciously suppress RPE cells migration and promote the mesenchymal–epithelial transition (MET) by delivering miR-27b-3p. Analysis of the latent binding of miR-27b-3p to HOXC6 was made by bioinformatics prediction and luciferase reporter assays. ResultsThe study showed that intravitreal injection of hucMSC-Exo effectively ameliorated laser-induced CNV and subretinal fibrosis via suppression of EMT process. In addition, hucMSC-Exo containing miR-27b repressed the EMT process in RPE cells induced by the TGF-β2 via inhibiting HOXC6 (Homeobox protein Hox-C6) expression. ConclusionsThis study provided novel insights into the anti-fibrotic mechanism of hucMSC-Exo on subretinal fibrosis. HucMSCs-derived exosomal miR-27b could reverse the process of EMT induced by TGF-β2 via inhibiting HOXC6, which indicated that exosomal miR-27b/HOXC6 axis could play a vital role on ameliorating subretinal fibrosis. Our study put forward a promising therapeutic agent for the treatment of ocular fibrotic diseases, as well as comprehension into the mechanism of hucMSC-Exo under subretinal fibrosis.

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Chemotherapeutic stress influences epithelial-mesenchymal transition and stemness in cancer stem cells of triple‐negative breast cancer

10.1055/s-0040-1717860 ◽

2020 ◽

Author(s):

X Li ◽

J Strietz ◽

A Bleilevens ◽

E Stickeler ◽

J Maurer

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Stress Influences

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The Epithelial-Mesenchymal Transition and Cancer Stem Cells: Functional and Mechanistic Links

Current Pharmaceutical Design ◽

10.2174/1381612821666141211115611 ◽

2015 ◽

Vol 21 (10) ◽

pp. 1279-1291 ◽

Cited By ~ 77

Author(s):

Xiangqiang Liu ◽

Daiming Fan

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition

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Human umbilical cord mesenchymal stem cell-derived exosomal miR-27b attenuates subretinal fibrosis via suppressing epithelial–mesenchymal transition by targeting HOXC6

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02064-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Dongli Li ◽

Junxiu Zhang ◽

Zijia Liu ◽

Yuanyuan Gong ◽

Zhi Zheng

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Umbilical Cord ◽

Mechanism Of Action ◽

Epithelial Mesenchymal Transition ◽

Human Umbilical Cord ◽

Mesenchymal Transition ◽

Rpe Cells ◽

Subretinal Fibrosis

Abstract Background and aim Subretinal fibrosis resulting from neovascular age-related macular degeneration (nAMD) is one of the major causes of serious and irreversible vision loss worldwide, and no definite and effective treatment exists currently. Retinal pigmented epithelium (RPE) cells are crucial in maintaining the visual function of normal eyes and its epithelial–mesenchymal transition (EMT) is associated with the pathogenesis of subretinal fibrosis. Stem cell-derived exosomes have been reported to play a crucial role in tissue fibrosis by transferring their molecular contents. This study aimed to explore the effects of human umbilical cord-derived mesenchymal stem cell exosomes (hucMSC-Exo) on subretinal fibrosis in vivo and in vitro and to investigate the anti-fibrotic mechanism of action of hucMSC-Exo. Methods In this study, human umbilical cord-derived mesenchymal stem cells (hucMSCs) were successfully cultured and identified, and exosomes were isolated from the supernatant by ultracentrifugation. A laser-induced choroidal neovascularization (CNV) and subretinal fibrosis model indicated that the intravitreal administration of hucMSC-Exo effectively alleviated subretinal fibrosis in vivo. Furthermore, hucMSC-Exo could efficaciously suppress the migration of retinal pigmented epithelial (RPE) cells and promote the mesenchymal–epithelial transition by delivering miR-27b-3p. The latent binding of miR-27b-3p to homeobox protein Hox-C6 (HOXC6) was analyzed by bioinformatics prediction and luciferase reporter assays. Results This study showed that the intravitreal injection of hucMSC-Exo effectively ameliorated laser-induced CNV and subretinal fibrosis via the suppression of epithelial–mesenchymal transition (EMT) process. In addition, hucMSC-Exo containing miR-27b repressed the EMT process in RPE cells induced by transforming growth factor-beta2 (TGF-β2) via inhibiting HOXC6 expression. Conclusions The present study showed that HucMSC-derived exosomal miR-27b could reverse the process of EMT induced by TGF-β2 via inhibiting HOXC6, indicating that the exosomal miR-27b/HOXC6 axis might play a vital role in ameliorating subretinal fibrosis. The present study proposed a promising therapeutic agent for treating ocular fibrotic diseases and provided insights into the mechanism of action of hucMSC-Exo on subretinal fibrosis.

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