Metastasis‑associated gene MAPK15 promotes the migration and invasion of osteosarcoma cells via the c‑Jun/MMPs pathway

Su,Zexin; Su,Zexin; Su,Zexin; Yang,Bingsheng; Yang,Bingsheng; Yang,Bingsheng; Zeng,Zhirui; Zeng,Zhirui; Zeng,Zhirui; Zhu,Shuang; Zhu,Shuang; Zhu,Shuang; Wang,Chenyang; Wang,Chenyang; Wang,Chenyang; Lei,Shan; Lei,Shan; Lei,Shan; Jiang,Yongfa; Jiang,Yongfa; Jiang,Yongfa; Lin,Lijun; Lin,Lijun; Lin,Lijun

doi:10.3892/ol.2020.11544

Metastasis‑associated gene MAPK15 promotes the migration and invasion of osteosarcoma cells via the c‑Jun/MMPs pathway

Authors:
- Zexin Su
- Bingsheng Yang
- Zhirui Zeng
- Shuang Zhu
- Chenyang Wang
- Shan Lei
- Yongfa Jiang
- Lijun Lin
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Affiliations: Department of Joint Surgery, Huadu District People's Hospital, Southern Medical University, Guangzhou, Guangdong 510800, P.R. China, Department of Orthopaedics, Zhujiang Hospital, Southern Medical University, Haizhu, Guangzhou, Guangdong 510282, P.R. China, Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China, Department of Neurosurgery, Zhujiang Hospital, Neurosurgery Institute of Guangdong Province, Key Laboratory on Brain Function Repair and Rehabilitation, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
Published online on: April 15, 2020 https://doi.org/10.3892/ol.2020.11544
Pages: 99-112
Copyright: © Su et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteosarcoma (OS) is the most common and destructive primary bone malignancy to affect children and adolescents. Metastases remain the primary cause of death in patients with OS. In the present study, weight gene co‑expressed network analysis (WGCNA) and differentially‑expressed gene analysis were used to identify key genes associated with the metastasis of OS. Reverse transcription‑quantitative PCR and immunohistochemical staining were then used to detect the expression levels of these key genes in OS tissues, and to determine the hub genes of interest. Wound‑healing and transwell assays, in addition to a lung metastasis model, were used to detect the effects of the hub genes on OS cell proliferation and metastasis in vitro and in vivo. Using WGCNA and differential expression analysis, deleted in lung and esophageal cancer protein 1 (DLEC1), Forkhead box J1 (FOXJ1) and mitogen‑activated protein kinase 15 (MAPK15) were predicted to be key metastasis‑associated genes, and highly expressed in metastatic OS tissues; among them, the protein and mRNA expression levels of MAPK15 were most significantly increased in our OS tissues from patients who exhibited metastases at diagnosis, and thus MAPK15 was determined to be a metastasis‑associated hub gene to further study. Furthermore, inhibiting MAPK15 expression significantly decreased OS cell metastasis in vitro and in vivo, as well as suppressing c‑Jun/matrix metalloproteinase (MMP)‑associated pathways. Overexpression of MAPK15 activated the c‑Jun/MMPs pathway and promoted OS cell metastasis, while inhibition of c‑Jun blocked this effect. Taken together, MAPK15 was indicated to be an OS metastasis‑associated gene, and was confirmed to promote the migration and invasion of OS cells via the c‑Jun/MMP pathway. MAPK15 may therefore be an effective target for the treatment of OS.

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1	Tang H, Tang Z, Jiang Y, Wei W and Lu J: Pathological and therapeutic aspects of matrix metalloproteinases: Implications in osteosarcoma. Asia Pac J Clin Oncol. 15:218–224. 2019.PubMed/NCBI
2	Limaiem F, Kuhn J and Khaddour K: Cancer, Telangiectatic Osteosarcoma. StatPearls. StatPearls Publishing, Treasure Island (FL). Online. 2019
3	Valery PC, Laversanne M and Bray F: Bone cancer incidence by morphological subtype: A global assessment. Cancer Causes Control. 26:1127–1139. 2015. View Article : Google Scholar : PubMed/NCBI
4	Roberts RD, Lizardo MM, Reed DR, Hingorani P, Glover J, Allen-Rhoades W, Fan T, Khanna C, Sweet-Cordero EA, Cash T, et al: Provocative questions in osteosarcoma basic and translational biology: A report from the Children's oncology group. Cancer. 25:3514–3525. 2019. View Article : Google Scholar
5	Bernthal NM, Federman N, Eilber FR, Nelson SD, Eckardt JJ, Eilber FC and Tap WD: Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer. 118:5888–5893. 2012. View Article : Google Scholar : PubMed/NCBI
6	Carina V, Costa V, Sartori M, Bellavia D, De Luca A, Raimondi L, Fini M and Giavaresi G: Adjuvant biophysical therapies in osteosarcoma. Cancers. 11:E3482019. View Article : Google Scholar : PubMed/NCBI
7	Daw NC, Chou AJ, Jaffe N, Rao BN, Billups CA, Rodriguez-Galindo C, Meyers PA and Huh WW: Recurrent osteosarcoma with a single pulmonary metastasis: A multi-institutional review. Br J Cancer. 112:278–282. 2015. View Article : Google Scholar : PubMed/NCBI
8	Isakoff MS, Bielack SS, Meltzer P and Gorlick R: Osteosarcoma: Current treatment and a collaborative pathway to success. J Clin Oncol. 33:3029–3035. 2015. View Article : Google Scholar : PubMed/NCBI
9	Xie B, Li Y, Zhao R, Xu Y, Wu Y, Wang J, Xia D, Han W and Chen D: Identification of key genes and miRNAs in osteosarcoma patients with chemoresistance by bioinformatics analysis. Biomed Res Int. 2018:47610642018. View Article : Google Scholar : PubMed/NCBI
10	Chen XG, Ma L and Xu JX: Abnormal DNA methylation may contribute to the progression of osteosarcoma. Mol Med Rep. 17:193–199. 2018.PubMed/NCBI
11	Wang JS, Duan MY, Zhong YS, Li XD, Du SX, Xie P, Zheng GZ and Han JM: Investigating ageinduced differentially expressed genes and potential molecular mechanisms in osteosarcoma based on integrated bioinformatics analysis. Mol Med Rep. 19:2729–2739. 2019.PubMed/NCBI
12	Tian H, Guan D and Li J: Identifying osteosarcoma metastasis associated genes by weighted gene co-expression network analysis (WGCNA). Medicine (Baltimore). 97:e107812018. View Article : Google Scholar : PubMed/NCBI
13	Wang JS, Wang YG, Zhong YS, Li XD, Du SX, Xie P, Zheng GZ and Han JM: Identification of co-expression modules and pathways correlated with osteosarcoma and its metastasis. World J Surg Oncol. 17:462019. View Article : Google Scholar : PubMed/NCBI
14	Najafi M, Ahmadi A and Mortezaee K: Extracellular-signal- regulated kinase/mitogen-activated protein kinase signaling as a target for cancer therapy: An updated review. Cell Biol Int. 43:1206–1222. 2019. View Article : Google Scholar : PubMed/NCBI
15	Papa S, Choy PM and Bubici C: The ERK and JNK pathways in the regulation of metabolic reprogramming. Oncogene. 38:2223–2240. 2019. View Article : Google Scholar : PubMed/NCBI
16	Abe MK, Saelzler MP, Espinosa R III, Kahle KT, Hershenson MB, Le Beau MM and Rosner MR: ERK8, a new member of the mitogen-activated protein kinase family. J Biol Chem. 277:16733–16743. 2002. View Article : Google Scholar : PubMed/NCBI
17	Lau ATY and Xu YM: Regulation of human mitogen-activated protein kinase 15 (extracellular signal-regulated kinase 7/8) and its functions: A recent update. J Cell Physiol. 234:75–88. 2018. View Article : Google Scholar : PubMed/NCBI
18	Cargnello M and Roux PP: Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 75:50–83. 2011. View Article : Google Scholar : PubMed/NCBI
19	Jin DH, Lee J, Kim KM, Kim S, Kim DH and Park J: Overexpression of MAPK15 in gastric cancer is associated with copy number gain and contributes to the stability of c-Jun. Oncotarget. 6:20190–20203. 2015. View Article : Google Scholar : PubMed/NCBI
20	Rossi M, Colecchia D, Ilardi G, Acunzo M, Nigita G, Sasdelli F, Celetti A, Strambi A, Staibano S, Croce CM and Chiariello M: MAPK15 upregulation promotes cell proliferation and prevents DNA damage in male germ cell tumors. Oncotarget. 7:20981–20998. 2016. View Article : Google Scholar : PubMed/NCBI
21	Li Z, Li N, Shen L and Fu J: Quantitative proteomic analysis identifies MAPK15 as a potential regulator of radioresistance in nasopharyngeal carcinoma cells. Front Oncol. 8:5482018. View Article : Google Scholar : PubMed/NCBI
22	Scott MC, Temiz NA, Sarver AE, LaRue RS, Rathe SK, Varshney J, Wolf NK, Moriarity BS, O'Brien TD, Spector LG, et al: Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression, and survival in osteosarcoma. Cancer Res. 78:326–337. 2018. View Article : Google Scholar : PubMed/NCBI
23	Robinson MD, McCarthy DJ and Smyth GK: edgeR: A bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 26:139–140. 2010. View Article : Google Scholar : PubMed/NCBI
24	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
25	Shimazui T, Yoshikawa K, Ishitsuka R, Kojima T, Kandori S, Yoshino T, Miyazaki J, Uchida K and Nishiyama H: Systemic transduction of p16(INK4a) antitumor peptide inhibits lung metastasis of the MBT-2 bladder tumor cell line in mice. Oncol Lett. 17:1203–1210. 2019.PubMed/NCBI
26	Meazza C and Scanagatta P: Metastatic osteosarcoma: A challenging multidisciplinary treatment. Expert Rev Anticancer Ther. 16:543–556. 2016. View Article : Google Scholar : PubMed/NCBI
27	Aljubran AH, Griffin A, Pintilie M and Blackstein M: Osteosarcoma in adolescents and adults: Survival analysis with and without lung metastases. Ann Oncol. 20:1136–1141. 2009. View Article : Google Scholar : PubMed/NCBI
28	Zhang Y, Yang J, Zhao N, Wang C, Kamar S, Zhou Y, He Z, Yang J, Sun B, Shi X, et al: Progress in the chemotherapeutic treatment of osteosarcoma. Oncol Lett. 16:6228–6237. 2018.PubMed/NCBI
29	Ahmed G, Zamzam M, Kamel A, Ahmed S, Salama A, Zaki I, Kamal N and Elshafiey M: Effect of timing of pulmonary metastasis occurrence on the outcome of metastasectomy in osteosarcoma patients. J Pediatr Surg. 54:775–779. 2019. View Article : Google Scholar : PubMed/NCBI
30	Coulombe P and Meloche S: Atypical mitogen-activated protein kinases: Structure, regulation and functions. Biochim Biophys Acta. 1773:1376–1387. 2007. View Article : Google Scholar : PubMed/NCBI
31	Wu DD, Lau ATY, Yu FY, Cai NL, Dai LJ, Ok Kim M, Jin DY and Xu YM: Extracellular signal-regulated kinase 8-mediated NF-KB activation increases sensitivity of human lung cancer cells to arsenic trioxide. Oncotarget. 8:49144–49155. 2017.PubMed/NCBI
32	Xu YM, Zhu F, Cho YY, Carper A, Peng C, Zheng D, Yao K, Lau AT, Zykova TA, Kim HG, et al: Extracellular signal-regulated kinase 8-mediated c-Jun phosphorylation increases tumorigenesis of human colon cancer. Cancer Res. 70:3218–3227. 2010. View Article : Google Scholar : PubMed/NCBI
33	Shay G, Lynch CC and Fingleton B: Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 44–46. 200–206. 2015. View Article : Google Scholar
34	Merchant N, Nagaraju GP, Rajitha B, Lammata S, Jella KK, Buchwald ZS, Lakka SS and Ali AN: Matrix metalloproteinases: Their functional role in lung cancer. Carcinogenesis. 38:766–780. 2017. View Article : Google Scholar : PubMed/NCBI
35	Ge HX, Zou FM, Li Y, Liu AM and Tu M: JNK pathway in osteoarthritis: Pathological and therapeutic aspects. J Recept Signal Transduct Res. 37:431–436. 2017. View Article : Google Scholar : PubMed/NCBI
36	Wang F, Ke ZF, Wang R, Wang YF, Huang LL and Wang LT: Astrocyte elevated gene-1 (AEG-1) promotes osteosarcoma cell invasion through the JNK/c-Jun/MMP-2 pathway. Biochem Biophys Res Commun. 452:933–939. 2014. View Article : Google Scholar : PubMed/NCBI
37	Yu Y, Li Y, Zhou L, Yang G, Wang M and Hong Y: Cryptochrome 2 (CRY2) suppresses proliferation and migration and regulates clock gene network in osteosarcoma cells. Med Sci Monit. 24:3856–3862. 2018. View Article : Google Scholar : PubMed/NCBI
38	Jie Z, Xie Z, Zhao X, Sun X, Yu H, Pan X, Shen S, Qin A, Fang X and Fan S: Glabridin inhibits osteosarcoma migration and invasion via blocking the p38- and JNK-mediated CREB-AP1 complexes formation. J Cell Physiol. 234:4167–4178. 2019. View Article : Google Scholar : PubMed/NCBI
39	Cheng HL, Hsieh MJ, Yang JS, Lin CW, Lue KH, Lu KH and Yang SF: Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression. Oncotarget. 7:35208–35223. 2016.PubMed/NCBI