Chronic stress stimulated HIF-AS3/HIF-1α loop in neoplastic cells and promoted lung cancer progression through macrophage inactivation [A549_xenograft]
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ABSTRACT:
PROVIDER: PRJNA1212021 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32033808_1.fastq.gz | Fastqsanger.gz | |||
| SRR32033808_2.fastq.gz | Fastqsanger.gz | |||
| SRR32033809_1.fastq.gz | Fastqsanger.gz | |||
| SRR32033809_2.fastq.gz | Fastqsanger.gz | |||
| SRR32033810_1.fastq.gz | Fastqsanger.gz |
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Project description:Chronic psychological stress is closely linked to malignant disorders, with novel modulators potentially mitigating tumor progression by regulating interactions between neoplastic cells and immune cells. This study identified lncRNA HIF1A-AS3 as a key driver of stress-induced lung cancer progression. Chronic stress models in mice with implanted lung cancer cells revealed significant upregulation of HIF1A-AS3 in stressed groups and human lung cancer tissues. Functional studies showed HIF1A-AS3 promotes cancer cell proliferation and invasion by activating HIF-1ɑ translation through interaction with YBX1, forming a positive feedback loop where HIF-1ɑ enhances HIF1A-AS3 transcription. Additionally, HIF1A-AS3 drove macrophage M2 polarization and reduced phagocytosis under hypoxia. Targeting the HIF1A-AS3/HIF-1ɑ loop effectively counteracted stress-induced lung cancer progression in vivo, highlighting its potential as a diagnostic and therapeutic target for stress-exacerbated lung cancer.
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Project description:Chronic psychological stress is closely linked to malignant disorders, with novel modulators potentially mitigating tumor progression by regulating interactions between neoplastic cells and immune cells. This study identified lncRNA HIF1A-AS3 as a key driver of stress-induced lung cancer progression. Chronic stress models in mice with implanted lung cancer cells revealed significant upregulation of HIF1A-AS3 in stressed groups and human lung cancer tissues. Functional studies showed HIF1A-AS3 promotes cancer cell proliferation and invasion by activating HIF-1ɑ translation through interaction with YBX1, forming a positive feedback loop where HIF-1ɑ enhances HIF1A-AS3 transcription. Additionally, HIF1A-AS3 drove macrophage M2 polarization and reduced phagocytosis under hypoxia. Targeting the HIF1A-AS3/HIF-1ɑ loop effectively counteracted stress-induced lung cancer progression in vivo, highlighting its potential as a diagnostic and therapeutic target for stress-exacerbated lung cancer.
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Project description:Chronic stress stimulated HIF-AS3/HIF-1α loop in neoplastic cells and promoted lung cancer progression through macrophage inactivation [A549 and H1299]
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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-1α in colon, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-1α+/+, Hif-1αLSL/LSL mice. Background & Aims: The progression and growth of solid tumors leads to a state where tumors outgrow their capacity for efficient oxygenation and nutrient uptake and an increase in tumor hypoxia. Tumor hypoxic response is mediated by hypoxia-inducible factor (HIF)-1a and HIF-2a. These transcription factors regulate a battery of genes that are critical for tumor oxygenation, tumor metabolism, and cell proliferation and survival. Therefore, inhibitors of HIF have been sought for as anti-neoplastic agents in several different kinds of cancers. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1a is beneficial, and can reduce intestinal inflammation. The efficacy of pharmacological agents that chronically activate HIF-1a are decreased due to the tumorigenic potential of HIF. However, recent advance in understanding HIF signaling have identified mechanisms, which could allow for isoform specific activators. Activation of HIF-2a increases colon carcinogenesis and progression in mouse models. However, the role of chronic HIF-1a activation is unclear in the progression in colon cancer. The present data demonstrates that activation of HIF-1a in epithelial cells does not increase colon carcinogens or progression in two mouse models of colon cancer, and provides the proof of principle that HIF-1a activation maybe safe as therapies for inflammatory bowel disease. Global gene expression profiling in colon RNAs isolated from 6- to 8-week-old Hif-1α+/+ (n=5, Shah 019) and Hif-1αLSL/LSL (n=5, Shah 020).
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2020-07-02 | PXD016630 | Pride
Project description:Hypoxia-inducible factor-1 (HIF-1) is a master regulator of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits PHD3 to PKM2 to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with hnRNPF to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly rescues their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-1α in colon, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-1α+/+, Hif-1αLSL/LSL mice. Background & Aims: The progression and growth of solid tumors leads to a state where tumors outgrow their capacity for efficient oxygenation and nutrient uptake and an increase in tumor hypoxia. Tumor hypoxic response is mediated by hypoxia-inducible factor (HIF)-1a and HIF-2a. These transcription factors regulate a battery of genes that are critical for tumor oxygenation, tumor metabolism, and cell proliferation and survival. Therefore, inhibitors of HIF have been sought for as anti-neoplastic agents in several different kinds of cancers. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1a is beneficial, and can reduce intestinal inflammation. The efficacy of pharmacological agents that chronically activate HIF-1a are decreased due to the tumorigenic potential of HIF. However, recent advance in understanding HIF signaling have identified mechanisms, which could allow for isoform specific activators. Activation of HIF-2a increases colon carcinogenesis and progression in mouse models. However, the role of chronic HIF-1a activation is unclear in the progression in colon cancer. The present data demonstrates that activation of HIF-1a in epithelial cells does not increase colon carcinogens or progression in two mouse models of colon cancer, and provides the proof of principle that HIF-1a activation maybe safe as therapies for inflammatory bowel disease.
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Project description:The identification of predictive markers to determine the premetastatic phase before metastasis is critical for developing effective strategies for early detection and prevention. By applying the dynamic network biomarker (DNB) approach to analyze time-series transcriptomic data from a pulmonary metastasis HCC mouse model, we revealed that the premetastatic phase occurred during the fourth week after implantation. A total of 142 DNB genes were identified as functionally important biomarkers of this critical phase, among which 60S ribosomal protein L6 (RPL6) was a core DNB member. RPL6 was significantly upregulated in HCC tissues with extrahepatic metastasis and was strongly correlated with poor prognosis in HCC patients. RPL6 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, RPL6 directly bound to the HMGCS1 mRNA 3’UTR, a rate-limiting enzyme in cholesterol biosynthesis, thus increasing HMGCS1 mRNA stability and protein expression and subsequently elevating intracellular cholesterol level. Elevated cholesterol inhibited of the ubiquitin-dependent degradation of HIF-1α by binding to PHD2 and reducing PHD2-mediated hydroxylation of HIF-1α, which further resulted in HIF-1α signaling pathway activation. Moreover, RPL6, HMGCS1 and HIF-1α were coexpressed in HCC tissues with extrahepatic metastasis. Taken together, this study provides new insights into the dynamic transcriptome profiles of HCC pulmonary metastasis and establishes an important role for the RPL6-HMGCS1-HIF-1α axis in HCC metastasis, suggesting potential prognostic biomarkers and therapeutic targets in HCC.
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