ITF2 Prevents Activation of the β-Catenin–TCF4 Complex in Colon Cancer Cells and Levels Decrease With Tumor Progression

Shin, Hyun–Woo; Choi, Han Sung; So, Daeho; Kim, Youngim; Cho, Kumsun; Chung, Hwan Hoon; Lee, Kyoung–Hwa; Chun, Yang–Sook; Cho, Chung–Hyun; Kang, Gyeong Hoon; Kim, Woo Ho; Park, Jong–Wan

doi:10.1053/j.gastro.2014.04.047

Cited by 22 publications

(25 citation statements)

References 42 publications

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“…TCF4 are a major class of transcription factors that control the nuclear response to Wnt/β-catenin signaling. Some studies indicated that TCF4 functions to promote cellular proliferation (44,45). TCF4 silencing sensitizes the CRC line to L-OHP as a common chemotherapeutic drug (46).…”

Section: Discussionmentioning

confidence: 99%

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Yang

Guan

et al. 2016

International Journal of Oncology

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Abstract. Certain microRNAs (miRNAs) play a key role in cancer cell chemoresistance. However, the pleiotropic functions of exosome-derived miRNAs on developing chemoresistance remain unknown. In the present study, we aimed to construct potential networks of miRNAs, which derived from the exosome of chemoresistant prostate cancer (PCa) cells, with their known target genes using miRNA expression profiling and bioinformatic tools. Global miRNA expression profiles were measured by microarray. Twelve miRNAs were initially selected and validated by qRT-PCR. Known targets of deregulated miRNAs were utilized using DIANA-TarBase database v6.0. The incorporation of deregulated miRNAs and target genes into KEGG pathways were utilized using DIANA-mirPath software. To construct potential miRNA regulatory networks, the overlapping parts of miRNAs and their targer genes from the selected KEGG pathway 'PCa progression (hsa05215)' were visualized by Cytoscape software. We identified 29 deregulated miRNAs, including 19 upregulated and 10 downregulated, in exosome samples derived from two kinds of paclitaxel resistance PCa cells (PC3-TXR and DU145-TXR) compared with their parental cells (PC3 and DU145). The enrichment results of deregulated miRNAs and known target genes showed that a few pathways were correlated with several critical cell signaling pathways. We found that hub hsa-miR3176, -141-3p, -5004-5p, -16-5p, -3915, -488-3p, -23c, -3673 and -3654 were potential targets to hub gene androgen receptor (AR) and phosphatase and tensin homolog (PTEN). Hub gene T-cell factors/lymphoid enhancer-binding factors 4 (TCF4) target genes were mainly regulated by hub hsa-miR-32-5, -141-3p, -606, -381 and -429. These results may provide a linkage between PCa chemoresistance and exosome regulatory networks and thus lead us to propose that AR, PTEN and TCF4 genes may be the important genes which are regulated by exosome miRNAs in chemoresistance cancer cells.

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Section: Discussionmentioning

confidence: 99%

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Yang

Guan

et al. 2016

International Journal of Oncology

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“…Activation of WNT/β‐catenin, MYC, and STAT transcription factors plays an important role in initiation and progression of several cancers . The role of β‐catenin activation and cancer is best exemplified in the cascade of colon carcinogenesis . The aberrant activation of the Wnt/β‐catenin signaling pathway has been described in 30%–60% of GC tissues and in GC cell lines .…”

Section: Introductionmentioning

confidence: 99%

Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia

Chen

Soutto

Rahman

et al. 2017

Genes Chromosomes & Cancer

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Gastric cancer is a leading cause of cancer-related deaths worldwide. The Tff1 knockout (KO) mouse model develops gastric lesions that include low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinomas. In this study, we used Affymetrix microarrays gene expression platforms for analysis of molecular signatures in the mouse stomach (Tff1-KO (LGD) and Tff1 wild-type (normal)) and human gastric cancer tissues and their adjacent normal tissue samples. Combined integrated bioinformatics analysis of mouse and human datasets indicated that 172 genes were consistently deregulated in both human gastric cancer samples and Tff1-KO LGD lesions (P<0.05). Using Ingenuity pathway analysis, these genes mapped to important transcription networks that include MYC, STAT3, β-catenin, RELA, NFATC2, HIF1A, and ETS1 in both human and mouse. Further analysis demonstrated activation of FOXM1 and inhibition of TP53 transcription networks in human gastric cancers but not in Tff1-KO LGD lesions. Using real-time RT-PCR, we validated the deregulated expression of several genes (VCAM1, BGN, CLDN2, COL1A1, COL1A2, COL3A1, EpCAM, IFITM1, MMP9, MMP12, MMP14, PDGFRB, PLAU, and TIMP1) that map to altered transcription networks in both mouse and human gastric neoplasia. Our study demonstrates significant similarities in deregulated transcription networks in human gastric cancer and gastric tumorigenesis in the Tff1-KO mouse model. The data also suggest that activation of MYC, STAT3, RELA, and β-catenin transcription networks could be an early molecular step in gastric carcinogenesis.

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“…In fact, ITF2 expression is induced by the ß-catenin/TCF complex, but at the same time, it acts as a repressor of this complex by interfering with the binding of Β-catenin to TCF4. This causes a decrease in the expression of Wnt target genes, leading to the repression of cell proliferation 35 . Consistent with these studies, we have observed that the resistant A2780 cells have increased activity of the ß-catenin/TCF transcription, which is concomitant with the increased expression of the downstream effector gene DKK1, probably due to the absence of ITF2.…”

Section: Discussionmentioning

confidence: 99%

“…We found a common deletion that includes the Transcription Factor 4, TCF4 (hereafter called ITF2). ITF2 is a downstream target gene of the Wnt/β-catenin pathway, that negatively regulates its activity 18,35 . Wnt signaling has been identified as one of the key signaling pathways in cancer, and more recently, also to be involved in drug resistance of primary tumors such as colon or ovarian cancer 6,26 .…”

Section: Introductionmentioning

confidence: 99%

A novel role for the tumor suppressor geneITF2in lung tumorigenesis and chemotherapy response

Pernía¹,

Sastre-Perona²,

Rodriguez-Antolín³

et al. 2019

Preprint

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Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyze the cytogenetic alterations that arise after cisplatin treatment providing novel insights into the molecular biology and the cellular mechanisms involved in the acquired resistance in these tumor types. Methods:In this study, we used 1 million array-CGH and qRT-PCR methodologies to identify and validate cytogenetic alterations that arise after cisplatin treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines. We used whole transcriptome sequencing (RNA-seq), functional transfection assays and gene-pathway activity analysis in our experimental cellular models and in fresh frozen primary NSCLC tumors to identify genes with a potential role in the development of this malignancy. Results were further explored in 55 lung and ovarian primary tumors and control samples and in two extensive in silico databases (TCGA and KMplotter) with 1,926 NSCLC and 1,425 additional epithelial tumors.Results: Long-term cell exposure to platinum induces the frequent deletion of ITF2 gene.Restoration of ITF2 expression re-sensitizes tumor cells to platinum and recovers the levels of Wnt/β-catenin transcriptional activity. ITF2 expression was also frequently downregulated in NSCLC, ovarian and other epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation in expression between ITF2 and HOXD9, revealing that NSCLC patients with lower expression of HOXD9 have a better overall survival rate that was independent of the tumor histology. Conclusion:We have defined the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. Our translational data suggest that ITF2 could be used as a general epithelial tumor platinum-predictive marker and have identified HOXD9 as a potential prognostic biomarker in NSCLC, a gene which expression is induced by Wnt signaling. Furthermore, this data highlights the possible role of ITF2 and HOXD9 as a novel therapeutic target for platinum resistant tumors.

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ITF2 Prevents Activation of the β-Catenin–TCF4 Complex in Colon Cancer Cells and Levels Decrease With Tumor Progression

Cited by 22 publications

References 42 publications

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia

A novel role for the tumor suppressor geneITF2in lung tumorigenesis and chemotherapy response

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