Helicobacter pylori infection enhances heparanase leading to cell proliferation via mitogen‑activated protein kinase signalling in human gastric cancer cells

Liu,Liping; Zhao,Yongxun; Fan,Guangrui; Shuai,Tiankui; Li,Bin; Li,Yumin

doi:10.3892/mmr.2018.9558

December-2018 Volume 18 Issue 6

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

December-2018 Volume 18 Issue 6

Full Size Image

Article

Helicobacter pylori infection enhances heparanase leading to cell proliferation via mitogen‑activated protein kinase signalling in human gastric cancer cells

Authors:
- Liping Liu
- Yongxun Zhao
- Guangrui Fan
- Tiankui Shuai
- Bin Li
- Yumin Li
View Affiliations / Copyright

Affiliations: The Second Clinical Medical School of Lanzhou University, Lanzhou, Gansu 730030, P.R. China, Department of Surgical Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China, Department of Critical Care Medicine, The Donggang Branch of The First Hospital of Lanzhou University, Lanzhou, Gansu 730030, P.R. China, Department of Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China, Department of General Surgery, The Second Hospital of Lanzhou University, Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu 730030, P.R. China
Pages: 5733-5741
|
Published online on: October 15, 2018

https://doi.org/10.3892/mmr.2018.9558
Expand metrics +

Abstract

Helicobacter pylori (H. pylori) infection is the most important factor in the development of gastric cancer. Heparanase (HPA) is involved in tissue remodelling and cell migration, which leads to inflammation and tumour metastasis. The current study aimed was to explore whether a H. pylori infection leads to an increase in the level of HPA in gastric cancer and to investigate the specific mechanism underlying this association. Reverse transcription‑polymerase chain reaction and western blotting were used to detect HPA mRNA and protein expression, respectively, in MKN‑45 cells infected by H. pylori, MKN‑45 cells treated with the mitogen‑activated protein kinase (MAPK) inhibitor SB203580 and MKN‑45 cells transfected with small interfering RNA against HPA. MAPK and nuclear factor (NF)‑κB expression were determined by western blotting in the different cells group. Cell Counting Kit‑8, Transwell method, and Scratch and Clone tests were conducted to detect proliferation, invasion, migration and clone formation ability of gastric cancer cells. It was demonstrated that HPA mRNA expression was highest at 6 h post‑infection, while the expression of the HPA protein was highest at 24 h post‑infection in H. pylori‑infected gastric cancer cells. Furthermore, it was demonstrated that H. pylori infection significantly enhanced the expression of MAPK and NF‑κB in MKN‑45 cells at the mRNA and protein levels. SB203580 significantly decreased the expression of NF‑κB in MKN‑45 cells infected with H. pylori. Exposure to SB203580 also significantly decreased the expression of HPA. In the present study, the inhibition of HPA significantly lowered H. pylori‑induced cell proliferation, suggesting that H. pylori infection induces the proliferation of gastric cancer cells through the upregulation of HPA. Taken together, the results of the present study demonstrated that HPA serves a critical role in the development of gastric cancer in H. pylori‑infected cells, which may be an important mechanism through which H. pylori infection leads to gastric cancer. In addition, H. pylori infection promotes the proliferation, invasion and metastasis of gastric cancer cells through the upregulation of HPA expression, and this is likely mediated via the MAPK and NF‑κB signalling pathways. These data suggest that HPA can be used as a therapeutic target in gastric cancer, particularly in cases induced by H. pylori infection.

View Figures

View References

1	Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC cancer base no. 11International agency for research on cancer. 2013, Lyon, France: http://globocan.iarc.fr
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
3	Zhang XM, Wang Z, Liang JW and Zhou ZX: Analysis of laparoscopy-assisted gastric cancer operations performed by inexperienced junior surgeons. Asian Pac J Cancer Prev. 15:5077–5081. 2014. View Article : Google Scholar : PubMed/NCBI
4	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
5	Figueiredo C, Garcia-Gonzalez MA and Machado JC: Molecular pathogenesis of gastric cancer. Helicobacter. 18 Suppl 1:S28–S33. 2013. View Article : Google Scholar
6	Matsuda K, Tanikawa C and Nakamura Y: Possible role of genetic factors on reduced risk for gastric cancer among duodenal ulcer patients. Nihon Rinsho. 71:1491–1496. 2013.PubMed/NCBI
7	Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the evaluation of carcinogenic risks to humans. Lyon, 7–7 June 1994. IARC Monogr Eval Carcinog Risks Hum. 61:1–241. 1994.PubMed/NCBI
8	Wang F, Meng W, Wang B and Qiao L: Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 345:196–202. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wang YH, Lv ZF, Zhong Y, Liu DS, Chen SP and Xie Y: The internalization of Helicobacter pylori plays a role in the failure of H. pylori eradication. Helicobacter. 22:2017. View Article : Google Scholar
10	Suerbaum S and Michetti P: Helicobacter pylori infection. N Engl J Med. 347:1175–1186. 2002. View Article : Google Scholar : PubMed/NCBI
11	Huang Y, Wang QL, Cheng DD, Xu WT and Lu NH: Adhesion and invasion of gastric mucosa epithelial cells by Helicobacter pylori. Front Cell Infect Microbiol. 6:1592016. View Article : Google Scholar : PubMed/NCBI
12	Li Z, Zou D, Ma X, Chen J, Shi X, Gong Y, Man X, Gao L, Zhao Y, Wang R, et al: Epidemiology of peptic ulcer disease: Endoscopic results of the systematic investigation of gastrointestinal disease in China. Am J Gastroenterol. 105:2570–2577. 2010. View Article : Google Scholar : PubMed/NCBI
13	Zhang M, Zhou YZ, Li XY, Tang Z, Zhu HM, Yang Y and Chhetri JK: Seroepidemiology of Helicobacter pylori infection in elderly people in the Beijing region, China. World J Gastroenterol. 20:3635–3639. 2014. View Article : Google Scholar : PubMed/NCBI
14	Vlodavsky I, Singh P, Boyango I, Gutter-Kapon L, Elkin M, Sanderson RD and Ilan N: Heparanase: From basic research to therapeutic applications in cancer and inflammation. Drug Resist Updat. 29:54–75. 2016. View Article : Google Scholar : PubMed/NCBI
15	Rivara S, Milazzo FM and Giannini G: Heparanase: A rainbow pharmacological target associated to multiple pathologies including rare diseases. Future Med Chem. 8:647–680. 2016. View Article : Google Scholar : PubMed/NCBI
16	Nadir Y and Brenner B: Heparanase multiple effects in cancer. Thromb Res. 133 Suppl 2:S90–S94. 2014. View Article : Google Scholar : PubMed/NCBI
17	Ilan N, Elkin M and Vlodavsky I: Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol. 38:2018–2039. 2006. View Article : Google Scholar : PubMed/NCBI
18	Ni M, Elli S, Naggi A, Guerrini M, Torri G and Petitou M: Investigating glycol-split-heparin-derived inhibitors of heparanase: A study of synthetic trisaccharides. Molecules. 21:E16022016. View Article : Google Scholar : PubMed/NCBI
19	Vlodavsky I, Iozzo RV and Sanderson RD: Heparanase: Multiple functions in inflammation, diabetes and atherosclerosis. Matrix Biol. 32:220–222. 2013. View Article : Google Scholar : PubMed/NCBI
20	Wilson JC, Laloo AE, Singh S and Ferro V: 1H NMR spectroscopic studies establish that heparanase is a retaining glycosidase. Biochem Biophys Res Commun. 443:185–188. 2014. View Article : Google Scholar : PubMed/NCBI
21	Jin H and Zhou S: The functions of heparanase in human diseases. Mini Rev Med Chem. 17:541–548. 2017. View Article : Google Scholar : PubMed/NCBI
22	Yingying X, Yong Z, Zhenning W, Xue Z, Li J, Yang L and Huimian X: Role ofheparanase-1 in gastric carcinoma invasion. Asian Pac J Cancer Prev. 10:151–154. 2009.PubMed/NCBI
23	Meirovitz A, Hermano E, Lerner I, Zcharia E, Pisano C, Peretz T and Elkin M: Role of heparanase in radiation-enhanced invasiveness of pancreatic carcinoma. Cancer Res. 71:2772–2780. 2011. View Article : Google Scholar : PubMed/NCBI
24	Shafat I, Pode D, Peretz T, Ilan N, Vlodavsky I and Nisman B: Clinical significance of urine heparanase in bladder cancer progression. Neoplasia. 10:125–130. 2008. View Article : Google Scholar : PubMed/NCBI
25	Gingis-Velitski S, Zetser A, Kaplan V, Ben-Zaken O, Cohen E, Levy-Adam F, Bashenko Y, Flugelman MY, Vlodavsky I and Ilan N: Heparanase uptake is mediated by cell membrane heparan sulfate proteoglycans. J Biol Chem. 279:44084–44092. 2004. View Article : Google Scholar : PubMed/NCBI
26	Vreys V, Delande N, Zhang Z, Coomans C, Roebroek A, Dürr J and David G: Cellular uptake of mammalian heparanase precursor involves low density lipoprotein receptor-related proteins, mannose 6-phosphate receptors, and heparan sulfate proteoglycans. J Biol Chem. 280:33141–33148. 2005. View Article : Google Scholar : PubMed/NCBI
27	Ben-Zaken O, Shafat I, Gingis-Velitski S, Bangio H, Kelson IK, Alergand T, Amor Y, Maya RB, Vlodavsky I and Ilan N: Low and high affinity receptors mediate cellular uptake of heparanase. Int J Biochem Cell Biol. 40:530–542. 2008. View Article : Google Scholar : PubMed/NCBI
28	Hermano E, Lerner I and Elkin M: Heparanase enzyme in chronic inflammatory bowel disease and colon cancer. Cell Mol Life Sci. 69:2501–2513. 2012. View Article : Google Scholar : PubMed/NCBI
29	Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, Zemans RL, Bowman JC, Koyanagi DE, Yunt ZX, et al: The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med. 18:1217–1223. 2012. View Article : Google Scholar : PubMed/NCBI
30	Maeda S, Akanuma M, Mitsuno Y, Hirata Y, Ogura K, Yoshida H, Shiratori Y and Omata M: Distinct mechanism of Helicobacter pylori-mediated NF-kappa Bactivation between gastric cancer cells and monocytic cells. J Biol Chem. 276:44856–44864. 2001. View Article : Google Scholar : PubMed/NCBI
31	Kim H, Lim JW and Kim KH: Helicobacter pylori-induced expression of interleukin-8 and cyclooxygenase-2 in AGS gastric epithelial cells: Mediation by nuclear factor-kappaB. Scand J Gastroenterol. 36:706–716. 2001. View Article : Google Scholar : PubMed/NCBI
32	Zhang J, Chen Y, Xin XL, Li QN, Li M, Lin LP, Geng MY and Ding J: Oligomannurarate sulfate blocks tumor growth by inhibiting NF-kappaB activation. Acta Pharmacol Sin. 31:375–381. 2010. View Article : Google Scholar : PubMed/NCBI
33	Wu WJ, Pan CE, Liu QG, Meng KW, Yu HB, Wang YL and Zhao L: Expression of heparanase and nuclear factor kappa B in pancreatic adenocarcinoma. Nan Fang Yi Ke Da Xue Xue Bao. 27:1267–1270. 2007.(In Chinese). PubMed/NCBI
34	Wu W, Pan C, Yu H, Gong H and Wang Y: Heparanase expression in gallbladder carcinoma and its correlation to prognosis. J Gastroenterol Hepatol. 23:491–497. 2008. View Article : Google Scholar : PubMed/NCBI
35	Ding SZ, Smith MF Jr and Goldberg JB: Helicobacter pylori and mitogen-activated protein kinases regulate the cell cycle, proliferation and apoptosis in gastric epithelial cells. J Gastroenterol Hepatol. 23:e67–e78. 2008. View Article : Google Scholar : PubMed/NCBI
36	Chen YC, Wang Y, Li JY, Xu WR and Zhang YL: H pylori stimulates proliferation of gastric cancer cells through activating mitogen-activated protein kinase cascade. World J Gastroenterol. 12:5972–5977. 2006. View Article : Google Scholar : PubMed/NCBI
37	Xiang Y, Ye W, Huang C, Lou B, Zhang J, Yu D, Huang X, Chen B and Zhou M: Brusatol inhibits growth and induces apoptosis in pancreatic cancer cells via JNK/p38MAPK/NF-κb/Stat3/Bcl-2 signaling pathway. Biochem Biophys Res Commun. 487:820–826. 2017. View Article : Google Scholar : PubMed/NCBI
38	Chao W, Deng JS, Li PY, Liang YC and Huang GJ: 3,4-Dihydroxybenzalactone suppresses human non-small cell lung carcinoma cells metastasis via suppression of epithelial to mesenchymal transition, ROS-mediated PI3K/AKT/MAPK/MMP and NFκB signaling pathways. Molecules. 22:E5372017. View Article : Google Scholar : PubMed/NCBI
39	Liu X, Fang H, Chen H, Jiang X, Fang D, Wang Y and Zhu D: An artificial miRNA against HPSE suppresses melanoma invasion properties, correlating with a down-regulation of chemokines and MAPK phosphorylation. PLoS One. 7:e386592012. View Article : Google Scholar : PubMed/NCBI
40	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
41	Lin CJ, Liao WC, Lin HJ, Hsu YM, Lin CL, Chen YA, Feng CL, Chen CJ, Kao MC, Lai CH and Kao CH: Statins attenuate Helicobacter pylori CagA translocation and reduce incidence of gastric cancer: In vitro and population-based case-control studies. PLoS One. 11:e01464322016. View Article : Google Scholar : PubMed/NCBI
42	Choi IJ, Kim JS, Kim JM, Jung HC and Song IS: Effect of inhibition of extracellular signal-regulated kinase 1 and 2 pathway on apoptosis and bcl-2 expression in Helicobacter pylori-infected AGS cells. Infect Immun. 71:830–837. 2003. View Article : Google Scholar : PubMed/NCBI
43	Sachs G, Wen Y and Scott DR: Gastric infection by Helicobacter pylori. Curr Gastroenterol Rep. 11:455–461. 2009. View Article : Google Scholar : PubMed/NCBI
44	Ahn HJ and Lee DS: Helicobacter pylori in gastric carcinogenesis. World J Gastrointest Oncol. 7:455–465. 2015. View Article : Google Scholar : PubMed/NCBI
45	Goh LY, Leow AH and Goh KL: Observations on the epidemiology of gastrointestinal and liver cancers in the Asia-Pacific region. J Dig Dis. 15:463–468. 2014. View Article : Google Scholar : PubMed/NCBI
46	Wu BW, Li DF, Ke ZF, Ma D, Li YJ, Gang D, Zheng ZG, Zhang KJ and Zhang YH: Expression characteristics of heparanase in colon carcinoma and its close relationship with cyclooxygenase-2 and angiogenesis. Hepatogastroenterology. 57:1510–1514. 2010.PubMed/NCBI
47	Zhou Y, Song B, Qin WJ, Zhang G, Zhang R, Luan Q, Pan TJ, Yang AG and Wang H: Heparanase promotes bone destruction and invasiveness in prostate cancer. Cancer Lett. 268:252–259. 2008. View Article : Google Scholar : PubMed/NCBI
48	Varchalama E, Rodolakis A, Strati A, Papageorgiou T, Valavanis C, Vorgias G, Lianidou E and Antsaklis A: Quantitative analysis of heparanase gene expression innormal cervical, cervical intraepithelial neoplastic, and cervical carcinoma tissues. Int J Gynecol Cancer. 19:1614–1619. 2009. View Article : Google Scholar : PubMed/NCBI
49	Ma XM, Shen ZH, Liu ZY, Wang F, Hai L, Gao LT and Wang HS: Heparanase promotes human gastric cancer cells migration and invasion by increasing Src and p38phosphorylation expression. Int J Clin Exp Pathol. 7:5609–5621. 2014.PubMed/NCBI
50	Vlodavsky I, Ilan N, Naggi A and Casu B: Heparanase: Structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des. 13:2057–2073. 2007. View Article : Google Scholar : PubMed/NCBI
51	Vlodavsky I, Friedmann Y, Elkin M, Aingorn H, Atzmon R, Ishai-Michaeli R, Bitan M, Pappo O, Peretz T, Michal I, et al: Mammalian heparanase: Gene cloning, expressionand function in tumor progression and metastasis. Nat Med. 5:793–802. 1999. View Article : Google Scholar : PubMed/NCBI
52	Mogler C, Herold-Mende C, Dyckhoff G, Jenetzky E, Beckhove P and Helmke BM: Heparanase expression in head and neck squamous cell carcinomas is associated with reduced proliferation and improved survival. Histopathology. 58:944–952. 2011. View Article : Google Scholar : PubMed/NCBI
53	Zheng L, Jiang G, Mei H, Pu J, Dong J, Hou X and Tong Q: Small RNA interference-mediated gene silencing of heparanase abolishes the invasion, metastasis and angiogenesis of gastric cancer cells. BMC Cancer. 10:332010. View Article : Google Scholar : PubMed/NCBI
54	Tang W, Nakamura Y, Tsujimoto M, Sato M, Wang X, Kurozumi K, Nakahara M, Nakao K, Nakamura M, Mori I and Kakudo K: Heparanase: A key enzyme in invasion and metastasis of gastric carcinoma. Mod Pathol. 15:593–598. 2002. View Article : Google Scholar : PubMed/NCBI
55	Johnson GL and Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 298:1911–1912. 2002. View Article : Google Scholar : PubMed/NCBI
56	Chang L and Karin M: Mammalian MAP kinase signalling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI
57	Chen Y, Li H, Li M, Niu S, Wang J, Shao H, Li T and Wang H: Salvia miltiorrhizapolysaccharide activates T lymphocytes of cancer patients through activation of TLRs mediated-MAPK and -NF-κB signaling pathways. J Ethnopharmacol. 200:165–173. 2017. View Article : Google Scholar : PubMed/NCBI
58	Huang FT, Peng JF, Cheng WJ, Zhuang YY, Wang LY, Li CQ, Tang J, Chen WY, Li YH and Zhang SN: MiR-143 targeting TAK1 attenuates pancreatic ductal adenocarcinoma progression via MAPK and NF-κB pathway in vitro. Dig Dis Sci. 62:944–957. 2017. View Article : Google Scholar : PubMed/NCBI
59	Thakkar N, Yadavalli T, Jaishankar D and Shukla D: Emerging roles of heparanase in viral pathogenesis. Pathogens. 6:E432017. View Article : Google Scholar : PubMed/NCBI
60	Ramani VC, Vlodavsky I, Ng M, Zhang Y, Barbieri P, Noseda A and Sanderson RD: Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype. Matrix Biol. 55:22–34. 2016. View Article : Google Scholar : PubMed/NCBI
61	Hao NB, Tang B, Wang GZ, Xie R, Hu CJ, Wang SM, Wu YY, Liu E, Xie X and Yang SM: Hepatocyte growth factor (HGF) upregulates heparanase expression via PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis. Cancer Lett. 361:57–66. 2015. View Article : Google Scholar : PubMed/NCBI
62	Cao HJ, Fang Y, Zhang X, Chen WJ, Zhou WP, Wang H, Wang LB and Wu JM: Tumor metastasis and the reciprocal regulation of heparanase gene expression by nuclear factor kappa B in human gastric carcinoma tissue. World J Gastroenterol. 11:903–907. 2005. View Article : Google Scholar : PubMed/NCBI