A positive feedback regulatory loop involving the lncRNA PVT1 and HIF-1α in pancreatic cancer.
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ABSTRACT:
SUBMITTER: Zhu Y
PROVIDER: S-EPMC8648389 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
2021-01-19 | GSE159490 | GEO
Project description:Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play important roles in human diseases, including cancer; however, only a few of them have been experimentally validated and functionally annotated. Here, we identify a novel lncRNA that we term HITT (HIF-1α inhibitor at translation level). HITT is commonly decreased in multiple human cancers. Decreased HITT is associated with advanced stages of colon cancer. Restoration of the expression of HITT in cancer cells inhibits angiogenesis and tumor growth in vivo in an HIF-1α-dependent manner. Further study reveals that HITT inhibits HIF-1α expression, mainly by interfering with its translation. Mechanically, HITT titrates away YB-1 from the 5'-UTR of HIF-1α mRNA via a high-stringency YB-1-binding motif. The reverse correlation between HITT and HIF-1α expression is further validated in human colon cancer tissues. Moreover, HITT is one of the most altered lncRNAs upon the hypoxic switch and HITT downregulation is required for hypoxia-induced HIF-1α expression. We further demonstrate that HITT and HIF-1α form an autoregulatory feedback loop where HIF-1α destabilizes HITT by inducing MiR-205, which directly targets HITT for degradation. Together, these results expand our understanding of the cancer-associated functions of lncRNAs, highlighting the HITT-HIF-1α axis as constituting an additional layer of regulation of angiogenesis and tumor growth, with potential implications for therapeutic targeting.
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Project description:Rationale: Emerging evidences have highlighted the critical roles of lncRNAs in human cancer development. The work sought to assess the biological role and potential underlying mechanisms of lncRNA-CF129 (CF129) which is significantly reduced in pancreatic cancer (PC). Methods: CF129 expression and its association with multiple clinicopathologic characteristics in PC specimens were analyzed. The role of CF129 both in vitro and in vivo was assessed, with RNA pull-down and immunoprecipitation assays being performed to detect the interaction between CF129 and p53 and E3 ligase MKRN1. Chromatin immunoprecipitation and luciferase assays were utilized to identify the interaction between p53 and FOXC2 promoter, HIF-1α/HDAC1 complex and CF129 promoter, FOXC2 and HIF-1α promoter, respectively. Results: CF129 levels were markedly lower in PC compared with paired non-tumor adjacent tissues. Low CF129 expression predicted short overall survival in PC patients. CF129 inhibited invasion and metastasis of PC cells in a FOXC2-dependent manner. In addition, CF129 regulates FOXC2 transcription through association with mutant p53. CF129 directly binds to p53 and E3 ligase MKRN1, and such an interaction leading to p53 protein ubiquitination and degradation. Furthermore, CF129 is a hypoxia-responsive lncRNA, which is transcriptionally downregulated by binding between HIF-1α/HDAC1 complex and CF129 promoter. Finally, it is revealed that HIF-1α is reciprocally regulated by FOXC2 in transcriptional level. Clinically, CF129 downregulation coordinates overexpression of FOXC2. Conclusions: Our study suggests that CF129 inhibits pancreatic cell proliferation and invasion by suppression of FOXC2 transcription, which depends on MKRN1-mediated ubiquitin-dependent p53 degradation. The HIF-1α/CF129/ p53/FOXC2 axis may function as a potential biomarker and therapeutic target.
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Project description:Background: Non-small cell lung cancer (NSCLC) is the most common malignancy worldwide. MiR-199a-5p has been reported to play important roles in multiple tumors, inclusive of NSCLC. However, little is definitively known pertaining to its explicit mechanism of action in NSCLC. Methods: The expressions of miR-199a-5p and hypoxia-inducible factor-1α (HIF-1α) mRNA were quantified employing qRT-PCR. H1299 and A549 cells were transiently transfected with miR-199a-5p mimics or inhibitors. Then, CCK-8 assays, flow cytometry analysis, and Transwell assay were performed for detecting cell proliferation, cell cycle, apoptosis, migration, and invasion of NSCLC cells, respectively. HIF-1α, signal transducer and activator of transcription 3 (STAT3), and p-STAT3 expressions were detected via Western blotting. Bioinformatic analysis and dual-luciferase assay were performed to investigate the interactions among miR-199a-5p, HIF-1α, and STAT3. Xenograft models were established with nude mice for further analyzing the bevacizumab resistance of NSCLC cells. Results: MiR-199a-5p expression was markedly attenuated in NSCLC tissues and cell lines. Overexpression of miR-199a-5p repressed the proliferation, migration, and invasion but induced the apoptosis of NSCLC cells. HIF-1α was identified as a direct target of miR-199a-5p. There was a positive feedback loop among miR-199a-5p, HIF-1α, and STAT3. Co-transfection of HIF-1α or STAT3 overexpression plasmids counteracted the effects of miR-199a-5p. In vivo experiments indicated that the feedback loop was in association with the bevacizumab resistance of NSCLC cells. Conclusion: MiR-199a-5p blocked the progression of NSCLC and sensitized NSCLC cells to bevacizumab by suppressing HIF-1α and STAT3, while the HIF-1α/STAT3 axis suppressed the expression of miR-199a-5p, which forms a positive feedback loop to promote the sustaining progression of NSCLC.
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Project description:Irreversible pulmonary fibrosis induced by paraquat (PQ) poisoning is the major cause of death in patients with PQ poisoning. The epithelial-mesenchymal transition (EMT) is postulated to be one of the main mechanisms of pulmonary fibrosis. Here, we investigated the role of miR-210 in PQ-induced EMT and its relationship with hypoxia-inducible factor-1α (HIF-1α). Western blotting, immunofluorescence, immunoprecipitation and other methods were used in this study. We found that miR-210 expression was significantly increased after PQ poisoning, and it may be regulated by HIF-1α. Overexpression of miR-210 further increased the HIF-1α protein level and promoted EMT. Moreover, miR-210 knock-down reduced the HIF-1α protein level and decreased the degree of EMT. Runt-related transcription factor-3 (RUNX3), a direct target of miR-210, was inhibited by miR-210 in response to PQ poisoning. RUNX3 increased the hydroxylation ability of prolyl hydroxylase domain-containing protein 2 (PHD2), a key enzyme that promotes HIF-1α degradation. PHD2 immunoprecipitated with RUNX3 and its level changed similarly to that of RUNX3. The expression of the HIF-1α protein was significantly reduced when RUNX3 was overexpressed. HIF-1α protein levels were markedly increased when RUNX3 was silenced. Based on these results, a positive feedback loop may exist between miR-210 and HIF-1α. The mechanism may function through miR-210-mediated repression of RUNX3, which further decreases the hydroxylation activity of PHD2, enhances the stability of HIF-1α, and promotes PQ-induced EMT, aggravating the progression of pulmonary fibrosis. This study further elucidates the mechanism of PQ-induced pulmonary fibrosis and may provide a new perspective for the future development of therapies.
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Project description:Long noncoding RNAs (lncRNAs) play important roles in regulating the development and progression of many cancers. However, the clinical significance of specific lncRNAs in the context of nasopharyngeal carcinoma (NPC) and the molecular mechanisms by which they regulate this form of cancer remain largely unclear. In this study we found that the lncRNA PVT1 was upregulated in NPC, and that in patients this upregulation was associated with reduced survival. RNA sequencing revealed that PVT1 was responsible for regulating NPC cell proliferation and for controlling a hypoxia-related phenotype in these cells. PVT1 knockdown reduced NPC cell proliferation, colony formation, and tumorigenesis in a subcutaneous mouse xenograft model systems. We further found that PVT1 serves as a scaffold for the chromatin modification factor KAT2A, which mediates histone 3 lysine 9 acetylation (H3K9), recruiting the nuclear receptor binding protein TIF1β to activate NF90 transcription, thereby increasing HIF-1α stability and promoting a malignant phenotype in NPC cells. Overexpression of NF90 or HIF-1α restored the proliferation in cells that had ceased proliferating due to PVT1 or KAT2A depletion. Conversely, overexpression of active KAT2A or TIF1β, but not of KAT2A acetyltransferase activity-deficient mutants or TIF1β isoforms lacking H3K9ac binding sites, promoted a PVT1-mediated increase in NF90 transcription, as well as increased HIF-1α stability and cell proliferation. PVT1 knockdown enhanced the radiosensitization effect in NPC cells via inhibiting binding between H3K9ac and TIF1β in a manner. Taken together, our results demonstrate that PVT1 serves an oncogenic role and plays an important role in radiosensitivity in malignant NPC via activating the KAT2A acetyltransferase and stabilizing HIF-1α.
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Project description:Background: Pancreatic cancer is a malignancy with poor prognosis. Importin 7 (IPO7) is a soluble nuclear transport factor, which has been linked to the pathogenesis of several human diseases. However, its role and underlying mechanism in pancreatic cancer are still obscure. Methods: Immunohistochemical staining and quantitative real-time polymerase chain reaction (qPCR) were performed to determine IPO7 expression in pancreatic cancer tissues and adjacent tissues. Western blot was used to measure IPO7 expression at the protein level in cell lines. Cell Counting Kit-8 (CCK-8), 5-bromo-2'-deoxyuridine (BrdU), flow cytometry, and Transwell assays were employed to explore the biological functions of IPO7. Subcutaneous xenograft transplanted tumor model and caudal vein injection model in mice were also established to validate the oncogenic role of IPO7. Western blot and qPCR were utilized to detect the regulatory function of IPO7 on p53 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), respectively. Interaction between MALAT1 and miR-129-5p and interaction between miR-129-5p and IPO7 were verified by bioinformatics prediction, qPCR, dual-luciferase reporter gene experiment, RNA immunoprecipitation (RIP), and pull-down assay. Results: Upregulation of IPO7 in pancreatic cancer tissues was associated with adverse prognosis of the patients with pancreatic cancer. Knocking down IPO7 remarkably suppressed cancer cell proliferation and metastasis, while it promoted apoptosis. Overexpression of IPO7 facilitated the malignant phenotypes of pancreatic cancer cells. Mechanistically, IPO7 could repress the expression of p53 and induce the expression of MALAT1 but reduce miR-129-5p expression. Furthermore, miR-129-5p was identified as a posttranscriptional regulator for IPO7, and its inhibition led to IPO7 overexpression in pancreatic cancer cells. Conclusion: IPO7 is a novel oncogene for pancreatic cancer, and IPO7/p53/MALAT1/miR-129-5p positive feedback loop facilitates the progression of this deadly disease.
| S-EPMC8517143 | biostudies-literature