scholarly journals MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2

2019 ◽  
Vol 316 (3) ◽  
pp. L547-L557 ◽  
Author(s):  
Ruifeng Zhang ◽  
Hua Su ◽  
Xiuqing Ma ◽  
Xiaoling Xu ◽  
Li Liang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Hypoxia Inducible Factor ◽  
Underlying Mechanism ◽  
Pulmonary Vessel ◽  
Hypoxic Pulmonary Hypertension ◽  
And Migration ◽  
Ventricle Hypertrophy ◽  
Proliferation And Migration

Angiotensin-converting enzyme 2 (ACE2) protects against hypoxic pulmonary hypertension (HPH) by inhibiting the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Under hypoxia, the hypoxia-inducible factor 1α (HIF-1α) inhibits ACE2 indirectly; however, the underlying mechanism is unclear. In the present study, we found that exposure to chronic hypoxia stimulated microRNA (miRNA) let-7b expression in rat lung via a HIF-1α-dependent pathway. Let-7b downregulated ACE2 expression by directly targeting the coding sequence of ACE2. Our in vitro and in vivo results revealed that let-7b contributed to the pathogenesis of HPH by inducing PASMCs proliferation and migration. Let-7b knockout mitigated right ventricle hypertrophy and pulmonary vessel remodeling in HPH by restoring ACE2 expression. Overall, we demonstrated that HIF-1α inhibited ACE2 expression via the HIF-1α-let-7b-ACE2 axis, which contributed to the pathogenesis of HPH by stimulating PASMCs proliferation and migration. Since let-7b knockout alleviated the development of HPH, let-7b may serve as a potential clinical target for the treatment of HPH.

Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension

2014 ◽  
Vol 306 (6) ◽  
pp. L574-L583 ◽  
Author(s):  
Ruifeng Zhang ◽  
Liuhong Shi ◽  
Lin Zhou ◽  
Gensheng Zhang ◽  
Xiaohong Wu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lentiviral Vector ◽  
Hypoxia Inducible Factor ◽  
Systolic Pressure ◽  
Cellular Migration ◽  
Regulation Mechanism ◽  
Migration Ability ◽  
Pulmonary Vessel ◽  
Hypoxic Pulmonary Hypertension

We previously observed that transgelin was preferentially expressed in human pulmonary arterial smooth muscle cells (PAMSCs) under hypoxia and that the upregulation of transgelin was independent of hypoxia-inducible factor 1α (HIF-1α). Reduced transgelin expression was accompanied by significantly impaired migration ability in vitro. However, the regulation mechanism of transgelin and its function in preventing hypoxic pulmonary hypertension (HPH) was unclear. In the present study, RNA interference with hypoxia-inducible factor 2α (HIF-2α) was employed in human PASMCs. Transgelin expression was diminished in HIF-2α-siRNA-treated cells at both the mRNA and protein levels under hypoxia. However, HIF-2α did not transactivate the transgelin promoter directly. TGF-β1 concentration in human PASMCs culture medium was higher under hypoxia, and the accumulated TGF-β1 under hypoxia was regulated by HIF-2α. Furthermore, luciferase and chromatin immunoprecipitation assays indicated that TGF-β1/Smad3 could bind to the transgelin promoter, resulting in increased transgelin expression. In addition to nonintact cellular migration, inhibition of transgelin expression resulted in impaired proliferation in vitro under hypoxia. A lentiviral vector used to inhibit transgelin expression was constructed and intratracheally instilled in rats 3 wk prior to hypoxia treatment. Our final results indicated that inhibition of transgelin expression locally could attenuate increased right ventricular systolic pressure and its associated cardiac and pulmonary vessel remodeling under hypoxia. Our findings indicate that HIF-2α upregulates transgelin indirectly and that accumulated TGF-β1 is a mediator in the upregulation of transgelin by HIF-2α under hypoxia. Inhibition of transgelin expression locally could prevent HPH and pulmonary vascular remodeling in vivo.

scholarly journals LOXL1-AS1 contributes to the proliferation and migration of laryngocarcinoma cells through miR-589-5p/TRAF6 axis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Guijun He ◽  
Wenfeng Yao ◽  
Liang Li ◽  
Yang Wu ◽  
Guojian Feng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Non Coding Rna ◽  
Reporter Assays ◽  
And Migration ◽  
Long Non Coding Rna ◽  
Proliferation And Migration

Abstract Background LOXL1-AS1 is a long non-coding RNA (lncRNA) that plays crucial roles in various cancers. However, the functional role of LOXL1-AS1 in laryngocarcinoma remains unclear. Thus we planned to probe into the function and underlying mechanism of LOXL1-AS1 in laryngocarcinoma. Methods Gene expression was evaluated in laryngocarcinoma cells using RT-qPCR. The ability of cell proliferation and migration was assessed by CCK8, colony formation, wound healing and transwell assays. The interaction among LOXL1-AS1, miR-589-5p and TRAF6 was detected by Ago2-RIP, RNA pull down and luciferase reporter assays. Results LOXL1-AS1 was overexpressed in laryngocarcinoma cells. Silencing of LOXL1-AS1 suppressed cell proliferation, migration and EMT in laryngocarcinoma. Moreover, miR-589-5p, the downstream of LOXL1-AS1, directly targeted TRAF6 in laryngocarcinoma. Importantly, LOXL1-AS1 augmented TRAF6 expression in laryngocarcinoma cells by sequestering miR-589-5p. Besides, miR-589-5p worked as a tumor-inhibitor while TRAF6 functioned as a tumor-facilitator in laryngocarcinoma. Of note, rescue experiments both in vitro and in vivo validated that LOXL1-AS1 aggravated the malignancy in laryngocarcinoma by targeting miR-589-5p/TRAF6 pathway. Conclusions LOXL1-AS1 promotes the proliferation and migration of laryngocarcinoma cells through absorbing miR-589-5p to upregulate TRAF6 expression.

scholarly journals IRF2 Destabilizes Oncogenic KPNA2 to Modulate the Tumorigenesis of Osteosarcoma via Regulating NF-κB/p65

2021 ◽  
Author(s):  
Shuchi Xia ◽  
Yiqun Ma
Keyword(s):  
Tumor Growth ◽  
Western Blot ◽  
Underlying Mechanism ◽  
Normal Human ◽  
And Migration ◽  
Oncogenic Function ◽  
Opposing Effect ◽  
Proliferation And Migration

Abstract Background: Osteosarcomas (OS) are the most frequent primary malignant bone tumor. Emerging evidence revealed that karyopherin alpha 2 (KPNA2) was strongly associated with the tumorigenesis and development of numerous human cancers. The aim of the present study was to investigate the expression pattern, biological functions and underlying mechanism of KPNA2 in OS. Methods: Bioinformatics TFBIND online was applied to forecast the transcription factor (TF) binding sites in the promoter region of KPNA2. The expression profile of KPNA2 in OS tissues were firstly assessed using TARGET dataset. The expression of KPNA2 in clinical OS samples and normal human adjacent samples were analyzed by RT-qPCR and western blot. CCK8, colony formation, wound-healing, and Transwell assays were used to assess cell viability, proliferation and migration in vitro, and in vivo experiments were performed to explore the effects of KPNA2 and interferon regulatory factor-2 (IRF2) on tumor growth. In addition, the correlation between IRF2 and KPNA2, and their roles on the NF-κB/p65 was investigated using chromatin immunoprecipitation (ChIP), RT-qPCR, western blot and dual-luciferase assays. Results: KPNA2 was obviously upregulated while IRF2 was significantly decreased in OS tissues and cell lines, as well as they were negatively correlated with each other. KPNA2 knockdown remarkably suppressed OS cell growth, migration, invasion in vitro and tumor growth in vivo, while IRF2 knockdown exerts an opposing effect. IRF2 binds to KPNA2 promoter to modulate the tumorigenic malignant phenotypes of OS via regulating NF-κB/p65 signaling. Conclusion: The present study demonstrated that KPNA2 performed the oncogenic function, possibly regulating tumorigenesis through NF-κB/p65 signaling pathway. Importantly, IRF2 was confirmed to serve a potential upstream TF of KPNA2 involving in the regulation of NF-κB/p65 pathway in OS.

scholarly journals Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jianye Xu ◽  
Jian Zhang ◽  
Zongpu Zhang ◽  
Zijie Gao ◽  
Yanhua Qi ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Autophagy Induction ◽  
Antitumor Immunotherapy ◽  
Novel Biomarkers ◽  
And Migration ◽  
Immunosuppressive Microenvironment ◽  
Proliferation And Migration ◽  
Glioma Progression

AbstractExosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

scholarly journals Cyr61 promotes Schwann cell proliferation and migration via αvβ3 integrin

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhenghui Cheng ◽  
Yawen Zhang ◽  
Yinchao Tian ◽  
Yuhan Chen ◽  
Fei Ding ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Peripheral Nerves ◽  
Molecular Mechanisms ◽  
Αvβ3 Integrin ◽  
Promoting Effect ◽  
Ccn Family ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background Schwann cells (SCs) play a crucial role in the repair of peripheral nerves. This is due to their ability to proliferate, migrate, and provide trophic support to axon regrowth. During peripheral nerve injury, SCs de-differentiate and reprogram to gain the ability to repair nerves. Cysteine-rich 61 (Cyr61/CCN1) is a member of the CCN family of matrix cell proteins and have been reported to be abundant in the secretome of repair mediating SCs. In this study we investigate the function of Cyr61 in SCs. Results We observed Cyr61 was expressed both in vivo and in vitro. The promoting effect of Cyr61 on SC proliferation and migration was through autocrine and paracrine mechanisms. SCs expressed αvβ3 integrin and the effect of Cyr61 on SC proliferation and migration could be blocked via αvβ3 integrin. Cyr61 could influence c-Jun protein expression in cultured SCs. Conclusions In this study, we found that Cyr61 promotes SC proliferation and migration via αvβ3 integrin and regulates c-Jun expression. Our study contributes to the understanding of cellular and molecular mechanisms underlying SC’s function during nerve injury, and thus, may facilitate the regeneration of peripheral nerves after injury.

scholarly journals Circular RNA hsa_circ_0006401 promotes proliferation and metastasis in colorectal carcinoma

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Chenjing Zhang ◽  
Xiaolu Zhou ◽  
Xiaoge Geng ◽  
Yu Zhang ◽  
Jingya Wang ◽  
...  
Keyword(s):  
Splice Junction ◽  
Circular Rna ◽  
Host Gene ◽  
Cell Counting ◽  
Tissue Samples ◽  
Proliferation And Metastasis ◽  
And Migration ◽  
Proliferation And Migration

AbstractDysregulation of circular RNA (circRNA) expression is involved in the progression of cancer. Here, we aimed to study the potential function of hsa_circ_0006401 in colorectal cancer (CRC). CircRNA hsa_circ_0006401 expression levels in CRC and adjacent nontumor tissues were analyzed by real-time quantitative PCR (qRT-PCR) and circRNA in situ hybridization (RNA-ISH). Then, CRC cell proliferation was assessed by cell counting. Wound-healing and transwell assays were utilized to detect the effect of hsa_circ_0006401 on CRC migration. A circRNA-ORF construct was created, and a specific antibody against the splice junction of hsa_circ_0006401 was prepared. Finally, the proteins directly binding to hsa_circ_0006401 peptides were identified by immunoprecipitation combined with mass spectrometry. In our study, we found hsa_circ_0006401 was closely related to CRC metastasis and exhibited upregulated expression in metastatic CRC tissue samples. Proliferation and migration were inhibited in vitro when hsa_circ_0006401 expression was silenced. Downregulation of hsa_circ_0006401 expression decreased CRC proliferation and liver metastasis in vivo. A 198-aa peptide was encoded by sequences of the splice junction absent from col6a3. Hsa_circ_0006401 promoted CRC proliferation and migration by encoding the hsa_circ_0006401 peptide. Hsa_circ_0006401 peptides decreased the mRNA and protein level of the host gene col6a3 by promoting col6a3 mRNA stabilation. In conclusion, our study revealed that circRNAs generated from col6a3 that contain an open-reading frame (ORF) encode a novel 198-aa functional peptide and hsa_circ_0006401 peptides promote stability of the host gene col6a3 mRNA to promote CRC proliferation and metastasis.

scholarly journals SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Heyun Zhang ◽  
Zhangyu Zheng ◽  
Rongqin Zhang ◽  
Yongcong Yan ◽  
Yaorong Peng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Histone Methylation ◽  
Cell Growth And Migration ◽  
Histone 3 ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Proliferation And Migration

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. SET and MYND domain-containing protein 3 (SMYD3) has been shown to promote the progression of various types of human cancers, including liver cancer; however, the detailed molecular mechanism is still largely unknown. Here, we report that SMYD3 expression in HCC is an independent prognostic factor for survival and promotes the proliferation and migration of HCC cells. We observed that SMYD3 upregulated sphingosine-1-phosphate receptor 1 (S1PR1) promoter activity by methylating histone 3 (H3K4me3). S1PR1 was expressed at high levels in HCC samples, and high S1PR1 expression was associated with shorter survival. S1PR1 expression was also positively correlated with SMYD3 expression in HCC samples. We confirmed that SMYD3 promotes HCC cell growth and migration in vitro and in vivo by upregulating S1PR1 expression. Further investigations revealed that SMYD3 affects critical signaling pathways associated with the progression of HCC through S1PR1. These findings strongly suggest that SMYD3 has a crucial function in HCC progression that is partially mediated by histone methylation at the downstream gene S1PR1, which affects key signaling pathways associated with carcinogenesis and the progression of HCC.

scholarly journals EXTH-64. SMALL GTPASES IN MENINGIOMAS: PROLIFERATION, MIGRATION, SURVIVAL, POTENTIAL TREATMENT AND INTERACTIONS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii101-ii101
Author(s):  
Christoph Kesseler ◽  
Julian Kahr ◽  
Natalie Waldt ◽  
Nele Stroscher ◽  
Josephine Liebig ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Lines ◽  
Small Gtpases ◽  
Potential Treatment ◽  
Rock Inhibitor ◽  
Meningioma Cell ◽  
And Migration ◽  
Proliferation And Migration

Abstract PURPOSE To evaluate the role of the small GTPases RhoA, Rac1 and Cdc42 in meningiomas as therapeutic targets and their interactions in meningiomas. EXPERIMENTAL DESIGN We analyzed expression of GTPases in human meningioma samples and meningioma cell lines of various WHO grades. Malignant IOMM-Lee meningioma cells were used to generate shRNA mediated knockdowns of GTPases RhoA, Rac1 or Cdc42 and to study knockdown effects on proliferation and migration, as well as analysis of cell morphology by confocal microscopy. The same tests were used to investigate effects of the two inhibitors Fasudil and EHT-1864 of malignant IOMM-Lee, KT21 and benign Ben-Men cells and the effects of these drugs on IOMM-Lee knockdown cells. The effects of GTPase knockdowns and Fasudil treatment were studied in terms of overall survival by intracranial xenografts of mice. Potential interactions of GTPases regarding NF2, mTOR and FAK-Paxillin were examined. RESULTS Small GTPases were upregulated in meningiomas of higher tumor grades. Reduced proliferation and migration could be achieved by GTPase knockdown in IOMM-Lee cells. Additionally, the ROCK-inhibitor Fasudil and Rac1-inhibitor EHT-1864 reduced proliferation in different meningioma cell lines and reduced proliferation and migration independent of GTPase knockdowns/status. Moreover, overall survival in vivo could also be increased by knockdowns of RhoA and Rac1 as well as Fasudil treatment. GTPase expression was affected dependent on the NF2 status but effects were not very distinct, indicating that NF2 is not strongly involved in GTPase regulation in meningiomas. In terms of mTOR and FAK-Paxillin signaling, each GTPase changes those pathways in a different manner. CONCLUSION Small GTPases are important effectors in meningioma proliferation and migration in vitro as well as survival in vivo and their inhibition should be considered as potential treatment option.

scholarly journals Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

2021 ◽  
Vol 22 (11) ◽  
pp. 5602
Author(s):  
Hyeon Young Park ◽  
Mi-Jin Kim ◽  
Seunghyeong Lee ◽  
Jonghwa Jin ◽  
Sungwoo Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Metabolic Reprogramming ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
And Migration ◽  
Proliferation And Migration

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

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