Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Overexpression of the Kininogen-1 inhibits proliferation and induces apoptosis of glioma cells

Authors: Jinfang Xu, Jun Fang, Zhonghao Cheng, Longlong Fan, Weiwei Hu, Feng Zhou, Hong Shen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Glioma is the most common primary central nervous system tumor derived from glial cells. Kininogen-1 (KNG1) can exert antiangiogenic properties and inhibit proliferation of endothelial cells. The effect of KNG1 on the glioma is rarely reported, so our purpose in to explore its mechanism in glioma cells.

Methods

The differentially expressed genes (DEGs) were identified based on The Cancer Genome Atlas (TCGA) database. The KNG1-vector was transfected into the two glioma cells. The viability, apoptosis and cell cycle of glioma cells and microvessel density (MVD) were detected by cell counting kit-8 assay, flow cytometry and immunohistochemistry, respectively. The expression were measured by quantitative real-time PCR and Western blot, respectively. A tumor mouse model was established to determine apoptosis rate of brain tissue by terminal deoxynucleotidyl transfer-mediated dUTP nick end labeling (TUNEL) analysis.

Results

KNG1 was identified as the core gene and lowly expressed in the glioma cells. Overexpression of KNG1 inhibited cell viability and angiogenesis of glioma cells. Overexpression of KNG1 promoted the apoptosis and G1 phase cell cycle arrest of glioma cells. Moreover, the expressions of VEGF, cyclinD1, ki67, caspase-3/9 and XIAP were regulated by overexpression of KNG1. In addition, overexpression of KNG1 inhibited the activity of PI3K/Akt. Furthermore, overexpression of KNG1 decreased the tumor growth and promoted the apoptosis of decreased by overexpression of KNG1 in vivo. .

Conclusions

Overexpression of KNG1 suppresses glioma progression by inhibiting the proliferation and promoting apoptosis of glioma cells, providing a therapeutic strategy for the malignant glioma.
Literature
1.
2.
Taylor LP. Diagnosis, treatment, and prognosis of glioma: five new things. Neurology. 2010;75(1):28–32.CrossRef
3.
Louis DN, Pomeroy SL, Cairncross JG. Focus on central nervous system neoplasia. Cancer Cell. 2002;1(2):125–8.CrossRefPubMed
4.
Preusser M, Haberler C, Hainfellner JA. Malignant glioma: neuropathology and neurobiology. Wien Med Wochenschr. 2006;156(11–12):332–7.CrossRefPubMed
5.
6.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of Tumours of the central nervous system. Cancer Imaging the Official Publication of the International Cancer Imaging Society. 2007;9 Spec No A(Special issue A):S1
7.
Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol. 2005;109(1):93–108.CrossRefPubMed
8.
9.
Tobias A, Ahmed A, Moon KS, Lesniak MS. The art of gene therapy for glioma: a review of the challenging road to the bedside. J Neurol Neurosurg Psychiatry. 2013;84(2):213–22.CrossRefPubMed
10.
Omuro AM, Faivre S, Raymond E. Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther. 2007;6(7):1909.CrossRefPubMed
11.
Fan S, Sun ZD, Dai C, Ma Y, Zhao Z, Liu H, Wu Y, Cao Z, Li W. BmKCT toxin inhibits glioma proliferation and tumor metastasis. Cancer Lett. 2010;291(2):158–66.CrossRefPubMed
12.
Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. 2011;59(8):1169–80.CrossRefPubMed
13.
14.
Charles N, Holland EC. The perivascular niche microenvironment in brain tumor progression. Cell Cycle. 2010;9(15):3084–93.CrossRef
15.
Godlewski J, Krichevsky AM, Johnson MD, Chiocca EA, Bronisz A. Belonging to a network-microRNAs, extracellular vesicles, and the glioblastoma microenvironment. Neuro Oncol. 2015;17(5):147–58.CrossRef
16.
Vos KEVD, Balaj L, Skog J, Breakefield XO. Brain tumor microvesicles: insights into intercellular communication in the nervous system. Cellular & Molecular Neurobiology. 2011;31(6):949–59.CrossRef
17.
Chistiakov DA, Chekhonin VP. Extracellular vesicles shed by glioma cells: pathogenic role and clinical value. Tumor Biol. 2014;35(9):8425–38.CrossRef
18.
Skog J, Würdinger T, Van RS MDH, Gainche L, Sena-Esteves M, Jr CW, Carter BS, Krichevsky AM, Breakefield XO. glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–6.CrossRefPubMedPubMedCentral
19.
Liu Y, Cao DJ, Sainz IM, Guo YL, Colman RW. The inhibitory effect of HKa in endothelial cell tube formation is mediated by disrupting the uPA-uPAR complex and inhibiting its signaling and internalization. Am J Physiol. 2008;295(1):257–67.CrossRef
20.
Kawasaki M, Maeda T, Hanasawa K, Ohkubo I, Tani T. Effect of his-Gly-Lys motif derived from domain 5 of high molecular weight kininogen on suppression of cancer metastasis both in vitro and in vivo. J Biol Chem. 2003;278(49):49301–7.CrossRefPubMed
21.
Ishihara K, Kamata M, Hayashi I, Yamashina S, Majima M. Roles of bradykinin in vascular permeability and angiogenesis in solid tumor. Int Immunopharmacol. 2002;2(4):499–509.CrossRefPubMed
22.
Silvestre JS, Bergaya S, Tamarat R, Duriez M, Boulanger CM, Levy BI. Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway. Circ Res. 2001;89(8):678–83.CrossRefPubMed
23.
Montana V, Sontheimer H. Bradykinin promotes the chemotactic invasion of primary brain tumors. Journal of Neuroscience the Official Journal of the Society for Neuroscience. 2011;31(13):4858.CrossRef
24.
Ren Y, Ji N, Kang X, Wang R, Ma W, Hu Z, Liu X, Wang Y. Aberrant ceRNA-mediated regulation of KNG1 contributes to glioblastoma-induced angiogenesis. Oncotarget. 2016;
25.
Avdieiev S, Gera L, Havrylyuk D, Hodges RS, Lesyk R, Ribrag V, Vassetzky Y, Kavsan V. Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds. Bioorg Med Chem. 2014;22(15):3815–23.CrossRefPubMed
26.
Avdieiev SS, Gera L, Hodges R, Vassetzky YS, Kavsan VM. Growth suppression activity of bradykinin antagonists in glioma cells. Biopolymers & Cell. 2014;30(1):77–9.CrossRef
27.
Colman RW, Jameson BA, Lin Y, Johnson D, Mousa SA. Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood. 2000;95(2):543.PubMed
28.
Wang J, Wang X, Lin S, Chen C, Wang C, Ma Q, Jiang B. Identification of kininogen-1 as a serum biomarker for the early detection of advanced colorectal adenoma and colorectal cancer. PLoS One. 2013;8(7):e70519.CrossRefPubMedPubMedCentral
29.
Yen CY, Jiang SS, Hsiao JR, Chen CH, Liu KJ. Identification of kininogen-1 as a potential prognostizc biomarker for oral cancer. Eur J Cancer. 2016;60:e10-e10.CrossRef
30.
Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huertacepas J, Simonovic M, Roth A, Santos A, Tsafou KP. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447.CrossRefPubMed
31.
Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4(1):44.CrossRef
32.
Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F, Adam A. The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci. 2005;99(1):6.CrossRefPubMed
33.
Rhaleb NE, Yang XP, Carretero OA. The Kallikrein-Kinin system as a regulator of cardiovascular and renal function. Comprehensive Physiology. 2011;1(2):971–93.PubMedPubMedCentral
34.
Abdullahsoheimi SS, Lim BK, Hashim OH, Shuib AS. Patients with ovarian carcinoma excrete different altered levels of urine CD59, kininogen-1 and fragments of inter-alpha-trypsin inhibitor heavy chain H4 and albumin. Proteome Sci. 2010;8(1):58.CrossRef
35.
Assifi MM, Hines OJ. Anti-angiogenic agents in pancreatic cancer: a review. Anticancer Agents Med Chem. 2011;11(5):464–9.
36.
Rustemeyer SM, Lamberson WR, Ledoux DR, Wells K, Austin KJ, Cammack KM. Effects of dietary aflatoxin on the hepatic expression of apoptosis genes in growing barrows. J Anim Sci. 2011;89(4):916–25.CrossRefPubMed
37.
Lang HL, et al., Glioma cells enhance angiogenesis and inhibit endothelial cell apoptosis through the release of exosomes that contain long non-coding RNA CCAT2. Oncol Rep. 2017;38(2):785–98.
38.
Li Q, Qiao G, Ma J, Li Y. Downregulation of VEGF expression attenuates malignant biological behavior of C6 glioma stem cells. Int J Oncol. 2014;44(5):1581–8.CrossRefPubMed
39.
Lian Y, Ming X, Xian LI, Tang YI, Wang YL. Arginine ADP-ribosyltransferase 1 promotes angiogenesis in colorectal cancer via the PI3K/Akt pathway. Int J Mol Med. 2016;37(3):734–42.CrossRef
40.
Filippichiela EC, Villodre ES, Zamin LL, Lenz G. Autophagy interplay with apoptosis and cell cycle regulation in the growth inhibiting effect of resveratrol in glioma cells. PLoS One. 2011;6(6):e20849.CrossRef
41.
Masuda M, Hirakawa N, Nakashima T, Kuratomi Y, Komiyama S. Cyclin D1 overexpression in primary hypopharyngeal carcinomas. Cancer. 2015;78(3):390–5.CrossRef
42.
Niikura N, Iwamoto T, Masuda S, Kumaki N, Xiaoyan T, Shirane M, Mori K, Tsuda B, Okamura T, Saito Y. Immunohistochemical Ki67 labeling index has similar proliferation predictive power to various gene signatures in breast cancer. Cancer Sci. 2012;103(8):1508–12.CrossRefPubMed
43.
Fadeel B, Orrenius S. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J Intern Med. 2005;258(6):479–517.CrossRefPubMed
44.
Kekre N, Griffin C, Mcnulty J, Pandey S. Pancratistatin causes early activation of caspase-3 and the flipping of phosphatidyl serine followed by rapid apoptosis specifically in human lymphoma cells. Cancer Chemotherapy & Pharmacology. 2005;56(1):29–38.CrossRef
45.
Liu J, Yao Y, Ding H, Chen R. Oxymatrine triggers apoptosis by regulating Bcl-2 family proteins and activating caspase-3/caspase-9 pathway in human leukemia HL-60 cells. Tumor Biol. 2014;35(6):5409–15.CrossRef
46.
Mufti AR, Burstein E, Csomos RA, Graf PCF, Wilkinson JC, Dick RD, Challa M, Son JK, Bratton SB. Su GL: XIAP is a copper binding protein deregulated in Wilson's disease and other copper Toxicosis disorders. Mol Cell. 2015;21(6):775–85.CrossRef
47.
McDowell KA, Riggins, GJ, Gallia GL. Targeting the AKT pathway in glioblastoma. Curr Pharm Des. 2011;17(23):2411–20.
48.
Wei MA, Meng NA, Tang C, Wang H, Lin Z. Overexpression of N-myc downstream-regulated gene 1 inhibits human glioma proliferation and invasion via phosphoinositide 3-kinase/AKT pathways. Mol Med Rep. 2015;12(1):1050–8.CrossRef
49.
Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, Inge L, Smith BL, Sawyers CL, Mischel PS. Analysis of the phosphatidylinosit ol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res. 2003;63(7):2742–6.PubMed
50.
Suzuki Y, Shirai K, Oka K, Mobaraki A, Yoshida Y, Noda S, Okamoto M, Suzuki Y, Itoh J, Itoh H. Higher pAkt expression predicts a significant worse prognosis in glioblastomas. J Radiat Res. 2010;51(3):343–8.CrossRefPubMed
51.
Metadata
Title
Overexpression of the Kininogen-1 inhibits proliferation and induces apoptosis of glioma cells
Authors
Jinfang Xu
Jun Fang
Zhonghao Cheng
Longlong Fan
Weiwei Hu
Feng Zhou
Hong Shen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0833-0

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Review

Role of the nervous system in cancer metastasis

Research

Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis

Research

Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells

Research

PCBP1 depletion promotes tumorigenesis through attenuation of p27Kip1 mRNA stability and translation

Research

MCM6 promotes metastasis of hepatocellular carcinoma via MEK/ERK pathway and serves as a novel serum biomarker for early recurrence

Research

Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits