Abstract
Studies have shown that miR-34c is associated with metastasis and the chemoresponse of several cancers, but its role in osteosarcoma (OS) is unclear. Here, we investigated the role and mechanism of miR-34c in OS metastasis and chemoresponse. In this study, we found that the expression of miR-34c was significantly decreased in specimens from OS patients with a poor chemoresponse or metastasis compared to those with a good chemoresponse and no metastasis. The inhibition of miR-34c significantly stimulated OS cell invasion and chemoresistance in vitro. In contrast, restoring miR-34c significantly inhibited OS cell invasion and chemoresistance. Furthermore, we identified Notch1 and lymphoid enhancer-binding factor 1 (LEF1) as target genes of miR-34c in OS cells and demonstrated that Notch1 and LEF1 have a major role in the effects of miR-34c on OS cell chemosensitivity and metastasis. Taken together, our data indicate that miR-34c suppresses OS metastasis and chemoresistance by targeting Notch1 and LEF1. Restoring miR-34c may have important implications for the development of strategies for inhibiting metastasis and overcoming OS cell resistance to chemotherapy.
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Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ. Osteosarcoma. J Am Acad Orthop Surg. 2009;17:515–27.
Thayanithy V, Sarver AL, Kartha RV, Li L, Angstadt AY, Breen M, et al. Perturbation of 14q32 miRNAs-cMYC gene network in osteosarcoma. Bone. 2012;50:171–81.
Broadhead ML, Clark JC, Myers DE, Dass CR, Choong PF. The molecular pathogenesis of osteosarcoma: a review. Sarcoma. 2011;2011:959248.
Marulanda GA, Henderson ER, Johnson DA, Letson GD, Cheong D. Orthopedic surgery options for the treatment of primary osteosarcoma. Cancer Control. 2008;15:13–20.
Huang J, Ni J, Liu K, Yu Y, Xie M, Kang R, et al. HMGB1 promotes drug resistance in osteosarcoma. Cancer Res. 2012;72:230–8.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNA expression and function in cancer. Trends Mol Med. 2006;12:580–7.
Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 2010;11:136–46.
Chistiakov DA, Chekhonin VP. Contribution of microRNAs to radio- and chemoresistance of brain tumors and their therapeutic potential. Eu J Pharmacol. 2012;684:8–18.
He C, Xiong J, Xu X, Lu W, Liu L, Xiao D, et al. Functional elucidation of MiR-34 in osteosarcoma cells and primary tumor samples. Biochem Biophys Res Communi. 2009;388:35–40.
van der Deen M, Taipaleenmaki H, Zhang Y, Teplyuk NM, Gupta A, Cinghu S, et al. MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma. J Biol Chem. 2013;288:21307–19.
Wu H, Huang M, Lu M, Zhu W, Shu Y, Cao P, et al. Regulation of microtubule-associated protein tau (MAPT) by miR-34c-5p determines the chemosensitivity of gastric cancer to paclitaxel. Cancer Chem Pharmacol. 2013;71:1159–71.
Yang S, Li Y, Gao J, Zhang T, Li S, Luo A, et al. MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene. 2013;32:4294–303.
Bacci G, Bertoni F, Longhi A, Ferrari S, Forni C, Biagini R, et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer. 2003;97:3068–75.
Xu CX, Jere D, Jin H, Chang SH, Chung YS, Shin JY, et al. Poly(ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. Am J Respir Crit Care Med. 2008;178:60–73.
Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005;23:2004–11.
Catuogno S, Cerchia L, Romano G, Pognonec P, Condorelli G, de Franciscis V. MiR-34c may protect lung cancer cells from paclitaxel-induced apoptosis. Oncogene. 2013;32:341–51.
Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010;11:537–61.
Di Leva G, Croce CM. Roles of small RNAs in tumor formation. Trends Mol Med. 2010;16:257–67.
Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celia-Terrassa T, et al. Direct targeting of Sec23a by miR-200 s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011;17:1101–8.
Bhattacharya A, Ziebarth JD, Cui Y. SomamiR: a database for somatic mutations impacting microRNA function in cancer. Nucleic Acids Res. 2013;41:D977–82.
Mu X, Isaac C, Greco N, Huard J, Weiss K. Notch signaling is associated with ALDH activity and an aggressive metastatic phenotype in murine osteosarcoma cells. Front Oncol. 2013;3:143.
Hsu KW, Hsieh RH, Huang KH, Fen-Yau Li A, Chi CW, Wang TY, et al. Activation of the Notch1/STAT3/twist signaling axis promotes gastric cancer progression. Carcinogenesis. 2012;33:1459–67.
Nguyen DX, Chiang AC, Zhang XH, Kim JY, Kris MG, Ladanyi M, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell. 2009;138:51–62.
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This work was supported by the National High Technology Research and Development Program of China (2011AA030101); and the China International Medical Foundation (CIMF-F-H001-240).
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Xu, M., Jin, H., Xu, CX. et al. MiR-34c inhibits osteosarcoma metastasis and chemoresistance. Med Oncol 31, 972 (2014). https://doi.org/10.1007/s12032-014-0972-x
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DOI: https://doi.org/10.1007/s12032-014-0972-x