The <scp>SHH</scp>/Gli axis regulates <scp>CD</scp>90‐mediated liver cancer stem cell function by activating the <scp>IL</scp>6/<scp>JAK</scp>2 pathway

Zhang, Ketao; Che, Siyao; Pan, C.; Su, Zheng‐Yuan; Zheng, Shusen; Yang, Shanglin; Zhang, Huayao; Li, Wenda; Wang, Weidong; Liu, Jianping

doi:10.1111/jcmm.13651

Cited by 31 publications

(10 citation statements)

References 33 publications

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“…In gastric cancer cell lines and tissues, CSCs identified by the CD44 + CD24 + phenotype have demonstrated an overexpression of the SHH , PTCH1 and GLI3 genes ( 41 ). Zhang et al demonstrated that in liver cancer, CD90 + CSCs with GLI1 or GLI3 knockdown, exhibited low proliferation rates, and decreased migratory ability and sphere formation capacity, as well as a decrease in tumour formation in vivo ; indicating that both genes are relevant to the maintenance of the stem cell properties observed in CD90 + cancer cells ( 42 ).…”

Section: Introductionmentioning

confidence: 99%

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Rodrigues

Miguita²,

Andrade³

et al. 2018

Int J Oncol

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Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following this, we examined the effects of GLI3 knockdown on CD44 and ESA expression, colony and sphere formation capability, stem-related gene expression, proliferation and invasion. The overexpression of genes related to the Notch, transforming growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency maintenance pathways was observed in the CD44high cells. GLI3 knockdown was associated with a significant decrease in different CSCLC fractions, spheres and colonies in addition to the downregulation of the CD44, Octamer-binding transcription factor 4 (OCT4; also known as POU5F1) and BMI1 genes. This downregulation was accompanied by an increase in the expression of the Involucrin (IVL) and S100A9 genes. Cellular proliferation and invasion were inhibited following GLI3 knockdown. In OSCC samples, a high GLI3 expression was associated with tumour size but not with prognosis. On the whole, the findings of this study demonstrate for the first time, at least to the best of our knowledge, that GLI3 contributes to OSCC stemness and malignant behaviour. These findings suggest the potential for the development of novel therapies, either in isolation or in combination with other drugs, based on CSCs in OSCC.

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Section: Introductionmentioning

confidence: 99%

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Rodrigues

Miguita²,

Andrade³

et al. 2018

Int J Oncol

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“…Previous research has shown that the SHH/GLI1 axis can activate IL-6 expression in liver cancer . The concentrations of immunosuppressive cytokine IL-10, cytokines, and chemokines IL-6, CXCL1 (GRO), and CXCL8 (IL-8) have been reported to be remarkably high in ACP .…”

Section: Resultsmentioning

confidence: 99%

Transcription Factor GLI1 Induces IL-6-Mediated Inflammatory Response and Facilitates the Progression of Adamantinomatous Craniopharyngioma

Zhao,

Yang,

Pan

et al. 2023

ACS Chem. Neurosci.

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Adamantinomatous craniopharyngioma (ACP) is a neuroendocrine tumor whose pathogenesis remains unclear. This study investigated the role of glioma-associated oncogene family zinc finger 1 (GLI1), a transcription factor in the sonic hedgehog (SHH) signaling pathway, in ACP. We discovered that GLI1 regulates the expression of IL-6, thereby triggering inflammatory responses in ACP and influencing the tumor's progression. Analyzing the Gene Expression Omnibus (GEO) database chip GSE68015, we found that GLI1 is overexpressed in ACP, correlating positively with the spite of ACP and inflammation markers. Knockdown of GLI1 significantly inhibited the levels of tumor necrosis factor α, interleukin-6 (IL-6), and IL-1β in ACP cells, as well as cell proliferation and migration. We further identified a binding site between GLI1 and the promoter region of IL-6, demonstrating that GLI1 can enhance the expression of IL-6. These findings were verified in vivo, where activation of the SHH pathway significantly promoted GLI1 and IL-6 expressions in nude mice, inducing inflammation and tumor growth. Conversely, GLI1 knockdown markedly suppressed these processes. Our study uncovers a potential molecular mechanism for the occurrence of inflammatory responses and tumor progression in ACP.

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“…It has been suggested as a surface marker for CSC in HCC that does not express EpCAM [ 112 , 113 ]. IL6, hedgehog, and AKT signaling pathways have been associated with CD90 [ 114 , 115 ].…”

Section: Resultsmentioning

confidence: 99%

Genetic heterogeneity of liver cancer stem cells

Kim

et al. 2022

Anat Cell Biol

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Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer.Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.

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The SHH/Gli axis regulates CD90‐mediated liver cancer stem cell function by activating the IL6/JAK2 pathway

Cited by 31 publications

References 33 publications

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Transcription Factor GLI1 Induces IL-6-Mediated Inflammatory Response and Facilitates the Progression of Adamantinomatous Craniopharyngioma

Genetic heterogeneity of liver cancer stem cells

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