MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma by targeting epidermal growth factor receptor and proliferating cell nuclear antigen

Yuan,Yuan; Wang,Yonggang; Liu,Zimei; Sun,Yong; Yao,Yang; Yu,Wenxi; Shen,Zan

doi:10.3892/ijo.2019.4764

MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma by targeting epidermal growth factor receptor and proliferating cell nuclear antigen

Authors:
- Yuan Yuan
- Yonggang Wang
- Zimei Liu
- Yong Sun
- Yang Yao
- Wenxi Yu
- Zan Shen
View Affiliations

Affiliations: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
Published online on: March 27, 2019 https://doi.org/10.3892/ijo.2019.4764
Pages: 2019-2029
Copyright: © Yuan 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

Osteosarcoma (OS) is the most commonly diagnosed bone tumor in young people with poor prognosis. At present, the mechanisms underlying tumorigenesis in OS are not well understood. The methionine adnosyltransferase 2B (MAT2B) gene encodes the regulatory subunit of methionine adenosyltransferase (MAT). Recent studies demonstrated that it is highly expressed in a number of human malignancies; however, is undefined in OS. In the present study, MAT2B expression was investigated in tumor samples and cell lines. In vivo and in vitro, lentivirus‑mediated small hairpin RNA was constructed to target the MAT2B gene and examine the role of MAT2B in OS proliferation. Microarray analysis was performed to examine the possible downstream molecular target of MAT2B in OS. MAT2B was markedly increased in OS specimens compared with the normal bone tissues, and it was additionally abundantly expressed in OS cell lines. Inhibition of MAT2B expression caused a marked decrease in proliferation and significant increase in apoptosis. In vivo, MAT2B silencing significantly inhibited OS cell growth. Microarray analysis suggested that epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) may function as downstream targets of MAT2B in OS, as confirmed by reverse transcription‑quantitative polymerase chain reaction assays and western blotting. Collectively, these results suggested that MAT2B serves a critical role in the proliferation of OS by regulating EGFR and PCNA and that it may be a potential therapeutic target and prognostic factor of OS.

View Figures

View References

1	Ferguson JL and Turner SP: Bone cancer: Diagnosis and treatment principles. Am Fam Physician. 98:205–213. 2018.PubMed/NCBI
2	Harrison DJ and Schwartz CL: Osteogenic sarcoma: Systemic chemotherapy options for localized disease. Curr Treat Options Oncol. 18:242017. View Article : Google Scholar : PubMed/NCBI
3	Ferrari S, Mercuri M, Bacci G, Bielack SS and Jürgens H: Comment on “Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols”. J Clin Oncol. 20:2910–2911; author reply 2910–2911. 2002. View Article : Google Scholar
4	Lu SC and Mato JM: S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. 92:1515–1542. 2012. View Article : Google Scholar : PubMed/NCBI
5	Sun H, Kang J, Su J, Zhang J, Zhang L, Liu X, Zhang J, Wang F, Lu Z, Xing X, et al: Methionine adenosyltransferase 2A regulates mouse zygotic genome activation and morula to blastocyst transition. Biol Reprod. Sep 27–2018.Epub ahead of print. View Article : Google Scholar
6	Inoue-Choi M, Nelson HH, Robien K, Arning E, Bottiglieri T, Koh WP and Yuan JM: One-carbon metabolism nutrient status and plasma S-adenosylmethionine concentrations in middle-aged and older Chinese in Singapore. Int J Mol Epidemiol Genet. 3:160–173. 2012.PubMed/NCBI
7	Yang H, Ara AI, Magilnick N, Xia M, Ramani K, Chen H, Lee TD, Mato JM and Lu SC: Expression pattern, regulation, and functions of methionine adenosyltransferase 2beta splicing variants in hepatoma cells. Gastroenterology. 134:281–291. 2008. View Article : Google Scholar
8	Ramani K and Lu SC: Methionine adenosyltransferases in liver health and diseases. Liver Res. 1:103–111. 2017. View Article : Google Scholar : PubMed/NCBI
9	Nordgren KK, Peng Y, Pelleymounter LL, Moon I, Abo R, Feng Q, Eckloff B, Yee VC, Wieben E and Weinshilboum RM: Methionine adenosyltransferase 2A/2B and methylation: Gene sequence variation and functional genomics. Drug Metab Dispos. 39:2135–2147. 2011. View Article : Google Scholar : PubMed/NCBI
10	Peng H, Dara L, Li TW, Zheng Y, Yang H, Tomasi ML, Tomasi I, Giordano P, Mato JM and Lu SC: MAT2B-GIT1 interplay activates MEK1/ERK 1 and 2 to induce growth in human liver and colon cancer. Hepatology. 57:2299–2313. 2013. View Article : Google Scholar : PubMed/NCBI
11	Lei Y, Zhang B, Zhang Y, Zhao Y, Sun J, Zhang X and Yang S: Lentivirus-mediated downregulation of MAT2B inhibits cell proliferation and induces apoptosis in melanoma. Int J Oncol. 49:981–990. 2016. View Article : Google Scholar : PubMed/NCBI
12	Tang Z, He G, Xu J and Zhongfu L: Knockdown of Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 inhibits cell division and increases apoptosis in gastric cancer. J Surg Res. 211:1–7. 2017. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Liu H, Zhao C, Li W, Xu H and Chen Y: The DEAD-box RNA helicase 51 controls non-small cell lung cancer proliferation by regulating cell cycle progression via multiple pathways. Sci Rep. 6:261082016. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)). Method Methods. 25:402–408. 2001. View Article : Google Scholar
15	Singh B, Carpenter G and Coffey RJ: EGF receptor ligands: Recent advances. F1000 Res. 5:52016. View Article : Google Scholar
16	Wang W, Zhao HF, Yao TF and Gong H: Advanced development of ErbB family-targeted therapies in osteosarcoma treatment. Invest New Drugs. Oct 24–2018.Epub ahead of print. View Article : Google Scholar
17	Prabhu VV and Devaraj N: Epidermal growth factor receptor tyrosine kinase: A potential target in treatment of non-small-cell lung carcinoma. J Environ Pathol Toxicol Oncol. 36:151–158. 2017. View Article : Google Scholar : PubMed/NCBI
18	Gonzalez-Conchas GA, Rodriguez-Romo L, Hernandez-Barajas D, Gonzalez-Guerrero JF, Rodriguez-Fernandez IA, Verdines-Perez A, Templeton AJ, Ocana A, Seruga B, Tannock IF, et al: Epidermal growth factor receptor overexpression and outcomes in early breast cancer: A systematic review and a meta-analysis. Cancer Treat Rev. 62:1–8. 2018. View Article : Google Scholar
19	Wen YH, Koeppen H, Garcia R, Chiriboga L, Tarlow BD, Peters BA, Eigenbrot C, Yee H, Steiner G and Greco MA: Epidermal growth factor receptor in osteosarcoma: Expression and mutational analysis. Hum Pathol. 38:1184–1191. 2007. View Article : Google Scholar : PubMed/NCBI
20	Kersting C, Gebert C, Agelopoulos K, Schmidt H, van Diest PJ, Juergens H, Winkelmann W, Kevric M, Gosheger G, Brandt B, et al: Epidermal growth factor receptor expression in high-grade osteosarcomas is associated with a good clinical outcome. Clin Cancer Res. 13:2998–3005. 2007. View Article : Google Scholar : PubMed/NCBI
21	Linder M, Glitzner E, Srivatsa S, Bakiri L, Matsuoka K, Shahrouzi P, Dumanic M, Novoszel P, Mohr T, Langer O, et al: EGFR is required for FOS-dependent bone tumor development via RSK2/CREB signaling. EMBO Mol Med. 10:e94082018. View Article : Google Scholar : PubMed/NCBI
22	Hou CH, Lin FL, Tong KB, Hou SM and Liu JF: Transforming growth factor alpha promotes osteosarcoma metastasis by ICAM-1 and PI3K/Akt signaling pathway. Biochem Pharmacol. 89:453–463. 2014. View Article : Google Scholar : PubMed/NCBI
23	Lin H, Zhang C, Zhang H, Xia YZ, Zhang CY, Luo J, Yang L and Kong LY: Physakengose induces apoptosis via EGFR/mTOR signaling and inhibits autophagic flux in human osteosarcoma cells. Phytomedicine. 42:190–198. 2018. View Article : Google Scholar : PubMed/NCBI
24	Do SI, Jung WW, Kim HS and Park YK: The expression of epidermal growth factor receptor and its downstream signaling molecules in osteosarcoma. Int J Oncol. 34:797–803. 2009.PubMed/NCBI
25	Wu H, Muscato NE, Gonzalez A and Shyr Y: An EGFR and AKT signaling pathway was identified with mediation model in osteosarcomas clinical study. Biomark Insights. 2:469–476. 2007. View Article : Google Scholar : PubMed/NCBI
26	Agarwal P, Sen AK, Bhardwaj M, Dinand V, Ahuja A and Sood R: Study of proliferating cell nuclear antigen expression and angiogenesis in urothelial neoplasms: Correlation with tumor grade and stage. Urol Ann. 10:209–214. 2018. View Article : Google Scholar : PubMed/NCBI
27	Tan Z, Wortman M, Dillehay KL, Seibel WL, Evelyn CR, Smith SJ, Malkas LH, Zheng Y, Lu S and Dong Z: Small-molecule targeting of proliferating cell nuclear antigen chromatin association inhibits tumor cell growth. Mol Pharmacol. 81:811–819. 2012. View Article : Google Scholar : PubMed/NCBI
28	Unal VS, Ayhan A and Tokgozoglu MA: Proliferating cell nuclear antigen index and nm23 expression in osteosarcoma in relation to disease- free survival and tumor grade. Saudi Med J. 26:1475–1477. 2005.PubMed/NCBI
29	Juríková M, Danihel Ľ, Polák Š and Varga I: Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. Acta Histochem. 118:544–552. 2016. View Article : Google Scholar : PubMed/NCBI
30	Lv Q, Zhang J, Yi Y, Huang Y, Wang Y, Wang Y and Zhang W: Proliferating cell nuclear antigen has an association with prognosis and risks factors of cancer patients: A systematic review. Mol Neurobiol. 53:6209–6217. 2016. View Article : Google Scholar : PubMed/NCBI
31	Dong Y, Liang G, Yuan B, Yang C, Gao R and Zhou X: MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumour Biol. 36:1477–1486. 2015. View Article : Google Scholar
32	Liang G, Xu E, Yang C, Zhang C, Sheng X and Zhou X: Nucleosome-binding protein HMGN2 exhibits antitumor activity in human SaO2 and U2-OS osteosarcoma cell lines. Oncol Rep. 33:1300–1306. 2015. View Article : Google Scholar
33	Tu B, Du L, Fan QM, Tang Z and Tang TT: STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma. Cancer Lett. 325:80–88. 2012. View Article : Google Scholar : PubMed/NCBI
34	Wang W, Luo H and Wang A: Expression of survivin and correlation with PCNA in osteosarcoma. J Surg Oncol. 93:578–584. 2006. View Article : Google Scholar : PubMed/NCBI
35	Aaltomaa S, Lipponen P and Syrjänen K: Proliferating cell nuclear antigen (PCNA) immunolabeling as a prognostic factor in axillary lymph node negative breast cancer. Anticancer Res. 13:533–538. 1993.PubMed/NCBI