HIF‐1 Alpha‐Induced Up‐Regulation of miR‐9 Contributes to Phenotypic Modulation in Pulmonary Artery Smooth Muscle Cells During Hypoxia

Shan, Fabo; Li, Junxia; Huang, Qingyuan

doi:10.1002/jcp.24593

Cited by 54 publications

(38 citation statements)

References 46 publications

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“…HIF-1 alpha is an important biomarker for the hypoxic microenvironment of CRC, and hypoxic situation will activate the expression of HIF-1 alpha [14, 43–45]. Our results also suggest that hypoxic microenvironment with low pO 2 increases the expression of HIF-1 alpha (Figure 6(b)).…”

Section: Discussionsupporting

confidence: 64%

Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF‐1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue

Zhang

Xi³

et al. 2016

Oxidative Medicine and Cellular Longevity

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Hypoxia is prognostically important in colorectal cancer (CRC) therapy. Partial oxygen pressure (pO2) is an important parameter of hypoxia. The correlation between pO2 levels and expression levels of prognostic biomarkers was measured in CRC tissues. Human CRC tissues were collected and pO2 levels were measured by OxyLite. Three methods for tissue fixation were compared, including formalin, Finefix, and Finefix-plus-microwave. Immunohistochemistry (IHC) staining was conducted by using the avidin-biotin complex technique for detecting the antibodies to hypoxia inducible factor-1 (HIF-1) alpha, cytokeratin 20 (CK20), and cell proliferation factor Ki67. The levels of pO2 were negatively associated with the size of CRC tissues. Finefix-plus-microwave fixation has the potential to replace formalin. Additionally, microwave treatment improved Finefix performance in tissue fixation and protein preservation. The percentage of positive cells and gray values of HIF-1 alpha, CK20, and Ki67 were associated with CRC development (P < 0.05). The levels of pO2 were positively related with the gray values of Ki67 and negatively related with the values of HIF-1 alpha and CK20 (P < 0.05). Thus, the levels of microenvironmental pO2 affect the expression of predictive biomarkers HIF-1 alpha, CK20, and Ki67 in the development of CRC tissues.

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Section: Discussionsupporting

confidence: 64%

Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF‐1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue

Zhang

Xi³

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…To address the mechanism leading to the reduction in gene and protein expression of COL4A1/A2 and EFNA1 observed with loss of BMPR2, we monitored levels of microRNAs that have been implicated in PAH, BMPR2 function, or regulation of COL4A1/A2; miRs-145 (22), -130a (23), -21 (24), -29a (25), -137 (26), and -9 (27) in PAECs from control subjects and patients, but no differences were found that could explain the changes in transcripts identified by loss of BMPR2 (data not shown). We also transfected control PAECs with dominant negative constructs of downstream effectors of BMPR2 signaling, SMAD1 or SMAD3 (3), or siRNA against ID1 (a downstream effector of pSMAD1/5) (28) but suppressing this axis could not reproduce any of the changes in the transcripts differentially expressed by loss of BMPR2 (see Figure E4).…”

Section: Reduced Bmp Signaling and Gene Expression Changes In Ipah Paecsmentioning

confidence: 99%

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

Rhodes

Cao

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.Objectives: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts.Methods: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse.Measurements and Main Results: Fold differences in 10 genes were significant (P , 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased b-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries. Conclusions:The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

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“…Previously, we demonstrated that hypoxia contributes to glioma migration by decreasing cell-to-cell adhesion rather than increasing individual cell motility [25]. It was recently reported that hypoxia promotes hypoxia inducible factor 1α (HIF-1α) -mediated up-regulation of miR-9 in pulmonary artery smooth muscle cells, however the effect of hypoxia upon miR-9 in tumor has yet to be investigated [11]. We therefore tested the effect of hypoxia upon miR-9 signaling in glioma cells.…”

Section: Resultsmentioning

confidence: 99%

“…Hypoxia and resulting anaerobic glycolysis plays a dual role in regulating tumor proliferation and invasion, and compelling evidence suggests that hypoxic stress upon pseudopalisading cells at the tumor periphery drives the invasive process [22,[58][59][60][61]. Numerous pro-invasive molecules have been shown to be inducible by hypoxia and HIF-1, including miR-9 [11,23,62]. Sequential switching between proliferation and invasion characterizes malignant glioma progression [61].…”

Section: Discussionmentioning

confidence: 99%

“…Guided by this finding, we performed a series of in vitro experiments to elucidate the influence of miR-9 upon the proliferation and invasion of glioma cells. miR-9 can be promoted by hypoxia [11]. As we observed a relative increase in HIF-1α within the invasive zone in brain, we also tested the effect of hypoxia upon miR-9 in glioma cells.…”

Section: Introductionmentioning

confidence: 96%

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Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

Katakowski

Charteris

Chopp

et al. 2016

Cancer Microenvironment

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The phenotypic axis of invasion and proliferation in malignant glioma cells is a well-documented phenomenon. Invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, and invasive tumor cells dispersed in brain subsequently revert to proliferation and contribute to secondary tumor formation. One miRNA can affect dozens of mRNAs, and some miRNAs are potent oncogenes. Multiple miRNAs are implicated in glioma malignancy, and several of which have been identified to regulate tumor cell motility and division. Using rat 9 L gliosarcoma and human U87 glioblastoma cell lines, we investigated miRNAs associated with the switch between glioma cell invasion and proliferation. Using micro-dissection of 9 L glioma tumor xenografts in rat brain, we identified disparate expression of miR-9 between cells within the periphery of the primary tumor, and those comprising tumor islets within the invasive zone. Modifying miR-9 expression in in vitro assays, we report that miR-9 controls the axis of glioma cell invasion/proliferation, and that its contribution to invasion or proliferation is biphasic and dependent upon local tumor cell density. In addition, immunohistochemistry revealed elevated hypoxia inducible factor 1 alpha (HIF-1α) in the invasive zone as compared to the primary tumor periphery. We also found that hypoxia promotes miR-9 expression in glioma cells. Based upon these findings, we propose a hypothesis for the contribution of miR-9 to the dynamics glioma invasion and satellite tumor formation in brain adjacent to tumor.

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HIF‐1 Alpha‐Induced Up‐Regulation of miR‐9 Contributes to Phenotypic Modulation in Pulmonary Artery Smooth Muscle Cells During Hypoxia

Cited by 54 publications

References 46 publications

Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF‐1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue

Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF‐1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

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