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

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 metacohort 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.

Expression of m6A Regulators Correlated With Immune Microenvironment Predicts Therapeutic Efficacy and Prognosis in Gliomas

“…These results suggested that although FTO was highly expressed in glioma tissues, it might play a protective role for patients with gliomas. Li J. et al (2020) found that the expression of m6A regulators was dysregulated in osteosarcoma, and low expression of FTO and high expression of YTHDF3 was associated with poor prognosis, which was consistent with our findings. Besides, FTO could suppress the self-renewal of ovarian cancer stem cells via inhibiting cyclic adenosine monophosphate (cAMP) signaling pathway ( Huang et al, 2020b ).…”

<p><em>METTL14</em> Overexpression Promotes Osteosarcoma Cell Apoptosis and Slows Tumor Progression via <em>Caspase 3</em> Activation</p>

“…Recent studies have shown that m 6 A methylation modifying enzymes are abnormally expressed in some malignant tumors. Li et al, 18 found that in OS patients, especially in metastatic tissues, disorders involving m6A-related regulatory factors, such as the low expression of METTL3 and METTL14, can be related to poor prognosis of patients. This observation is consistent with the results of our study.…”

Construction of a circRNA-miRNA-mRNA network based on competitive endogenous RNA reveals the key pathways and central genes of osteosarcoma in vivo

“…In addition, studies have found that COL1A1 polymorphism is associated with risks of OS transfer and patient death in which COL1A1 polymorphism at rs1061970 has value for overall survival in Chinese OS patients [32] . Research by Li et al found that high expression of HNRNPA2B1 is associated with poor prognosis of OS, and Cox regression analysis showed that HNRNPA2B1 is an independent risk factor for OS [33] . But in our study, the expression level of HNRNPA2B1 does not shown the signi cantly correlated with overall survival in patients with osteosarcoma.…”