Inhibition of lysyl oxidase expression by dextran sulfate affects invasion and migration of gastric cancer cells

Xu,Yuanyi; Wang,Xiaofei; Huang,Yunning; Ma,Yanmei; Jin,Xiu; Wang,Honghong; Wang,Juan

doi:10.3892/ijmm.2018.3855

Inhibition of lysyl oxidase expression by dextran sulfate affects invasion and migration of gastric cancer cells

Authors:
- Yuanyi Xu
- Xiaofei Wang
- Yunning Huang
- Yanmei Ma
- Xiu Jin
- Honghong Wang
- Juan Wang
View Affiliations

Affiliations: Department of Pathology, Ningxia Medical University, Yinchuan, Ningxia 750001, P.R. China, Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China, Department of Gastrointestinal Surgery, Ningxia People's Hospital, Yinchuan, Ningxia 750021, P.R. China, Department of Pathology, Affiliated Hospital of Jining Medical College, Jining, Shandong 272029, P.R. China, Department of Pathology, Ningxia People's Hospital, Yinchuan, Ningxia 750021, P.R. China
Published online on: September 4, 2018 https://doi.org/10.3892/ijmm.2018.3855
Pages: 2737-2749
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In the present study, the effect of dextran sulfate (DS) on the metastasis and invasion of human gastric cancer cells and its key underlying mechanism were investigated. The levels of hypoxia‑inducible factor 1α (HIF‑1α), transforming growth factor β (TGF‑β) and lysyl oxidase (LOX) expression were evaluated in human gastric cancer and peritumoral tissues by immunohistochemical analysis. Cell proliferation and apoptosis were also examined using the Cell Counting Kit‑8 assay and flow cytometry. The effect of DS on the invasion and migration of BGC‑823 cells was assessed using a Transwell assay. BGC‑823 cells were divided into the control (phosphate‑buffered saline‑treated) and experimental (DS‑treated) groups, and cultured for different times under hypoxic conditions. Subsequently, LOX and TGF‑β expression levels in the cells were measured by immunocytochemistry, immunofluorescence, reverse transcription‑quantitative polymerase chain reaction and western blot analysis. HIF‑1α, TGF‑β and LOX expression levels were significantly higher in human gastric cancer tissues as compared with that in adjacent tissues. DS influenced cell proliferation and apoptosis in a dose‑dependent manner. Furthermore, DS reduced the number of invaded and migrated cells. Under hypoxic conditions, DS reduced HIF‑1α, TGF‑β and LOX expression levels in BGC‑823 cells. After 12 h, the effect of combination of DS and β‑aminopropionitrile (BAPN) on LOX and TGF‑β protein levels was more significant compared with that of DS or BAPN alone. Therefore, DS may inhibit the invasion and migration of human gastric cancer cells under hypoxic conditions by influencing LOX.

View Figures

View References

1	Ajani JA: Evolving chemotherapy for advanced gastric cancer. Oncologist. 3(Suppl 10): 49–58. 2005. View Article : Google Scholar
2	Gou WF, Shen DF, Yang XF, Zhao S, Liu YP, Sun HZ, Su RJ, Luo JS and Zheng HC: ING5 suppresses proliferation, apoptosis, migration and invasion, and induces autophagy and differentiation of gastric cancer cells: A good marker for carcinogenesis and subsequent progression. Oncotarget. 6:19552–19579. 2015. View Article : Google Scholar : PubMed/NCBI
3	Fioroni I, Dell'aquila E, Pantano F, Intagliata S, Caricato M, Vincenzi B, Coppola R, Santini D and Tonini G: Role of c-mesenchymal-epithelial transition pathway in gastric cancer. Expert Opin Pharmacother. 16:1195–1207. 2015. View Article : Google Scholar : PubMed/NCBI
4	Nieto MA, Huang RY, Jackson RA and Thiery JP: EMT: 2016. Cell. 166:21–45. 2016. View Article : Google Scholar : PubMed/NCBI
5	Peng Z, Wang CX, Fang EH, Wang GB and Tong Q: Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. 20:5403–5410. 2014. View Article : Google Scholar : PubMed/NCBI
6	Yang YJ, Na HJ, Suh MJ, Ban MJ, Byeon HK, Kim WS, Kim JW, Choi EC, Kwon HJ, Chang JW and Koh YW: Hypoxia induces epithelial-mesenchymal transition in follicular thyroid cancer: Involvement of regulation of twist by hypoxia inducible factor-1α. Yonsei Med J. 56:1503–1514. 2015. View Article : Google Scholar : PubMed/NCBI
7	Guo J, Wang B, Fu Z, Wei J and Lu W: Hypoxic microenvironment induces EMT and upgrades stem-like properties of gastric cancer cells. Technol Cancer Res Treat. 15:60–68. 2016. View Article : Google Scholar
8	Tian M, Neil JR and Schiemann WP: Transforming growth factor-β and the hallmarks of cancer. Cell Signal. 23:951–962. 2011. View Article : Google Scholar
9	Kasashima H, Yashiro M, Kinoshita H, Fukuoka T, Morisaki T, Masuda G, Sakurai K, Kubo N, Ohira M and Hirakawa K: Lysyl oxidase is associated with the epithelial-mesenchymal transition of gastric cancer cells in hypoxia. Gastric Cancer. 19:431–442. 2016. View Article : Google Scholar
10	Leng A, Liu T, He Y, Li Q and Zhang G: Smad4/Smad7 balance: A role of tumorigenesis in gastric cancer. Exp Mol Pathol. 87:48–53. 2009. View Article : Google Scholar : PubMed/NCBI
11	Noda S, Yashiro M, Nshii T and Hirakawa K: Hypoxia upregulates adhesion ability to peritoneum through a transforming growth factor-beta-dependent mechanism in diffuse-type gastric cancer cells. Eur J Cancer. 46:995–1005. 2010. View Article : Google Scholar : PubMed/NCBI
12	Taylor MA, Amin JD, Kirschmann DA and Schiemann WP: Lysyl oxidase contributes to mechanotransduction-mediated regulation of transforming growth factor-β signaling in breast cancer cells. Neoplasia. 13:406–418. 2011. View Article : Google Scholar : PubMed/NCBI
13	Oskarsson T: Extracellular matrix components in breast cancer progression and metastasis. Breast. 2(Suppl 22): S66–S72. 2013. View Article : Google Scholar
14	Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, et al: Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 16:1009–1017. 2010. View Article : Google Scholar : PubMed/NCBI
15	Cuevas EP, Moreno-Bueno G, Canesin G, Santos V, Portillo F and Cano A: LOXL2 catalytically inactive mutants mediate epithelial-to-mesenchymal transition. Biol Open. 3:129–137. 2014. View Article : Google Scholar : PubMed/NCBI
16	Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, Chi JT, Jeffrey SS and Giaccia AJ: Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 440:1222–1226. 2006. View Article : Google Scholar : PubMed/NCBI
17	Matsuoka J, Yashiro M, Doi Y, Fuyuhiro Y, Kato Y, Shinto O, Noda S, Kashiwagi S, Aomatsu N, Hirakawa T, et al: Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFβ signaling. PLoS One. 8:e623102013. View Article : Google Scholar
18	Zhu J, Huang S, Wu G, Huang C, Li X, Chen Z, Zhao L and Zhao Y: Lysyl oxidase is predictive of unfavorable outcomes and essential for regulation of vascular endothelial growth factor in hepatocellular carcinoma. Dig Dis Sci. 60:3019–3031. 2015. View Article : Google Scholar : PubMed/NCBI
19	Lai H, Jin Q, Lin Y, Mo X, Li B, He K and Chen J: Combined use of lysyl oxidase, carcino-embryonic antigen, and carbohydrate antigens improves the sensitivity of biomarkers in predicting lymph node metastasis and peritoneal metastasis in gastric cancer. Tumour Biol. 35:10547–10554. 2014. View Article : Google Scholar : PubMed/NCBI
20	Xu Y, Jin X, Huang Y, Dong J, Wang H, Wang X and Cao X: Inhibition of peritoneal metastasis of human gastric cancer cells by dextran sulphate through the reduction in HIF-1α and ITGβ1 expression. Oncol Rep. 35:2624–2634. 2016. View Article : Google Scholar : PubMed/NCBI
21	Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A and Arnold D: Gastric cancer: ESMO-esso-estro clinical practice guidelines for diagnosis, treatment and follow-up. Radiother Oncol. 110:189–194. 2014. View Article : Google Scholar : PubMed/NCBI
22	Yang X, Li S, Li W, Chen J, Xiao X, Wang Y, Yan G and Chen L: Inactivation of lysyl oxidase by β-aminopropionitrile inhibits hypoxia-induced invasion and migration of cervical cancer cells. Oncol Rep. 29:541–548. 2013. View Article : Google Scholar
23	Ding W, Zhang W, Hui FM, Zhang YH, Zhang FF, Li XM and Shi FX: Cell-specific expression and immunolocalization of nitric oxide synthase isoforms and soluble guanylyl cyclase α1 and β1 subunits in the ovary of fetal, neonatal and immature pigs. Anim Reprod Sci. 131:172–180. 2012. View Article : Google Scholar : PubMed/NCBI
24	Riquelme I, Saavedra K, Espinoza J A, Weber H, García P, Nervi B, Garrido M, Corvalán AH, Roa JC and Bizama C: Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget. 6:24750–24779. 2015. View Article : Google Scholar : PubMed/NCBI
25	Gordan JD and Simon MC: Hypoxia-inducible factors: Central regulators of the tumor phenotype. Curr opin Genet Dev. 17:71–77. 2007. View Article : Google Scholar : PubMed/NCBI
26	Hagiwara A, Sakakura C, Shirasu M, Togawa T, Sonoyama Y, Fujiyama J, Ebihara Y, Itoh T and Yamagishi H: Intraperitoneal injection of dextran sulfate as an anti-adherent drug for the prevention of peritoneal metastasis of cancer shows low toxicity in animals. Anticancer Drugs. 11:393–399. 2000. View Article : Google Scholar : PubMed/NCBI
27	Kawamura N, Sun-Wada GH, Aoyama M, Harada A, Takasuga S, Sasaki T and Wada Y: Delivery of endosomes to lysosomes via microautophagy in the visceral endoderm of mouse embryos. Nat Commun. 3:10712012. View Article : Google Scholar : PubMed/NCBI
28	Erez N: Cancer: Opening lox to metastasis. Nature. 522:41–42. 2015. View Article : Google Scholar : PubMed/NCBI
29	Vaupel P and Harrison L: Tumor hypoxia: Causative factors, compensatory mechanisms, and cellular response. Oncologist. 5(Suppl 9): S4–S9. 2004. View Article : Google Scholar
30	Wang Y, Ma J, Shen H, Wang C, Sun Y, Howell SB and Lin X: Reactive oxygen species promote ovarian cancer progression via the HIF-1α/LOX/E-cadherin pathway. Oncol Rep. 32:2150–2158. 2014. View Article : Google Scholar : PubMed/NCBI
31	Lim S, Bae E, Kim HS, Kim TA, Byun K, Kim B, Hong S, Im JP, Yun C, Lee B, et al: TRAF6 mediates IL-1β/LPS-induced suppression of TGF-β signaling through its interaction with the type III TGF-β receptor. PLoS One. 7:e327052012. View Article : Google Scholar
32	Massague J: TGFβ signalling in context. Nat Rev Mol Cell Biol. 13:616–630. 2012. View Article : Google Scholar
33	Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J, Pietras K, Virtanen I, Philipson L, Leopold PL, et al: A SNAIL1SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 11:943–950. 2009. View Article : Google Scholar : PubMed/NCBI
34	Hu WQ, Wang LW, Yuan JP, Yan SG, Li JD, Zhao HL, Peng CW, Yang GF and Li Y: High expression of transform growth factor beta 1 in gastric cancer confers worse outcome: Results of a cohort study on 184 patients. Hepatogastroenterology. 61:245–250. 2014.PubMed/NCBI
35	Moon HJ, Finney J, Xu L, Moore D, Welch DR and Mure M: MCF-7 cells expressing nuclear associated lysyl oxidase-like 2 (LOXL2) exhibit an epithelial-to-mesenchymal transition (EMT) phenotype and are highly invasive in vitro. J Biol Chem. 288:30000–30008. 2013. View Article : Google Scholar : PubMed/NCBI
36	Osawa T, Ohga N, Akiyama K, Hida Y, Kitayama K, Kawamoto T, Yamamoto K, Maishi N, Kondoh M, Onodera Y, et al: Lysyl oxidase secreted by tumour endothelial cells promotes angio-genesis and metastasis. Br J Cancer. 109:2237–2247. 2013. View Article : Google Scholar : PubMed/NCBI
37	Cox TR, Rumney RMH, Schoof EM, Perryman L, Høye AM, Agrawal A, Bird D, Latif NA, Forrest H, Evans HR, et al: The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature. 522:106–110. 2015. View Article : Google Scholar : PubMed/NCBI
38	Hua YJ, Wang HY, Tang LQ, Chen QY, Shao JY and Mai HQ: LOX expression in primary nasopharyngeal carcinoma: Correlation with prognostic parameters and outcome. Oncotarget. 7:8200–8207. 2016. View Article : Google Scholar : PubMed/NCBI