Dysregulated m6A-Related Regulators Are Associated With Tumor Metastasis and Poor Prognosis in Osteosarcoma

Jianhao Li; Benchen Rao; Jie Yang; Liwen Liu; Maoxin Huang; Xin Liu; Guangying Cui; Chao Li; Qicai Han; Hao Yang; Xichun Cui; Ranran Sun

doi:10.3389/fonc.2020.00769

Dysregulated m6A-Related Regulators Are Associated With Tumor Metastasis and Poor Prognosis in Osteosarcoma

Front Oncol. 2020 Jun 2:10:769. doi: 10.3389/fonc.2020.00769. eCollection 2020.

Authors

Jianhao Li^{1

2}, Benchen Rao^{1

2}, Jie Yang³, Liwen Liu^{1

2}, Maoxin Huang⁴, Xin Liu^{1

2}, Guangying Cui^{1

2}, Chao Li⁵, Qicai Han⁶, Hao Yang⁶, Xichun Cui², Ranran Sun^{1

2}

Affiliations

¹ Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Department of Orthopedics, Zhengzhou Central Affiliated Hospital to Zhengzhou University, Zhengzhou, China.
⁴ Dermatology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁶ Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.

Abstract

Background: Osteosarcoma (OS) is the most common primary bone tumor. The disease has a poor prognosis due to the delay in the diagnosis and the development of metastasis. N6-Methyladenosine (m6A)-related regulators play an essential role in various tumors. In this study, a comprehensive analysis was conducted to elucidate the relationship between the expression profiles of m6A-related molecules and the clinical outcome of OS patients. Materials and Methods: Public genome datasets and a tissue microarray (TMA) cohort were used to analyze the mRNA and protein expression levels of m6A regulators. Next, immunofluorescence (IF) analysis was used to determine the subcellular localization of m6A-related molecules. Kaplan-Meier and Cox regression analyses were performed to confirm the prognostic value of m6A-related molecules in OS. A comprehensive bioinformatic analysis was conducted to identify the potential molecular mechanisms mediated by m6A modification in OS. Results: We found that m6A-related regulator expression was dysregulated in OS tissues, especially in metastatic tumor tissues. Low expression of METTL3, METTL14, and YTHDF2 and high expression of KIAA1429 and HNRNPA2B1 were significantly associated with poor prognosis in the TMA cohort. Simultaneously, the genome meta-cohort analysis revealed that low expression of FTO and METTL14 and high expression of METTL3, HNRNPA2B1, and YTHDF3 were associated with poor prognosis in OS. Cox regression analysis showed that HNRNPA2B1 might be an independent risk factor for OS. Bioinformatic analysis indicated that m6A regulators might be involved in OS progression through humoral immune response and cell cycle pathways. Conclusion: M6A-related regulators are frequently dysregulated and correlate with metastasis and prognosis in OS. M6A-related regulators may serve as novel therapeutic targets and prognostic biomarkers for OS.

Keywords: N6-methyladenosine; biomarkers; osteosarcoma; prognosis; tumor metastasis.