LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients

Zhang, Jin; Cai, Hong‐Qing; Sun, Lixin; Zhan, Panpan; Chen, Meng; Zhang, Feng; Ran, Yu-liang; Wan, Jinghai

doi:10.1186/s13046-018-0864-6

Cited by 137 publications

(107 citation statements)

References 43 publications

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“…PKCζ affects β‐catenin stability, further affecting stem cell function . The Wnt/β‐catenin pathway plays an important role in tumor cell EMT and stemness; such report is consistent with our results from KEGG pathway analysis based on the differential genes between cPLA2α KD and KD/SCR CSCs and from mass spectrometry analysis. Many β‐catenin molecules bound to the cytomembrane with E‐cadherin, and less nuclear translocation of β‐catenin occurred when PKCζ was knocked down regulated by cPLA2α inhibition, leading to increased E‐cadherin‐mediated cell‐to‐cell adhesion and blockage of EMT and metastasis.…”

Section: Discussionsupporting

confidence: 91%

cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer

Manyu

et al. 2020

Stem Cells

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Cervical cancer stem cells (CCSCs) are considered major causes of chemoresistance/radioresistance and metastasis. Although several cell surface antigens have been identified in CCSCs, these markers vary among tumors because of CSC heterogeneity. However, whether these markers specifically distinguish CCSCs with different functions is unclear. Here, we demonstrated that CCSCs exist in two biologically distinct phenotypes characterized by different levels of cytosolic phospholipase A2α (cPLA2α) expression. Overexpression of cPLA2α results in a CD44+CD24− phenotype associated with mesenchymal traits, including increased invasive and migration abilities, whereas CCSCs with cPLA2α downregulation express CD133 and show quiescent epithelial characteristics. In addition, cPLA2α regulates the reversible transition between mesenchymal and epithelial CCSC states through PKCζ, an atypical protein kinase C, which governs cancer cell state changes and the maintenance of various embryonic stem cell characteristics, further inhibiting β‐catenin‐E‐cadherin interaction in membrane and promoting β‐catenin translocation into the nucleus to affect the transcriptional regulation of stemness signals. We propose that reversible transitions between mesenchymal and epithelial CCSC states regulated by cPLA2α are necessary for cervical cancer metastasis and recurrence. Thus, cPLA2α might be an attractive therapeutic target for eradicating different states of CCSCs to eliminate tumors more effectively.

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Section: Discussionsupporting

confidence: 91%

cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer

Manyu

et al. 2020

Stem Cells

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“…The Wnt signaling pathway is an evolutionarily conserved developmental signaling cascade that plays a critical role in regulating organ development and tissue homeostasis. Leucine‐rich repeat‐containing G protein‐coupled receptor 5 (LGR5) is a novel functional marker in glioma stem cells that promotes EMT by activating the Wnt/β‐catenin signaling pathway . Sry‐like high‐mobility group box 8 regulated cancer stem‐like properties and cisplatin‐induced EMT by the Wnt/β‐catenin signaling pathway in tongue squamous cell carcinoma .…”

Section: Small Molecules Against Emtmentioning

confidence: 92%

“…(LGR5) is a novel functional marker in glioma stem cells that promotes EMT by activating the Wnt/β-catenin signaling pathway. 138 Sry-like high-mobility group box 8 regulated cancer stem-like properties and cisplatin-induced EMT by the Wnt/β-catenin signaling pathway in tongue squamous cell carcinoma. 139 In addition, bone marrow mesenchymal stromal cells suppressed EMT by inhibiting the Wnt/β-catenin signaling pathway in silica-induced pulmonary fibrosis.…”

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

104

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Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

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“…This is consistent with a former work that suggested miR‐150‐5p suppressed chemoresistance in ovarian cancer cells (Xia et al, 2017). In addition, the Wnt/β‐catenin pathway has been reported to regulate the population of glioma stem cells (Hsieh et al, 2013; Zhang et al, 2018a). These results indicated that miR‐150‐5p suppressed the characteristics of glioma stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…The Wnt/β‐catenin pathway regulates cell invasion, proliferation, and apoptosis in glioma cells via varying mechanisms (Gao et al, 2017). Moreover, the Wnt/β‐catenin pathway is associated with epithelial–mesenchymal transition and prognosis of glioma patients (Zhang et al, 2018a). Besides, catenin beta 1 (CTNNB1, which encodes β‐catenin) has been suggested as one of the key transducers in the Wnt/β‐catenin pathway (Su et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

miR‐150‐5p suppresses the stem cell‐like characteristics of glioma cells by targeting the Wnt/β‐catenin signaling pathway

Tian

Zhu

Jiang

2020

Cell Biology International

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Glioma is the most common brain tumor malignancy with high mortality and poor prognosis. Emerging evidence suggests that cancer stem cells are the key culprit in the development of cancer. MicroRNAs have been reported to be dysregulated in many cancers, while the mechanism underlying miR-150-5p in glioma progression and proportion of stem cells is unclear. The expression levels of miR-150-5p and catenin beta 1 (CTNNB1, which encodes β-catenin) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The expression levels of downstream genes of the Wnt/β-catenin pathway and stem cell markers were detected by qRT-PCR. Tumorigenesis was investigated by cell viability, colony formation, and tumor growth in vitro and in vivo. The interaction between miR-150-5p and β-catenin was explored via bioinformatics analysis and luciferase activity assay. We found that miR-150-5p was downregulated in glioma and its overexpression inhibited cell proliferation, colony formation, and tumor growth. Moreover, miR-150-5p directly suppressed CTNNB1 and negatively regulated the abundances of downstream genes of the Wnt/β-catenin pathway and stem cell markers. Furthermore, miR-150-5p expression was decreased and β-catenin level was enhanced in CD133+ glioma stem cells. Knockdown of miR-150-5p contributed to CD133− cells with stem cell-like phenotype, whereas overexpression of miR-150-5p suppressed CD133+ glioma stem cell-like characteristics. In conclusion, miR-150-5p inhibited the progression of glioma by controlling stem cell-like characteristics via regulating the Wnt/β-catenin pathway, providing a novel target for glioma treatment.

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LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients

Cited by 137 publications

References 43 publications

cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer

cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

miR‐150‐5p suppresses the stem cell‐like characteristics of glioma cells by targeting the Wnt/β‐catenin signaling pathway

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