Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

Aims:Hypoxia and the resulting oxidative stress play a major role in postoperative tissue fibrosis. The objective of this study was to determine the effect of l-alanyl-l-glutamine (Ala-Gln) on key markers of postoperative tissue fibrosis: hypoxia-inducible factor (HIF) 1α and type I collagen.Methods:Primary cultures of human normal peritoneal fibroblasts (NPF) established from normal peritoneal tissue were treated with increasing doses of Ala-Gln (0, 1, 2, or 10 mM) with hypoxia ([2% O2] 0-48 hours; continuous hypoxia) or after hypoxia (0.5, 1, 2, 4 hours) and restoration of normoxia (episodic hypoxia) with immediate treatment with Ala-Gln. Hypoxia-inducible factor 1α and type 1 collagen levels were determined by enzyme-linked immunosorbent assay. Data were analyzed with 1-way analysis of variance followed by Tukey tests with Bonferroni correction.Results:Hypoxia-inducible factor 1α and type I collagen levels increased in untreated controls by 3- to 4-fold in response to continuous and episodic hypoxia in human NPF. Under continuous hypoxia, HIF-1α and type I collagen levels were suppressed by Ala-Gln in a dose-dependent manner. l-alanyl-l-glutamine treatment after episodic hypoxia also suppressed HIF-1α and type I collagen levels for up to 24 hours for all doses and up to 48 hours at the highest dose, regardless of exposure time to hypoxia.Conclusions:l-alanyl-l-glutamine significantly suppressed hypoxia-induced levels of key tissue fibrosis (adhesion) phenotype markers under conditions of continuous as well as episodic hypoxia in vitro. This effect of glutamine on molecular events involved in the cellular response to insult or injury suggests potential therapeutic value for glutamine in the prevention of postoperative tissue fibrosis.

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Type II endometrial cancers: original research on a series

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20172300 ◽

2017 ◽

Vol 6 (6) ◽

pp. 2306

Author(s):

B. L. Nayak ◽

Sujata Misra ◽

Suryakant Jaysingh ◽

S. K. Giri

Keyword(s):

Clear Cell ◽

Myometrial Invasion ◽

Serous Carcinoma ◽

Original Research ◽

Clear Cell Adenocarcinoma ◽

Type I ◽

Type Ii ◽

Clinicopathological Analysis ◽

Hematoxylin And Eosin ◽

Endometrial Carcinomas

Background: Endometrial carcinoma, which ranks 3rd in India amongst the gynecological malignancies, is of two histological types: I and II. These differ in molecular as well as in clinical and histopathological profiles. Type II is estrogen independent, nonendometrioid, with higher grade histologies, more aggressive and carries an adverse prognosis.Methods: Endometrial carcinomas diagnosed from endometrial biopsies and hysterectomy specimens in the Dept of Gynaec-oncology, AHRCC, Cuttack from November 2009 to January 2015 were included in the study. All specimens were fixed in 10% neutral buffered formalin and paraffin embedded for histological examination with hematoxylin and eosin staining. The clinicopathological analysis of the cases of EC was done with an emphasis on morphology.Results: Of a total of 150 cases of EC reported, 20 cases were classified as type II EC (13.33%) as per histology. The age of the patients ranged from 36 to 73 years, with mean age is 61 years. In 11 cases (55%), the myometrial invasion was more than half. the histological type was a clear cell adenocarcinoma in 50% of the cases. All were treated with hysterectomy and chemotherapy.Conclusions: Of the type II EC, serous carcinoma is the most common type. Clinical presentation and prognosis differs in comparison to type I EC, thus the recognition of this type of EC is pivotal.

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Propofol attenuates hypoxia-induced apoptosis in alveolar epithelial type II cells through down-regulating hypoxia-inducible factor-1α

Injury ◽

10.1016/j.injury.2011.05.037 ◽

2012 ◽

Vol 43 (3) ◽

pp. 279-283 ◽

Cited By ~ 11

Author(s):

X.Y. He ◽

X.Y. Shi ◽

H.B. Yuan ◽

H.T. Xu ◽

Y.K. Li ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Type Ii Cells ◽

Type Ii ◽

Hypoxia Inducible Factor 1Α ◽

Alveolar Epithelial ◽

Induced Apoptosis

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Hypertonic induction of aquaporin-5: novel role of hypoxia-inducible factor-1α

AJP Cell Physiology ◽

10.1152/ajpcell.00070.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. C1280-C1290 ◽

Cited By ~ 30

Author(s):

Beiyun Zhou ◽

David K. Ann ◽

Xian Li ◽

Kwang-Jin Kim ◽

Helen Lin ◽

...

Keyword(s):

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Water Channel ◽

Alveolar Epithelial Cells ◽

Mouse Lung ◽

Type I ◽

Apical Surface ◽

Aquaporin 5 ◽

Hypoxia Inducible Factor 1Α ◽

Alveolar Epithelial

Aquaporin-5 (AQP5) is a water channel protein expressed on the apical surface of alveolar epithelial type I cells in distal rat lung, suggesting a role for AQP5 in regulating alveolar surface liquid tonicity and/or cell volume. We investigated the molecular mechanisms underlying hypertonic induction of AQP5 in primary rat alveolar epithelial cells (AEC). Steady-state levels of AQP5 mRNA and protein were increased by exposure to sorbitol (200 mM in culture fluid) for 24 h. The increase in AQP5 was not accompanied by changes in mRNA half-life. Transduction of mouse lung epithelial (MLE-15) cells and primary rat AEC with lentivirus vectors encoding AQP5-luciferase demonstrated transcriptional activation of the reporter by exposure to hypertonic sorbitol solution. Hybridization of proteins from sorbitol-treated cells to a transcription factor DNA array demonstrated induction of hypoxia-inducible factor-1α (HIF-1α) by hypertonicity, which was confirmed by quantitative RT-PCR. Cotransfections of AQP5-luciferase with HIF-1α and HIF-1β expression plasmids in MLE-15 cells led to dose-dependent transcriptional enhancement, which was partially abrogated by mutagenesis of putative HIF-1α binding sites in the proximal AQP5 promoter. Importantly, hypertonic induction of AQP5 was significantly inhibited by preventing HIF-1α induction with small interfering RNA. Hypertonicity induced activation of a transiently transfected vascular endothelial growth factor (VEGF) hypoxia response element-driven luciferase construct and increased expression of endogenous VEGF. These results demonstrate that hypertonic induction of both AQP5 and VEGF is transcriptionally regulated and mediated, at least in part, by HIF-1α, suggesting a novel role for HIF-1α in modulating cellular adaptive responses to osmotic stress.

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Hysteroscopic and Immunohistochemical Findings in Type I and Type II Endometrial Carcinomas

The Journal of the American Association of Gynecologic Laparoscopists ◽

10.1016/s1074-3804(05)60582-8 ◽

2001 ◽

Vol 8 (2) ◽

pp. 222-230 ◽

Cited By ~ 6

Author(s):

Hugo Maia ◽

Amélia Maltez ◽

Paulo Fahel ◽

Elsimar Coutinho

Keyword(s):

Type I ◽

Type Ii ◽

Endometrial Carcinomas

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Reduced liver fibrosis in hypoxia-inducible factor-1α-deficient mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90368.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. G582-G592 ◽

Cited By ~ 131

Author(s):

Jeon-OK Moon ◽

Timothy P. Welch ◽

Frank J. Gonzalez ◽

Bryan L. Copple

Keyword(s):

Liver Fibrosis ◽

Type I Collagen ◽

Smooth Muscle Actin ◽

Hypoxia Inducible Factor ◽

Type I ◽

Mrna Levels ◽

Chronic Injury ◽

Hypoxia Inducible Factor 1Α ◽

Duct Ligation ◽

Deficient Mice

Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. In the present study, the hypothesis was tested that hypoxia-inducible factor-1α (HIF-1α) is activated in the liver during chronic injury and regulates expression of profibrotic proteins. To investigate this hypothesis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1α protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1α is required for the development of fibrosis, control and HIF-1α-deficient mice were subjected to BDL. Levels of type I collagen and α-smooth muscle actin mRNA and protein were increased in control mice by 14 days after BDL. These levels were significantly reduced in HIF-1α-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1α promotes liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in control mice subjected to BDL compared with HIF-1α-deficient mice at 7 and 14 days after BDL. Results from these studies suggest that HIF-1α is a critical regulator of profibrotic mediator production during the development of liver fibrosis.

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Molecular Profiling of Endometrial Malignancies

Obstetrics and Gynecology International ◽

10.1155/2010/162363 ◽

2010 ◽

Vol 2010 ◽

pp. 1-16 ◽

Cited By ~ 63

Author(s):

Norasate Samarnthai ◽

Kevin Hall ◽

I-Tien Yeh

Keyword(s):

Fusion Gene ◽

Endometrial Stromal Sarcoma ◽

Molecular Profiling ◽

Genetic Alterations ◽

Endometrial Neoplasms ◽

Low Grade ◽

Type I ◽

Type Ii ◽

Molecular Changes ◽

Endometrial Carcinomas

Molecular profiling of endometrial neoplasms reveals genetic changes in endometrial carcinomas that support the dualistic model, in which type I carcinomas are estrogen-dependent, low grade lesions and type II carcinomas are nonestrogen dependent and high grade. The molecular changes in type I endometrial carcinomas include mutations inPTEN, PIK3CA, KRAS,and -catenin, along with microsatellite instability, whereas type II endometrial carcinomas are characterized by genetic alterations inp53, HER2/neu, p16,and E-cadherin. For endometrial neoplasms with a malignant mesenchymal component,C-MYCmutations and loss of heterozygosity are frequently seen in carcinosarcomas, and a fusion gene,JAZF1/JJAZ1, is distinctive for endometrial stromal sarcoma. In addition,p53mutations may play an important role in tumorigenesis of undifferentiated endometrial sarcoma. These molecular changes can help in the diagnosis of endometrial neoplasms, as well as form the basis of molecular targeted therapy.

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Combined genetic mutations and DNA-methylated genes as biomarkers for endometrial cancer detection from cervical scrapings

Clinical Epigenetics ◽

10.1186/s13148-019-0765-3 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Phui-Ly Liew ◽

Rui-Lan Huang ◽

Tzu-I Wu ◽

Chi-Chun Liao ◽

Chien-Wen Chen ◽

...

Keyword(s):

Dna Methylation ◽

Endometrial Cancer ◽

Cancer Detection ◽

Type I ◽

Type Ii ◽

Normal Endometrium ◽

Epigenetic Biomarkers ◽

Pap Smear Screening ◽

Endometrial Cancers ◽

Endometrial Carcinomas

Abstract Background Endometrial cancer is a common gynecologic cancer. Noninvasive molecular biomarkers for triage of high-risk patients for invasive procedures are needed. Based on the success of cytological Pap smear screening, cervical scrapings are a good source of DNA for molecular testing. In addition to genetic lesions, DNA methylation is a promising biomarker. We assessed the usefulness of combining genetic and epigenetic biomarkers from cervical scrapings to detect endometrial carcinomas. Methods We performed a retrospective case–control study of 96 consecutive cervical scrapings from patients with abnormal uterine bleeding who underwent surgery for diagnostic evaluation. Thirty and 16 cases were diagnosed with type I and type II endometrial cancers, respectively. The remaining non-cancer cases included normal endometrium (n = 12), benign uterine lesions (n = 20), and endometrial hyperplasia (n = 18). Quantitative methylation-specific PCR and mass spectrometry were used for DNA methylation and genetic mutation analysis. Logistic regression was used to evaluate the clinical performance of these candidate biomarkers. Results We tested the effectiveness of the methylation status of four genes (BHLHE22, CDO1, TBX5, and HAND2) in endometrial cancer detection. The area under the receiver operating characteristic curves ranged from 0.703 to 0.878, and panels of hypermethylated BHLHE22/CDO1/HAND2 (87.0% sensitivity and 86.0% specificity) and BHLHE22/CDO1/TBX5 (89.1% sensitivity and 80.0% specificity) showed significant differences and could distinguish benign from malignant endometrial lesions. The sensitivity and specificity in endometrial cancer detection for BHLHE22/CDO1 were 84.8% and 88.0%, respectively. Both type I and II endometrial carcinomas could be detected using a BHLHE22/CDO1-based methylation profile, suggesting that they may have common epigenomes. Moreover, PTEN and TP53 mutations were found in 63.3% of type I and 93.6% of type II endometrial cancers. Unexpectedly, PTEN and TP53 mutations were commonly found in cervical scrapings of the normal endometrium (25% and 33.3%, respectively) and in cases with benign uterine lesions (10% and 50%, respectively). Finally, combinations of any one mutation of PTEN and TP53 mutations had a sensitivity of 91.3%, but a specificity of only 42.0%. Conclusions Adding PTEN/TP53 mutation testing to BHLHE22/CDO1-based methylation testing did not improve the detection of endometrial cancer.

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Hypoxia-inducible factor-1α mediates TGF-β-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00146.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. L740-L752 ◽

Cited By ~ 59

Author(s):

Manabu Ueno ◽

Toshitaka Maeno ◽

Miyuki Nomura ◽

Kana Aoyagi-Ikeda ◽

Hiroki Matsui ◽

...

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Alveolar Macrophages ◽

Transforming Growth Factor ◽

Hypoxia Inducible Factor ◽

Protein Accumulation ◽

Type I ◽

Hypoxia Inducible Factor 1Α ◽

Pai 1

Hypoxia-inducible factor-1α (HIF-1α), a transcription factor that functions as a master regulator of oxygen homeostasis, has been implicated in fibrinogenesis. Here, we explore the role of HIF-1α in transforming growth factor-β (TGF-β) signaling by examining the effects of TGF-β1on the expression of plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of lung tissue from a mouse bleomycin (BLM)-induced pulmonary fibrosis model revealed that expression of HIF-1α and PAI-1 was predominantly induced in alveolar macrophages. Real-time RT-PCR and ELISA analysis showed that PAI-1 mRNA and activated PAI-1 protein level were strongly induced 7 days after BLM instillation. Stimulation of cultured mouse alveolar macrophages (MH-S cells) with TGF-β1induced PAI-1 production, which was associated with HIF-1α protein accumulation. This accumulation of HIF-1α protein was inhibited by SB431542 (type I TGF-β receptor/ALK receptor inhibitor) but not by PD98059 (MEK1 inhibitor) and SB203580 (p38 MAP kinase inhibitor). Expression of prolyl-hydroxylase domain (PHD)-2, which is essential for HIF-1α degradation, was inhibited by TGF-β1, and this decrease was abolished by SB431542. TGF-β1induction of PAI-1 mRNA and its protein expression were significantly attenuated by HIF-1α silencing. Transcriptome analysis by cDNA microarray of MH-S cells after HIF-1α silencing uncovered several pro-fibrotic genes whose regulation by TGF-β1required HIF-1α, including platelet-derived growth factor-A. Taken together, these findings expand our concept of the role of HIF-1α in pulmonary fibrosis in mediating the effects of TGF-β1on the expression of the pro-fibrotic genes in activated alveolar macrophages.

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