Downregulation of miR‑136 promotes the progression of osteosarcoma and is associated with the prognosis of patients with osteosarcoma

Chu,Yanchen; Hu,Xiaoli; Wang,Guangfeng; Wang,Zhijie; Wang,Yanjin

doi:10.3892/ol.2019.10203

Downregulation of miR‑136 promotes the progression of osteosarcoma and is associated with the prognosis of patients with osteosarcoma

Authors:
- Yanchen Chu
- Xiaoli Hu
- Guangfeng Wang
- Zhijie Wang
- Yanjin Wang
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Affiliations: Department of Spinal Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China, Department of Obstetrics and Gynecology, Women and Children's Hospital of Linyi City, Linyi, Shandong 276000, P.R. China, Department of Medical Administration, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China, Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
Published online on: April 1, 2019 https://doi.org/10.3892/ol.2019.10203
Pages: 5210-5218

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Abstract

Osteosarcoma (OS) is the most common bone tumor in children and young adults, and is an aggressive tumor with poor prognosis. MicroRNAs (miRNAs) are aberrantly expressed in various types of cancer, and contribute to cancer tumorigenesis and progression. In the present study, the potential prognostic value and biological function of miRNA‑136 (miR‑136) in OS was investigated. Reverse transcription‑quantitative polymerase chain reaction analysis was used to evaluate the expression of miR‑136 in OS tissues and cell lines. Kaplan‑Meier survival analysis and Cox regression analysis were conducted to investigate the prognostic significance of miR‑136. Various in vitro cell based assays were used to evaluate the effects of miR‑136 on the biological behavior of OS cells. A luciferase assay was performed to determine the key miR‑136 targets associated with OS. The expression of miR‑136 was significantly downregulated in osteosarcoma tissues and cells compared with the normal controls (all P<0.05). Decreased miR‑136 expression was significantly associated with Enneking staging (P=0.030) and distant metastasis (P=0.016). Decreased miR‑136 expression in patients was associated with shorter overall survival compared with patients with increased expression levels (log‑rank test; P<0.05). The expression of miR‑136 was indicated as an independent prognostic factor for the patients (hazard ratio=0.496; 95% confidence interval=0.250‑0.987; P=0.046). MTT, transwell and Matrigel assays demonstrated that upregulation of miR‑136 decreased proliferation, migration and invasion of OS cells. Bioinformatics and luciferase assays demonstrated that migration and invasion enhancer 1 (MIEN1) is a direct target of miR‑136. Together, the results suggested that miR‑136 functions as a tumor suppressor gene to regulate proliferation, migration and invasion of OS cells. MIEN1 was a potential target of miR‑136. Additionally, miR‑136 may serve as a prognostic biomarker for OS.

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1	Ottaviani G and Jaffe N: The epidemiology of osteosarcoma. Cancer Treat Res. 152:3–13. 2009. View Article : Google Scholar : PubMed/NCBI
2	Ritter J and Bielack SS: Osteosarcoma. Ann Oncol. 21 (Suppl):vii320–325. 2010. View Article : Google Scholar : PubMed/NCBI
3	Jones KB, Ferguson PC, Lam B, Biau DJ, Hopyan S, Deheshi B, Griffin AM, White LM and Wunder JS: Effects of neoadjuvant chemotherapy on image-directed planning of surgical resection for distal femoral osteosarcoma. J Bone Joint Surg Am. 94:1399–1405. 2012. View Article : Google Scholar : PubMed/NCBI
4	Wong KC, Lee V, Shing MM and Kumta S: Surgical resection of relapse may improve postrelapse survival of patients with localized osteosarcoma. Clin Orthop Relat Res. 471:814–819. 2013. View Article : Google Scholar : PubMed/NCBI
5	Gill J, Ahluwalia MK, Geller D and Gorlick R: New targets and approaches in osteosarcoma. Pharmacol Ther. 137:89–99. 2013. View Article : Google Scholar : PubMed/NCBI
6	Meazza C and Scanagatta P: Metastatic osteosarcoma: A challenging multidisciplinary treatment. Exp Rev Anticancer Ther. 16:543–556. 2016. View Article : Google Scholar
7	Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013. View Article : Google Scholar : PubMed/NCBI
8	Wang G, Zhu S, Gu Y, Chen Q, Liu X and Fu H: MicroRNA-145 and microRNA-133a inhibited proliferation, migration, and invasion, while promoted apoptosis in hepatocellular carcinoma cells via targeting FSCN1. Dig Dis Sci. 60:3044–3052. 2015. View Article : Google Scholar : PubMed/NCBI
9	Li C, Zhao L, Chen Y, He T, Chen X, Mao J, Li C, Lyu J and Meng QH: MicroRNA-21 promotes proliferation, migration, and invasion of colorectal cancer, and tumor growth associated with down-regulation of sec23a expression. BMC Cancer. 16:6052016. View Article : Google Scholar : PubMed/NCBI
10	Nishikawa R, Goto Y, Kurozumi A, Matsushita R, Enokida H, Kojima S, Naya Y, Nakagawa M, Ichikawa T and Seki N: MicroRNA-205 inhibits cancer cell migration and invasion via modulation of centromere protein F regulating pathways in prostate cancer. Int J Urol. 22:867–877. 2015. View Article : Google Scholar : PubMed/NCBI
11	Zhu J, Liu F, Wu Q and Liu X: MiR-221 increases osteosarcoma cell proliferation, invasion and migration partly through the downregulation of PTEN. Int J Mol Med. 36:1377–1383. 2015. View Article : Google Scholar : PubMed/NCBI
12	Xu M, Jin H, Xu CX, Bi WZ and Wang Y: MiR-34c inhibits osteosarcoma metastasis and chemoresistance. Med Oncol. 31:9722014. View Article : Google Scholar : PubMed/NCBI
13	Zhao H, Ma B, Wang Y, Han T, Zheng L, Sun C, Liu T, Zhang Y, Qiu X and Fan Q: miR-34a inhibits the metastasis of osteosarcoma cells by repressing the expression of CD44. Oncol Rep. 29:1027–1036. 2013. View Article : Google Scholar : PubMed/NCBI
14	Mosakhani N, Pazzaglia L, Benassi MS, Borze I, Quattrini I, Picci P and Knuutila S: MicroRNA expression profiles in metastatic and non-metastatic giant cell tumor of bone. Histol Histopathol. 28:671–678. 2013.PubMed/NCBI
15	Yuan Q, Cao G, Li J, Zhang Y and Yang W: MicroRNA-136 inhibits colon cancer cell proliferation and invasion through targeting liver receptor homolog-1/Wnt signaling. Gene. 628:48–55. 2017. View Article : Google Scholar : PubMed/NCBI
16	Lu HJ, Jin PY, Tang Y, Fan SH, Zhang ZF, Wang F, Wu DM, Lu J and Zheng YL: microRNA-136 inhibits proliferation and promotes apoptosis and radiosensitivity of cervical carcinoma through the NF-kappaB pathway by targeting E2F1. Life Sci. 199:167–178. 2018. View Article : Google Scholar : PubMed/NCBI
17	Jia H, Wang H, Yao Y, Wang C and Li P: miR-136 inhibits malignant progression of hepatocellular carcinoma cells by targeting cyclooxygenase 2. Oncol Res. 26:967–976. 2018. View Article : Google Scholar : PubMed/NCBI
18	Biermann JS, Chow W, Reed DR, Lucas D, Adkins DR, Agulnik M, Benjamin RS, Brigman B, Budd GT, Curry WT, et al: NCCN guidelines insights: Bone cancer, version 2.2017. J Natl Compr Canc Netw. 15:155–167. 2017. View Article : Google Scholar : PubMed/NCBI
19	Cates JM: Comparison of the AJCC, MSTS, and modified spanier systems for clinical and pathologic staging of osteosarcoma. Am J Surg Pathol. 41:405–413. 2017. View Article : Google Scholar : PubMed/NCBI
20	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
21	Shen S, Yue H, Li Y, Qin J, Li K, Liu Y and Wang J: Upregulation of miR-136 in human non-small cell lung cancer cells promotes Erk1/2 activation by targeting PPP2R2A. Tumour Biol. 35:631–640. 2014. View Article : Google Scholar : PubMed/NCBI
22	Zhang H, Cai X, Wang Y, Tang H, Tong D and Ji F: microRNA-143, down-regulated in osteosarcoma, promotes apoptosis and suppresses tumorigenicity by targeting Bcl-2. Oncol Rep. 24:1363–1369. 2010.PubMed/NCBI
23	Poos K, Smida J, Maugg D, Eckstein G, Baumhoer D, Nathrath M and Korsching E: Genomic heterogeneity of osteosarcoma-shift from single candidates to functional modules. PLoS One. 10:e01230822015. View Article : Google Scholar : PubMed/NCBI
24	Hass HG, Jobst J, Vogel U, Scheurlen M and Nehls O: Overexpression of tumor-associated trypsin inhibitor (SPINK1/TATI) in hepatitis C-associated hepatocellular carcinoma: Potential implications for viral hepatocarcinogenesis. Oncol Res Treat. 37:732–738. 2014. View Article : Google Scholar : PubMed/NCBI
25	Karakus N, Kara N, Ulusoy AN, Ozaslan C, Tural S and Okan I: Evaluation of CYP17A1 and LEP gene polymorphisms in breast cancer. Oncol Res Treat. 38:418–422. 2015. View Article : Google Scholar : PubMed/NCBI
26	Dimberg J, Olsen RS, Skarstedt M, Lofgren S, Zar N and Matussek A: Polymorphism of the p38β gene in patients with colorectal cancer. Oncol Lett. 8:1093–1095. 2014. View Article : Google Scholar : PubMed/NCBI
27	Hou G, Chen B, Xu W, Zhao H, Liu K and Yao H: Expression level of CDC2 gene in osteosarcoma and its clinical significance. Oncol Lett. 15:7884–7888. 2018.PubMed/NCBI
28	Fernanda Amary M, Ye H, Berisha F, Khatri B, Forbes G, Lehovsky K, Frezza AM, Behjati S, Tarpey P, Pillay N, et al: Fibroblastic growth factor receptor 1 amplification in osteosarcoma is associated with poor response to neo-adjuvant chemotherapy. Cancer Med. 3:980–987. 2014. View Article : Google Scholar : PubMed/NCBI
29	Liang S, Ren Z, Han X, Yang J, Shan L, Li L, Wang B, Zhang Q, Mu T, Chen K, et al: PLA2G16 expression in human osteosarcoma is associated with pulmonary metastasis and poor prognosis. PLoS One. 10:e01272362015. View Article : Google Scholar : PubMed/NCBI
30	Fesler A, Zhai H and Ju J: miR-129 as a novel therapeutic target and biomarker in gastrointestinal cancer. Onco Targets Ther. 7:1481–1485. 2014.PubMed/NCBI
31	Zavala V, Perez-Moreno E, Tapia T, Camus M and Carvallo P: miR-146a and miR-638 in BRCA1-deficient triple negative breast cancer tumors, as potential biomarkers for improved overall survival. Cancer Biomark. 16:99–107. 2016. View Article : Google Scholar : PubMed/NCBI
32	Jiang Y, Luan Y, Chang H and Chen G: The diagnostic and prognostic value of plasma microRNA-125b-5p in patients with multiple myeloma. Oncol Lett. 16:4001–4007. 2018.PubMed/NCBI
33	Taheriazam A, Talaei AJ, Jamshidi M, Shakeri M, Khoshbakht S, Yahaghi E and Shokrani M: Up-regulation of miR-130b expression level and down-regulation of miR-218 serve as potential biomarker in the early detection of human osteosarcoma. Diagn Pathol. 10:1842015. View Article : Google Scholar : PubMed/NCBI
34	Ren H, Qi Y, Yin X and Gao J: miR-136 targets MIEN1 and involves the metastasis of colon cancer by suppressing epithelial-to-mesenchymal transition. Onco Targets Ther. 11:67–74. 2018. View Article : Google Scholar : PubMed/NCBI
35	Chen P, Zhao L, Pan X, Jin L, Lin C, Xu W, Xu J, Guan X, Wu X, Wang Y, et al: Tumor suppressor microRNA-136-5p regulates the cellular function of renal cell carcinoma. Oncol Lett. 15:5995–6002. 2018.PubMed/NCBI
36	Rajendiran S, Kpetemey M, Maji S, Gibbs LD, Dasgupta S, Mantsch R, Hare RJ and Vishwanatha JK: MIEN1 promotes oral cancer progression and implicates poor overall survival. Cancer Biol Ther. 16:876–885. 2015. View Article : Google Scholar : PubMed/NCBI
37	Kpetemey M, Dasgupta S, Rajendiran S, Das S, Gibbs LD, Shetty P, Gryczynski Z and Vishwanatha JK: MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression. Mol Cancer. 14:1562015. View Article : Google Scholar : PubMed/NCBI
38	Li D, Wei Y, Wang D, Gao H and Liu K: MicroRNA-26b suppresses the metastasis of non-small cell lung cancer by targeting MIEN1 via NF-kappaB/MMP-9/VEGF pathways. Biochem Biophys Res Commun. 472:465–470. 2016. View Article : Google Scholar : PubMed/NCBI
39	Rajendiran S, Parwani AV, Hare RJ, Dasgupta S, Roby RK and Vishwanatha JK: MicroRNA-940 suppresses prostate cancer migration and invasion by regulating MIEN1. Mol Cancer. 13:2502014. View Article : Google Scholar : PubMed/NCBI
40	Yan M, Li X, Tong D, Han C, Zhao R, He Y and Jin X: miR-136 suppresses tumor invasion and metastasis by targeting RASAL2 in triple-negative breast cancer. Oncol Rep. 36:65–71. 2016. View Article : Google Scholar : PubMed/NCBI
41	Yang Y, Liu L, Cai J, Wu J, Guan H, Zhu X, Yuan J, Chen S and Li M: Targeting Smad2 and Smad3 by miR-136 suppresses metastasis-associated traits of lung adenocarcinoma cells. Oncol Res. 21:345–352. 2013. View Article : Google Scholar : PubMed/NCBI