Paired related homeobox 1 is associated with the invasive properties of glioblastoma cells

Sugiyama, Mai; Hasegawa, Hitoki; Ito, Satoko; Sugiyama, Kazuya; Maeda, Masao; Wakabayashi, Toshihiko; Hamaguchi, Michinari; Natsume, Atsushi; Senga, Takeshi

doi:10.3892/or.2014.3681

Cited by 19 publications

(22 citation statements)

References 33 publications

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“…It was initially thought to be a biomarker associated with patient survival and was believed to decrease metastasis by uncoupling EMT and stemness [48]. Recently, it was reported that up-regulated PRRX1 is closely correlated with metastasis and poor prognosis in colorectal and pancreatic cancers [49, 50] and enhances invasiveness in glioblastoma cell lines [51]. These observations are in line with our results that PRRX1 is highly co-expressed with BMI1 and TWIST1 .…”

Section: Discussionsupporting

confidence: 91%

LGR5 Is a Gastric Cancer Stem Cell Marker Associated with Stemness and the EMT Signature Genes NANOG, NANOGP8, PRRX1, TWIST1, and BMI1

et al. 2016

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BackgroundAccumulating evidence supports the hypothesis that cancer stem cells (CSCs) are essential for cancer initiation, metastasis and drug resistance. However, the functional association of gastric CSC markers with stemness and epithelial-mesenchymal transition (EMT) signature genes is unclear.MethodsqPCR was performed to measure the expression profiles of stemness and EMT signature genes and their association with putative CSC markers in gastric cancer tissues, cancer cell lines and sphere cells. Western blot analysis was used to confirm the results of the transcript analysis. Cell proliferation, cell migration, drug resistance and sphere cell growth assays were conducted to measure the expansion and invasion abilities of the cells. Tumor xenograft experiments were performed in NOD/SCID mice to test cell stemness in vivo. Flow cytometry and immunofluorescence staining were used to analyze cell subpopulations.ResultsThe expression of LGR5 was strikingly up-regulated in sphere cells but not in cancer tissues or parental adherent cells. The up-regulation of LGR5 was also positively associated with stemness regulators (NANOG, OCT4, SOX2, and AICDA) and EMT inducers (PRRX1, TWIST1, and BMI1). In addition, sphere cells exhibited up-regulated vimentin and down-regulated E-cadherin expression. Using gene-specific primers, we found that the NANOG expression primarily originates from the retrogene NANOGP8. Western blot analysis showed that the expression of both LGR5 and NANOG is significantly higher in sphere cells. LGR5 over-expression significantly enhanced sphere cell growth, cell proliferation, cell migration and drug resistance in MGC803 cells. Tumor xenografts in nude mice showed that sphere cells are at least 10 times more efficient at tumor initiation than adherent cells. Flow cytometry analysis showed that ~20% of sphere cells are LGR5+/CD54+, but only ~3% of adherent cells are Lgr5+/CD54+. Immunofluorescence staining supports the above results.ConclusionThe LGR5-expressing fraction of CD54+ cells represents gastric cancer CSCs, in which LGR5 is closely associated with stemness and EMT core genes, and NANOG expression is mainly contributed by the retrogene NANOGP8. Sphere cells are the best starting materials for the characterization of CSCs.

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Section: Discussionsupporting

confidence: 91%

LGR5 Is a Gastric Cancer Stem Cell Marker Associated with Stemness and the EMT Signature Genes NANOG, NANOGP8, PRRX1, TWIST1, and BMI1

et al. 2016

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“…Additional IDH1 wt super-enhancers marked by 5hmC in our dataset and implicated in GBM pathogenesis included WDR1 , TGFBI and PVT1 [ 11 , 36 , 43 , 74 ]. IDH1 mt-specific super-enhancer targets marked by 5hmC in our cohort and previously implicated in GBM pathogenesis included PDGFC , PRRX1 , LIF , A XL , and CD44 [ 14 , 18 , 31 , 50 , 55 , 63 , 71 ]. Taken together, these data demonstrated enhancer/super-enhancer targeting by 5hmC as a prominent feature in HGG, with differential targeting observed between IDH1 cohorts.…”

Section: Discussionmentioning

confidence: 92%

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

et al. 2018

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Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1821-3) contains supplementary material, which is available to authorized users.

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“…[33,34] . Also, the paired related homeobox 1 (PRRX1) was associated with glioblastoma cell invasion [35] . An improved understanding of the mechanistic insights of these effects may reveal a means to create tailored, precision treatment of several malignancies.…”

Section: String Database Defines the Functional Interaction Partners mentioning

confidence: 99%

HOXD8 exerts a tumor-suppressing role in colorectal cancer as an apoptotic inducer

Mansour

Senga

2017

The International Journal of Biochemistry & Cell Biology

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Homeobox (HOX) genes are conserved transcription factors which determine the anterior-posterior body axis patterning. HOXD8 is a member of HOX genes deregulated in several tumors such as lung carcinoma, neuroblastoma, glioma and colorectal cancer (CRC) in a context-dependent manner. In CRC, HOXD8 is downregulated in cancer tissues and metastatic foci as compared to normal tissues. Whether HOXD8 acts as a tumor suppressor of malignant progression and metastasis is still unclear. Also, the underlying mechanism of its function including the downstream targets is totally unknown. Here, we clarified the lower expression of HOXD8 in clinical colorectal cancer vs. normal colon tissues. Also, we showed that stable expression of HOXD8 in colorectal cancer cells significantly reduced the cell proliferation, anchorage-independent growth and invasion. Further, using The Cancer Genome Atlas (TCGA), we identified the genes associated with HOXD8 in order to demonstrate its function as a suppressor or a promoter of colorectal carcinoma. Among inversely related genes, apoptotic inhibitors like STK38 kinase and MYC were shown to be negatively associated with HOXD8. We demonstrated the ability of HOXD8 to upregulate executioner caspases 6 & 7 and cleaved PARP, thus inducing the apoptotic events in colorectal cancer cells.

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Paired related homeobox 1 is associated with the invasive properties of glioblastoma cells

Cited by 19 publications

References 33 publications

LGR5 Is a Gastric Cancer Stem Cell Marker Associated with Stemness and the EMT Signature Genes NANOG, NANOGP8, PRRX1, TWIST1, and BMI1

LGR5 Is a Gastric Cancer Stem Cell Marker Associated with Stemness and the EMT Signature Genes NANOG, NANOGP8, PRRX1, TWIST1, and BMI1

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

HOXD8 exerts a tumor-suppressing role in colorectal cancer as an apoptotic inducer

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