Abstract:Human Hox genes (Homeobox) have crucial roles in development and differentiation, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrant expression of Hoxc6 gene has been reported in several tumor tissues and cancer cell lines. The prognostic significance of Hoxc6 in gastric cancer remains largely unknown.This study was aimed to investigate the clinical significance of Hoxc6 in gastric cancer.Total RNA of paired tissue samples (n=25) and a t… Show more
“…Transcription factor HOXC6 is a member of a highly conserved homeobox family of transcription factors that play an important role in proliferation as well as in morphogenesis and metastasis and regulates genes with both oncogenic and tumor suppressor activities and may contribute to the progression of gastric carcinogenesis [30]. Recently was shown that knockdown of endothelial PAS domain protein 1 (EPAS1), which also known as hypoxiainducible transcription factor-2alpha (HIF-2α), as well as HIF-1α decreased cell proliferation under normoxic as well as hypoxic conditions in pulmonary vascular endothelial cells and that EPAS1/HIF-2α and SOX9 regulate TUBB3 gene expression and affect ovarian cancer aggressiveness [31]. Moreover, the expression of EPAS1 gene was significantly correlated with tumor size, invasion, and necrosis as well as with VEGF gene expression, which supported the correlation of EPAS1 up-regulation with tumor angiogenesis [32].…”
Glycolysis and glutaminolysis as well as endoplasmic reticulum stress are required for tumor progression suggests through regulation of the cell cycle. Inhibition of ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1/inositol requiring enzyme 1), a central mediator of endoplasmic reticulum stress, significantly suppresses glioma cell proliferation and tumor growth as well as modifies sensitivity gene expressions to glucose and glutamine deprivation. We have studied the expression of genes encoded transcription factors such as E2F8 (E2F transcription factor 8), EPAS1 (endothelial PAS domain protein 1), HOXC6 (homeobox C6), TBX3 (T-box 3), TBX2 (T-box 2), GTF2F2 (general transcription factor IIF), GTF2B (general transcription factor IIB), MAZ (MYC-associated zinc finger protein, purine-binding transcription factor), SNAI2 (snail family zinc finger 2), TCF3 (transcription factor 3), and TCF8/ZEB1 (zinc finger E-box binding homeobox 1)in U87 glioma cells upon glucose and glutamine deprivation in relation to inhibition of IRE1.We demonstrated that glutamine deprivation leads to up-regulation of the expression of EPAS1, TBX3, GTF2B, and MAZ genes and down-regulation of E2F8, GTF2F2, TCF8, and TBX2 genes in control glioma cells.At the same time, glucose deprivation enhances the expression of EPAS1 and GTF2B genes and decreases of E2F8, HOXC6, TCF3, and TBX2 genes in these glioma cells. Inhibition of IRE1 by dnIRE1 significantly modifies the expression most of studied genes with different magnitude. Present study demonstrates that fine-tuning of the expression of proliferation related transcription factor genes depends upon glucose and glutamine deprivation in IRE1-dependent manner and possibly contributes to slower tumor growth after inhibition of IRE1.
“…Transcription factor HOXC6 is a member of a highly conserved homeobox family of transcription factors that play an important role in proliferation as well as in morphogenesis and metastasis and regulates genes with both oncogenic and tumor suppressor activities and may contribute to the progression of gastric carcinogenesis [30]. Recently was shown that knockdown of endothelial PAS domain protein 1 (EPAS1), which also known as hypoxiainducible transcription factor-2alpha (HIF-2α), as well as HIF-1α decreased cell proliferation under normoxic as well as hypoxic conditions in pulmonary vascular endothelial cells and that EPAS1/HIF-2α and SOX9 regulate TUBB3 gene expression and affect ovarian cancer aggressiveness [31]. Moreover, the expression of EPAS1 gene was significantly correlated with tumor size, invasion, and necrosis as well as with VEGF gene expression, which supported the correlation of EPAS1 up-regulation with tumor angiogenesis [32].…”
Glycolysis and glutaminolysis as well as endoplasmic reticulum stress are required for tumor progression suggests through regulation of the cell cycle. Inhibition of ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1/inositol requiring enzyme 1), a central mediator of endoplasmic reticulum stress, significantly suppresses glioma cell proliferation and tumor growth as well as modifies sensitivity gene expressions to glucose and glutamine deprivation. We have studied the expression of genes encoded transcription factors such as E2F8 (E2F transcription factor 8), EPAS1 (endothelial PAS domain protein 1), HOXC6 (homeobox C6), TBX3 (T-box 3), TBX2 (T-box 2), GTF2F2 (general transcription factor IIF), GTF2B (general transcription factor IIB), MAZ (MYC-associated zinc finger protein, purine-binding transcription factor), SNAI2 (snail family zinc finger 2), TCF3 (transcription factor 3), and TCF8/ZEB1 (zinc finger E-box binding homeobox 1)in U87 glioma cells upon glucose and glutamine deprivation in relation to inhibition of IRE1.We demonstrated that glutamine deprivation leads to up-regulation of the expression of EPAS1, TBX3, GTF2B, and MAZ genes and down-regulation of E2F8, GTF2F2, TCF8, and TBX2 genes in control glioma cells.At the same time, glucose deprivation enhances the expression of EPAS1 and GTF2B genes and decreases of E2F8, HOXC6, TCF3, and TBX2 genes in these glioma cells. Inhibition of IRE1 by dnIRE1 significantly modifies the expression most of studied genes with different magnitude. Present study demonstrates that fine-tuning of the expression of proliferation related transcription factor genes depends upon glucose and glutamine deprivation in IRE1-dependent manner and possibly contributes to slower tumor growth after inhibition of IRE1.
“…The expression of fz2, hoxc6a, tcf3b and wnt5b was much higher in whsc1 −/− zebrafishes than that in wild-type ones (Figure 7). Coincidently, abnormal expression of hoxc6a
[23], [24], [25] and wnt5b
[26], [27], [28] have been shown to be related with cancers.Figure 7 whsc1 −/− zebrafish exhibited disordered expression of genes involved in swim bladder formation. mRNA levels of indicated genes were normalized to b-actin.…”
Wolf–Hirschhorn syndrome candidate 1 (WHSC1) is a histone 3 lysine 36 (H3K36) specific methyltransferase that is frequently deleted in Wolf–Hirschhorn syndrome (WHS). Whsc1 is also found mutated in a subgroup of B-cell derived malignant diseases by genomic translocation or point mutation, both of which resulted in hyperactivity of WHSC1 mediated H3K36 methylation and uncontrolled cell proliferation, suggesting that whsc1 functions as an oncogene. However, here we provided evidences to show that whsc1 also has tumor suppressor functions. We used zebrafish as an in vivo model and generated homozygous whsc1 mutant lines via clustered regularly interspaced short palindromic repeats-associated protein Cas9 (CRISPR/Cas9) technology. Then western-blot (WB) and immunofluorescence (IF) were performed to analysis the expression level of H3K36Me2 and H3K36Me3, and we identified the diseased tissue via hematoxylin–eosin (HE) staining, IF staining or immunohistochemistry (IHC). Whsc1 lose-of-function led to significant decrease in di- and tri-methylation of H3K36. A series of WHS related phenotypes were found in whsc1−/− zebrafish, including growth retardation, neural development defects and heart failure. In addition, loss of function of whsc1 led to defects in the development of swim bladder, possibly through the dis-regulation of key genes in swim bladder organogenesis and inhibition of progenitor cell differentiation, which was correlated with its expression in this organ during embryonic development. At later stage, these whsc1−/− zebrafishes are inclined to grow tumors in the swim bladder. Our work suggested that whsc1 may function as a tumor suppressor by governing progenitor cell differentiation.
“…ACTB (β-actin) from Santa Cruz Biotechnology was used as control of analyzed protein quantity in extracts of glioma cells. Western blot analysis was performed as described previously [34].…”
Section: Methodsmentioning
confidence: 99%
“…Transcription factor HOXC6 is a member of a highly conserved homeobox family of transcription factors that play an important role in proliferation as well as in morphogenesis and metastasis and regulate genes with both oncogenic and tumor suppressor activities and may contribute to the progression of gastric carcinogenesis [27,33,34]. Recently it was shown that the forkhead box transcription factor FOXF1 is a target of the TP53 family and its ectopic expression inhibits cancer cell invasion and migration, whereas the inactivation of FOXF1 stimulated both these processes [28,35].…”
Section: Hypoxia As Well As the Endoplasmic Reticulum Stress Are Impomentioning
confidence: 99%
“…1-3) and that blockade of ERN1 signaling enzyme function strongly decreases the level of these gene expressions as well as modifies its expression level. Transcription factor HOXC6 predominantly has pro-proliferative functions, plays an important role in proliferation as well as in morphogenesis and metastasis and its up-regulation upon hypoxia may contribute to tumor growth [27,34]. At the same time, blockade of ERN1 signaling enzyme function decreases HOXc6 gene expression as well as removes its hypoxic regulation (Fig.…”
Section: Fig 1 Effect Of Hypoxia On the Expression Of Hoxc6 (Homeobmentioning
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