ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma

Huang, Lifeng; Cai, Jie; Guo, Han; Gu, Jinyang; Tong, Ying; Qiu, Bijun; Wang, Chenchen; Li, Meng; Xia, Lei; Zhang, Jianjun; Wu, Hailong; Kong, Xiaoni; Xia, Qiang

doi:10.1002/hep.30404

Cited by 35 publications

(36 citation statements)

References 41 publications

(54 reference statements)

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“…A). CD133 has been consistently reported to be a marker of chemo‐resistant cancer cells, which are enriched after treatment, and CD133+ BTC cells were shown to be tumorigenic and express features of cancer stem cells (CSCs) . Therefore, we speculated that MIR1249 could affect chemo‐resistance by inducing the expansion of CD133+ BTC cells.…”

Section: Resultsmentioning

confidence: 98%

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Modulation of Biliary Cancer Chemo‐Resistance Through MicroRNA‐Mediated Rewiring of the Expansion of CD133+ Cells

et al. 2020

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BaCKgRoUND aND aIMS: Changes in single micro-RNA (miRNA) expression have been associated with chemoresistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy. appRoaCH aND ReSUltS: High-throughput screening (HTS) of 997 locked nucleic acid miRNA inhibitors was performed in six cholangiocarcinoma cell lines treated with cisplatin and gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with mir-Vana probes. MicroRNA and gene expression was assessed by TaqMan assay, RNA-sequencing, and in situ hybridization in four independent cohorts of human BTCs. Knockout of microRNA was achieved by CRISPR-CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in vitro and in vivo. HTS revealed that MIR1249 inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTCs. In validation experiments, MIR1249 inhibition did not alter cell viability in untreated or dimethyl sulfoxidetreated cells; however, it did increase the CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem cell niche of human BTCs as well as in CD133+ chemo-resistant CCLP cells. MIR1249 modulated the chemotherapy-induced enrichment of CD133+ cells by controlling their clonal expansion through the Wnt-regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of cancer stem cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumor shrinkage after exposure to weekly CG, whereas wildtype models showed only stable disease over treatment. CoNClUSIoNS: MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics. (Hepatology 2020;0:1-15). B iliary tract cancers (BTCs) include cholangiocarcinoma (CCA) and gallbladder cancer, and their incidence is increasing worldwide. (1-4) Lack of effective radical treatments and rapid failure of palliative ones highlight the need for a better understanding of BTC biology and mechanisms of response to treatment. (2,5) Eighty percent of patients

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Section: Resultsmentioning

confidence: 98%

“…Several mechanisms of chemo‐resistance may act synergistically and drive cancer cells to escape biochemical inhibition or cell death caused by chemotherapy . Acquisition of stemness features in cancer cells appears to be a driver of resistance that is common with other tumor types …”

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confidence: 99%

Modulation of Biliary Cancer Chemo‐Resistance Through MicroRNA‐Mediated Rewiring of the Expansion of CD133+ Cells

et al. 2020

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“…Targeting EGFR with an existing therapy might be a potential strategy for EOC treatment through the eradication of CSCs. In intrahepatic cholangiocarcinoma, ID3 promotes CSCs by activating β-catenin and is correlated with poor prognosis [ 50 ]. This gene expression may be associated with OC prognosis.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Behera

Ashraf

Srivastava

et al. 2020

Heliyon

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Background Epithelial ovarian cancer (EOC) is a lethal and aggressive gynecological malignancy. Despite recent advances, existing therapies are challenged by a high relapse rate, eventually resulting in disease recurrence and chemoresistance. Emerging evidence indicates that a subpopulation of cells known as cancer stem-like cells (CSLCs) exists with non-tumorigenic cancer cells (non-CSCs) within a bulk tumor and is thought to be responsible for tumor recurrence and drug-resistance. Therefore, identifying the molecular drivers for cancer stem cells (CSCs) is critical for the development of novel therapeutic strategies for the treatment of EOC. Methods Two gene datasets were downloaded from the Gene Expression Omnibus (GEO) database based on our search criteria. Differentially expressed genes (DEGs) in both datasets were obtained by the GEO2R web tool. Based on log 2 (fold change) >2, the top thirteen up-regulated genes and log 2 (fold change) < -1.5 top thirteen down-regulated genes were selected, and the association between their expressions and overall survival was analyzed by OncoLnc web tool. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways analysis, and protein-protein interaction (PPI) networks were performed for all the common DEGs found in both datasets. SK-OV-3 cells were cultured in an adherent culture medium and spheroids were generated in suspension culture with CSCs specific medium. RNA from both cell population was extracted to validate the selected DEGs expression by q-PCR. Growth inhibition assay was performed in SK-OV-3 cells after carboplatin treatment. Results A total of 200 DEGs, 117 up-regulated and 83 down-regulated genes were commonly identified in both datasets. Analysis of pathways and enrichment tests indicated that the extracellular matrix part, cell proliferation, tissue development, and molecular function regulation were enriched in CSCs. Biological pathways such as interferon-alpha/beta signaling, molecules associated with elastic fibers, and synthesis of bile acids and bile salts were significantly enriched in CSCs. Among the top 13 up-regulated and down-regulated genes, MMP1 and PPFIBP1 expression were associated with overall survival. Higher expression of ADM, CXCR4, LGR5, and PTGS2 in carboplatin treated SK-OV-3 cells indicate a potential role in drug resistance. Conclusions The molecular signature and signaling pathways enriched in ovarian CSCs were identified by bioinformatics analysis. This analysis could provide further research ideas to find the new mechanism and novel potential therapeutic targets for ovarian CSCs.

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“…Reportedly, a recent study found that mitochondrial impairment activated the Wallerian pathway and caused the axon degeneration by the depletion of NMNAT2 [36]. Moreover, ID3 was reported to act as a biomarker promoting the stemness of intrahepatic cholangiocarcinoma by promoting the transcriptional activity of β-catenin [37]. Furthermore, high-grade serous ovarian carcinoma patients with higher expression of FXYD5 owned a shorter survival time than patients with lower expression of FXYD5, and FXYD5 played a critical role in survival and prognosis of HCSOC [38].…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptomic Analysis Reveals the Molecular Mechanism of Meningiomas by Weighted Gene Coexpression Network Analysis

Yang

Wei

et al. 2020

BioMed Research International

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Meningiomas are the most common primary intracranial tumor in adults. However, to date, systemic coexpression analyses for meningiomas fail to explain its pathogenesis. The aim of the present study was to construct coexpression modules and identify potential biomarkers associated with meningioma progression. Weighted gene coexpression network analysis (WGCNA) was performed based on GSE43290, and module preservation was tested by GSE74385. Functional annotations were performed to analyze biological significance. Hub genes were selected for efficacy evaluations and correlation analyses using two independent cohorts. A total of 14 coexpression modules were identified, and module lightcyan was significantly associated with WHO grades. Functional enrichment analyses of module lightcyan were associated with tumor pathogenesis. The top 10 hub genes were extracted. Ten biomarkers, particularly AHCYL2, FGL2, and KCNMA1, were significantly related to grades and prognosis of meningioma. These findings not only construct coexpression modules leading to the better understanding of its pathogenesis but also provide potential biomarkers that represent specific on tumor grades and identify recurrence, predicting prognosis and progression of meningiomas.

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ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma

Cited by 35 publications

References 41 publications

Modulation of Biliary Cancer Chemo‐Resistance Through MicroRNA‐Mediated Rewiring of the Expansion of CD133+ Cells

Modulation of Biliary Cancer Chemo‐Resistance Through MicroRNA‐Mediated Rewiring of the Expansion of CD133+ Cells

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Integrated Transcriptomic Analysis Reveals the Molecular Mechanism of Meningiomas by Weighted Gene Coexpression Network Analysis

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