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The Estrogen Receptor variants β2 and β5 Induce Stem Cell Characteristics and Chemotherapy Resistance in Prostate Cancer through activation of Hypoxic Signaling

ABSTRACT: The Estrogen Receptor variants β2 and β5 Induce Stem Cell Characteristics and Chemotherapy Resistance in Prostate Cancer through activation of Hypoxic Signaling

PROVIDER: PRJNA485690 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7687650.fastq.gz	Fastqsanger.gz
	SRR7687651.fastq.gz	Fastqsanger.gz
	SRR7687652.fastq.gz	Fastqsanger.gz
	SRR7687653.fastq.gz	Fastqsanger.gz
	SRR7687648.fastq.gz	Fastqsanger.gz

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The Estrogen Receptor variants β2 and β5 Induce Stem Cell Characteristics and Chemotherapy Resistance in Prostate Cancer through activation of Hypoxic Signaling

Project description:Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer’s stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer’s stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.

2018-08-14 | GSE118449 | GEO

The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling.

Project description:Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer's stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated Notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer's stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.

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Hypoxic microenvironment activates GLI2 through synergistic action of TGF-β2 and HIF-1α to confer chemoresistance and poor clinical outcome in colorectal cancer [IlluminaExpr_2_CAF_SF_SD208]

Project description:Microenvironment has been suggested as an important factor contributing to how the colorectal cancer cells escape therapy, but the exact mechanism leading to chemoresistance remains elusive. Here, through modeling in vitro by cocultivation of patient-derived cancer associated fibroblasts (CAFs) with cancer stem cells (CSCs), we show that CAFs-secreted TGF-β2 is a key stromal factor that coordinates with hypoxia to promote CSC stemness and resistance to chemotherapy. GLI2, a key transcription factor of Hedgehog pathway, was identified as both necessary and sufficient in this process in which TGF-β and hypoxia-inducible factor (HIF-1α) synergize to directly induce GLI2 expression. Conversely, CSC-secreted TGF-β is also important to support the growth of CAFs but instead induce death of normal fibroblasts, suggesting a reciprocal mechanism to selectively support the CAF-CSC interaction. Small molecule inhibition of both TGF-β and GLI2 effectively reversed the chemoresistance. Finally, expression of TGFB2/HIF1A/GLI2 gene signature as a functional readout of this resistance pathway defines worse clinical outcomes and predicts patients relapse. Our observations uncover a key role of TGF-β/HIF-1α/GLI2 in microenvironment-mediated chemoresistance and reveal novel biomarker and targeting strategies to identify and treat the high risk CRC patients.

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Quiescent ovarian cancer cells, in response to chemotherapy, secrete follistatin to induce chemotherapy resistance in surrounding cells.

Project description:Quiescent ovarian cancer cells, in response to chemotherapy, secrete follistatin to induce chemotherapy resistance in surrounding cells.

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β2→1-fructans modulate the immune system in vivo in a microbiota-dependent and -independent fashion

Project description:It has been shown in vitro that only specific dietary-fibers contribute to immunity but studies in vivo are not conclusive. Here we investigated degree of polymerization (DP) dependent effects of β2→1-fructans on immunity via microbiota-dependent and -independent effects. To this end, conventional or germ-free mice received short- or long-chain β2→1-fructan for 5 days. Immune cell populations in the spleen, mesenteric lymph nodes (MLN), and Peyer's patches (PPs) were analyzed with flow cytometry, genome-wide gene expression in the ileum was measured with microarray, and gut microbiota composition was analyzed with 16S rRNA sequencing of fecal samples. We found that β2→1-fructans modulated immunity by both microbiota and microbiota-independent effects. Moreover, effects were dependent on the chain-length of the β2→1-fructans type polymer. Both short- and long-chain β2→1-fructans enhanced T-helper 1 cells in Peyer's patches, whereas only short-chain β2→1-fructans increased regulatory T cells and CD11b-CD103- DCs in the MLN. A common feature after short- and long-chain β2→1-fructan treatment was enhanced Fut2 expression and other IL-22-dependent genes in the ileum of conventional mice. These effects were not associated with shifts in gut microbiota composition, or altered production of short-chain fatty acids. Both short- and long-chain β2→1-fructans also induced immune effects in germ-free animals, demonstrating direct effect independent from the gut microbiota. Also, these effects were dependent on the chain-length of the β2→1-fructans. Short-chain β2→1-fructan induced lower CD80 expression by CD11b-CD103- DCs in PPs, whereas long-chain β2→1-fructan specifically modulated B cell responses in germ-free mice. In conclusion, support of immunity is determined by the chemical structure of β2→1-fructans and is partially microbiota-independent.

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Molecular Characteristics and Biological Functions of Hypoxic Microenvironment in Hepatocellular Carcinoma

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