Osteoponin Promoter Controlled by DNA Methylation: Aberrant Methylation in Cloned Porcine Genome

Shen, Chi–Yen; Tsou, Yung‐An; Chen, Hsiao‐Ling; Huang, Hung-Jin; Wu, Shinn-Chih; Cheng, Weijia; Chen, Calvin Yu-Chian; Chen, Chuan-Mu

doi:10.1155/2014/327538

Cited by 11 publications

(9 citation statements)

References 31 publications

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“…Thus overexpression of OPN appears to be due to transcriptional regulation. Treatment of SPP1 endogenous low-expressing Flo cells with 5-aza-2′-deoxycytidine (decitabine), an epigenetic modifier that inhibits DNA methyltransferase activity, resulted in detectable expression of the gene, whereas abundantly SPP1 -expressing H460 cells were not affected by treatment (Figure 1E ), suggesting that SPP1 expression could be epigenetically regulated, consistent with results recently reported in pigs [ 56 ].…”

Section: Resultssupporting

confidence: 88%

Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma

et al. 2015

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Esophageal adenocarcinoma (EAC) is often diagnosed at an advanced stage, thus understanding the molecular basis for EAC invasion and metastasis is critical. Here we report that SPP1/OPN was highly overexpressed in primary EACs and intracellularly localized to tumor cells. We further demonstrate that all known OPN isoforms (OPNa, b, c, 4 and 5) were frequently co-overexpressed in primary EACs. Distinct pro-invasion and dissemination phenotypes of isoform-specific OPNb and OPNc stable transfectants were observed. Expression of OPNb significantly enhanced cell migration and adhesion to laminin. In contrast, OPNc cells showed significantly decreased cell migration yet increased cell detachment. Enhanced invasion, both in vitro and in vivo, was observed for OPNb- but not OPNc-expressing cells. Inhibition of RGD integrins, one family of OPN receptors, attenuated OPNb cell migration, abrogated OPNb cell adhesion and significantly reduced OPNb cell clonogenic survival but did not affect OPNc phenotypes, indicating that OPNb but not OPNc acts through integrin-dependent signaling. Differential expression of vimentin, E-cadherin and β-catenin in OPN stable cells may account for the variation in cell adhesion and detachment between these isoforms. We conclude that while all OPN isoforms are frequently co-overexpressed in primary EACs, isoforms OPNb and OPNc enhance invasion and dissemination through collective yet distinct mechanisms.

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Section: Resultssupporting

confidence: 88%

Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma

et al. 2015

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“…Inhibition of CDK4/6 extended OPN expression upon removal from stiffness, yet it did not induce expression de novo in soft-preconditioned cells that had already lost their memory (Fig.3n). Similar results were obtained when we inhibited DNMT1 (Fig.3n), which is also consistent with reports showing OPN expression is regulated by promoter methylation 31 . Together, these results suggest that in mechanically-sensitive cells, RUNX2 activity is associated with the maintenance of mechanical memory, and low-proliferative cells possess more durable mechanical memory.…”

supporting

confidence: 92%

Breast tumor stiffness instructs bone metastasis via mechanical memory

Watson

Grant

Parker

et al. 2019

Preprint

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The mechanical microenvironment of primary breast tumors plays a substantial role in promoting tumor progression 1 . While the transitory response of cancer cells to pathological stiffness in their native microenvironment has been well described 2 , it is still unclear how mechanical stimuli in the primary tumor influence distant, late-stage metastatic phenotypes across time and space in absentia. Here, we show that primary tumor stiffness promotes stable, nongenetically heritable phenotypes in breast cancer cells. This "mechanical memory" instructs cancer cells to adopt and maintain increased cytoskeletal dynamics, traction force, and 3D invasion in vitro, in addition to promoting osteolytic bone metastasis in vivo. Furthermore, we established a mechanical conditioning (MeCo) score comprised of mechanically-regulated genes as a global gene expression measurement of tumor stiffness response. Clinically, we show that a high MeCo score is strongly associated with bone metastasis in patients. Using a discovery approach, we mechanistically traced mechanical memory in part to ERK-mediated mechanotransductive activation of RUNX2, an osteogenic gene bookmarker and bone metastasis driver 3,4 . The combination of these RUNX2 traits permits the stable transactivation of osteolytic target genes that remain upregulated after cancer cells disseminate from their activating microenvironment in order to modify a distant microenvironment. Using genetic, epigenetic, and functional approaches, we were able to simulate, repress, select and extend RUNX2-mediated mechanical memory and alter cancer cell behavior accordingly. In concert with previous studies detailing the influence of biochemical properties of the primary tumor stroma on distinct metastatic phenotypes 5-9 , our findings detailing the influence of biomechanical properties support a generalized model of cancer progression in which the integrated properties of the primary tumor microenvironment govern the secondary tumor microenvironment, i.e., soil instructs soil.

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“…Another limitation to our study is that we only assessed one mechanism of EGCG’s effects. It is well known that EGCG can epigenetically modify protein expression through interaction with DNA methyltransferase [53] and that OPN expression can be modified through this same modality [54]. Furthermore, in vivo analysis did not directly assess the effects of miRNAs on OPN expression and hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis

et al. 2016

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Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury.

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Osteoponin Promoter Controlled by DNA Methylation: Aberrant Methylation in Cloned Porcine Genome

Cited by 11 publications

References 31 publications

Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma

Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma

Breast tumor stiffness instructs bone metastasis via mechanical memory

Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis

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