MiR-33b inhibits osteosarcoma cell proliferation through suppression of glycolysis by targeting Lactate Dehydrogenase A (LDHA)

Xin-Min Zheng; Chun-Wei Xu; Fei Wang

doi:10.14715/cmb/2018.64.11.6

Issue

Vol. 64 No. 11: Issue 11

Issue Published : August 31, 2018

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MiR-33b inhibits osteosarcoma cell proliferation through suppression of glycolysis by targeting Lactate Dehydrogenase A (LDHA)

https://doi.org/10.14715/cmb/2018.64.11.6

Xin-Min Zheng

Department of Emergency Surgery, General Hospital of Daqing Oil Field, Heilongjiang 163001, China

Chun-Wei Xu

Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian,350014, China

Fei Wang

Department of Orthopedics, China-Japan Union Hospital Jilin University, Changchun, Jilin, 130033, China

Corresponding Author(s) : Xin-Min Zheng

zheng_xin_min@163.com

Cellular and Molecular Biology, Vol. 64 No. 11: Issue 11
Article Published : August 30, 2018

Abstract

Osteosarcoma (OS) is one of the most common types of malignant bone tumor in adolescent. MicroRNAs (miRNAs) are widely studied regulatory molecules which play important roles in tumor development, differentiation, growth, invasion, chemosensitivity and cellular metabolism. Recently, miR-33b has been reported to act as a tumor suppressor in osteosarcoma. However, the detailed mechanism of miR-33b in regulating osteosarcoma cell proliferation remains unclear. In this study, we detected miR-33b was significantly downregulated in osteosarcoma tissues compared to their matched adjacent nontumor tissues. The decreased expressions of miR-33b were also found in multiple osteosarcoma cell lines, including MG63, Saos-2, U2OS and SOSP-9607 when compared to normal osteoblast cell line hFOB. Overexpression of miR-33b suppressed U2OS cell proliferation and anaerobic glycolysis. We identified Lactate dehydrogenase-A (LDHA) as a direct target of miR-33b in osteosarcoma tumors and cells by Western blot and luciferase assay. Moreover, inhibition of LDHA significantly suppressed glycolysis and cell proliferation of osteosarcoma cells. Restoration of LDHA in miR-33b-overexpressing osteosarcoma cells reversed the suppressive effect of miR-33b on cell proliferation. In addition, we report a significantly negative correlation between LDHA mRNA and miR-33b expression in osteosarcoma tumors: miR-33b is downregulated in OS tumors with high levels of LDHA (92.9%). Meanwhile, high miR-33b expressions were found majorly in OS tumors with low LDHA mRNA levels (82.4%). This study reveals that miR-33b plays a suppressive role in the regulation of osteosarcoma cell proliferation through direct targeting LDHA. The miR-33b/glycolysis/LDHA axis may contribute to development of therapeutic anti-tumor agents for osteosarcoma.

Keywords

MiR-33b osteosarcoma cell glycolysis Lactate Dehydrogenase A (LDHA).

Zheng, X.-M., Xu, C.-W., & Wang, F. (2018). MiR-33b inhibits osteosarcoma cell proliferation through suppression of glycolysis by targeting Lactate Dehydrogenase A (LDHA). Cellular and Molecular Biology, 64(11), 31–35. https://doi.org/10.14715/cmb/2018.64.11.6

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References

References
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Lin Y, Liu AY, Fan C, Zheng H, Li Y, Zhang C, et al. MicroRNA-33b inhibits breast cancer metastasis by targeting HMGA2, SALL4 and twist1. Sci Rep 2015; 5:9995.
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Liao W, Gu C, Huang A, Yao J, Sun R. MicroRNA-33b inhibits tumor cell growth and is associated with prognosis in colorectal cancer patients. Clin Transl Oncol 2016; 18:449-456.
Li F, Hao M, Feng X, Zang M, Qin Y, Yi S, et al. Downregulated miR-33b is a novel predictor associated with disease progression and poor prognosis in multiple myeloma. Leuk Res 2015; 39:793-799.
Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The regulation and function of lactate dehydrogenase a: Therapeutic potential in brain tumor. Brain Pathol 2016; 26:3-17.
Allison SJ, Knight JR, Granchi C, Rani R, Minutolo F, Milner J, et al. Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53-independent pathways. Oncogenesis 2014; 3:e102.
Miao P, Sheng S, Sun X, Liu J, Huang G. Lactate dehydrogenase a in cancer: A promising target for diagnosis and therapy. IUBMB Life 2013; 65:904-910.
Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci 2016; 41:211-218.
Zou C, Xu Q, Mao F, Li D, Bian C, Liu LZ, et al. MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF. Cell Cycle 2012; 11:2137-2145.
Lin S, Shao NN, Fan L, Ma XC, Pu FF, Shao ZW. Effect of microRNA-101 on proliferation and apoptosis of human osteosarcoma cells by targeting mTOR. J Huazhong Univ Sci Technolog Med Sci 2014; 34:889-895.
Zhang P, Bai H, Liu G, Wang H, Chen F, Zhang B, et al. MicroRNA-33b, upregulated by EF24, a curcumin analog, suppresses the epithelial-to-mesenchymal transition (EMT) and migratory potential of melanoma cells by targeting HMGA2. Toxicol Lett 2015; 234:151-161.
Zhou Y, Yang C, Wang K, Liu X, Liu Q. MicroRNA-33b inhibits the proliferation and migration of osteosarcoma cells via targeting Hypoxia-Inducible factor-1alpha. Oncol Res 2017; 25:397-405.
Gao S, Tu DN, Li H, Jiang JX, Cao X, You JB, et al. Pharmacological or genetic inhibition of LDHA reverses tumor progression of pediatric osteosarcoma. Biomed Pharmacother 2016; 81:388-393.

References

Durfee RA, Mohammed M, Luu HH. Review of osteosarcoma and current management. Rheumatol Ther 2016; 3:221-243.

Kager L, Tamamyan G, Bielack S. Novel insights and therapeutic interventions for pediatric osteosarcoma. Future Oncol 2017; 13:357-368.

Morrow JJ, Khanna C. Osteosarcoma genetics and epigenetics: Emerging biology and candidate therapies. Crit Rev Oncog 2015; 20:173-197.

Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 2015; 16:421-433.

Hayes J, Peruzzi PP, Lawler S. MicroRNAs in cancer: Biomarkers, functions and therapy. Trends Mol Med 2014; 20:460-469.

Rupaimoole R, Slack FJ. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2017; 16:203-222.

Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 2015; 15:321-333.

Qu J, Li M, An J, Zhao B, Zhong W, Gu Q, et al. MicroRNA-33b inhibits lung adenocarcinoma cell growth, invasion, and epithelial-mesenchymal transition by suppressing Wnt/beta-catenin/ZEB1 signaling. Int J Oncol 2015; 47:2141-2152.

Lin Y, Liu AY, Fan C, Zheng H, Li Y, Zhang C, et al. MicroRNA-33b inhibits breast cancer metastasis by targeting HMGA2, SALL4 and twist1. Sci Rep 2015; 5:9995.

Yang X, Zhao Q, Yin H, Lei X, Gan R. MiR-33b-5p sensitizes gastric cancer cells to chemotherapy drugs via inhibiting HMGA2 expression. J Drug Target 2017; 25:653-660.

Liao W, Gu C, Huang A, Yao J, Sun R. MicroRNA-33b inhibits tumor cell growth and is associated with prognosis in colorectal cancer patients. Clin Transl Oncol 2016; 18:449-456.

Li F, Hao M, Feng X, Zang M, Qin Y, Yi S, et al. Downregulated miR-33b is a novel predictor associated with disease progression and poor prognosis in multiple myeloma. Leuk Res 2015; 39:793-799.

Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The regulation and function of lactate dehydrogenase a: Therapeutic potential in brain tumor. Brain Pathol 2016; 26:3-17.

Allison SJ, Knight JR, Granchi C, Rani R, Minutolo F, Milner J, et al. Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53-independent pathways. Oncogenesis 2014; 3:e102.

Miao P, Sheng S, Sun X, Liu J, Huang G. Lactate dehydrogenase a in cancer: A promising target for diagnosis and therapy. IUBMB Life 2013; 65:904-910.

Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci 2016; 41:211-218.

Zou C, Xu Q, Mao F, Li D, Bian C, Liu LZ, et al. MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF. Cell Cycle 2012; 11:2137-2145.

Lin S, Shao NN, Fan L, Ma XC, Pu FF, Shao ZW. Effect of microRNA-101 on proliferation and apoptosis of human osteosarcoma cells by targeting mTOR. J Huazhong Univ Sci Technolog Med Sci 2014; 34:889-895.

Zhang P, Bai H, Liu G, Wang H, Chen F, Zhang B, et al. MicroRNA-33b, upregulated by EF24, a curcumin analog, suppresses the epithelial-to-mesenchymal transition (EMT) and migratory potential of melanoma cells by targeting HMGA2. Toxicol Lett 2015; 234:151-161.

Zhou Y, Yang C, Wang K, Liu X, Liu Q. MicroRNA-33b inhibits the proliferation and migration of osteosarcoma cells via targeting Hypoxia-Inducible factor-1alpha. Oncol Res 2017; 25:397-405.

Gao S, Tu DN, Li H, Jiang JX, Cao X, You JB, et al. Pharmacological or genetic inhibition of LDHA reverses tumor progression of pediatric osteosarcoma. Biomed Pharmacother 2016; 81:388-393.

Author biographies is not available.