Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), one of the first found cancer-associated long noncoding RNAs (lncRNAs), involves in the development and progression of many types of tumors. An aberrant expression of MALAT1 was observed in hepatocellular carcinoma, cervical cancer, breast cancer, ovarian cancer, and colorectal cancer. However, the exact effects and molecular mechanisms of MALAT1 in osteosarcoma progression are still unknown up to now. Here, we investigated the role of MALAT1 in human osteosarcoma cell lines and clinical tumor samples in order to determine the function of this molecule. In our research, the MALAT1 messenger RNA (mRNA) was highly expressed in human osteosarcoma tissues, and its expression level was closely correlated with pulmonary metastasis. Then, we employed lentivirus-mediated knockdown of MALAT1 in U-2 OS and SaO2 to determine the role of MALAT1 in osteosarcoma cell lines. Lentivirus-mediated MALAT1 small interfering RNA (siRNA) could efficiently downregulated the expression level of MALAT1 in osteosarcoma cell lines. Knockdown of MALAT1 inhibited the proliferation and invasion of human osteosarcoma cell and suppressed its metastasis in vitro and vivo. At the same time, the proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 9 (MMP-9), phosphorylated PI3Kp85α, and Akt expressions were significantly inhibited in MALAT1-deleted cells. These findings indicated that MALAT1 might suppress the tumor growth and metastasis via PI3K/AKT signaling pathway. Taken together, our data indicated that MALAT1 might be an oncogenic lncRNA that promoted proliferation and metastasis of osteosarcoma and could be regarded as a therapeutic target in human osteosarcoma.

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Background: Osteosarcoma (OS) is the most prevalent bone cancer among children and adolescents, with relatively high mortality rates. RNA N6-methyladenosine (m6A) is the most common human mRNA modification with diverse functions in a variety of biological processes. Previous studies indicated that methyltransferase-like 3 (METTL3), the first methyltransferase to be identified, acted as an oncogene or tumor suppressor in multiple human cancers. However, its functions and underlying mechanisms in OS progression remain unclear; therefore, we explored these processes.Methods: We used real-time quantitative PCR (RT-qPCR) and Western blot assays to explore METTL3 expression in OS tumor tissues and five OS cell lines to assess its clinical significance. To further examine the functional role of METTL3 during OS progression, CCK-8 analyses, transwell assays, and xenograft model studies were conducted after silencing METTL3. Additionally, underlying mechanisms were also explored using RIP-seq and RIP-qPCR approaches.Results: METTL3 was upregulated in OS tumor tissues and cell lines and was associated with a worse prognosis. Moreover, METTL3 silencing suppressed OS cell proliferation, migration, and invasion. Also, in vivo METTL3 oncogenic functions were confirmed in the xenograft model. Comprehensive mechanistic analyses identified long non-coding RNA (lncRNA) DANCR as a potential target of METTL3, as indicated by reduced DANCR levels after METTL3 silencing. Also, lncRNA DANCR knockdown repressed OS cell proliferation, migration, and invasion. Furthermore, both METTL3 and lncRNA DANCR silencing significantly suppressed OS growth and metastasis. Finally, we hypothesized that METTL3 regulated DANCR expression via m6A modification-mediated DANCR mRNA stability.Conclusion: METTL3 contributes to OS progression by increasing DANCR mRNA stability via m6A modification, meaning that METTL3 may be a promising therapeutic target for OS treatment.

CXCL2, a member of the CXC family, is involved in various immune and inflammatory processes, while its effects on bone formation have not been reported. We first revealed here that CXCL2 is enriched in bone marrow and further showed abundant CXCL2 expression in osteoblasts of osteoporotic mice. CXCL2 neutralization in the bone marrow alleviated bone loss in the mice, indicating negative role of CXCL2 in bone formation. In line with this, CXCL2 over-expression attenuated proliferation as well as differentiation of osteoblasts in vitro. On the contrary, CXCL2 down-regulation promoted osteoblast expansion and differentiation. Mechanistically, CXCL2 inhibited ERK1/2 signaling in osteoblasts. Activation of ERK1/2 abolished the inhibitory effect of CXCL2 on osteoblasts, while ERK1/2 inactivation reversed the osteogenic role of CXCL2 inhibition. These results proved that CXCL2 attenuates osteoblasts differentiation via inhibiting ERK1/2 signaling pathway. Thus, we demonstrate that CXCL2 is a negative regulator of bone formation and clarify the mechanisms responsible. Pharmaceutical coordination of CXCL2 and the pathways in osteoblasts maybe beneficial in bone formation.

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