Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Cell Death Dis. 2020 Sep 18;11(9):777. doi: 10.1038/s41419-020-02978-w.
Long non-coding RNAs (lncRNAs), which may be modulated by chemokines, are key regulators in many cancers including oral squamous cell carcinoma (OSCC). An understanding of lncRNAs involved in chemokine (CC motif) ligand 18 (CCL18)-induced OSCC promotion remains elusive. The present study using lncRNA sequencing found LINC00319 to be significantly upregulated in OSCC cells subjected to rCCL18 stimulation. Furthermore, LINC00319 knockdown was found to attenuate the carcinogenic function of CCL18 in OSCC, reducing OSCC proliferation, metastasis, epithelial-mesenchymal transition (EMT), and angiogenesis. LINC00319 was demonstrated to act as a ceRNA in OSCC, which directly responded to miR-199a-5p and rescued the repression of FZD4 by miR-199a-5p. Functionally, in vitro and in vivo experiments showed that LINC00319 promoted OSCC growth and metastasis via downregulating miR-199a-5p and upregulating FZD4. In vitro rescue assays demonstrated that miR-199a-5p inhibitor or FZD4 overexpression reversed the effects of LINC00319 silencing in OSCC. Importantly, the expression of miR-199a-5p and FZD4 were found to be mediated by CCL18, and miR-199a-5p mimics inhibited the CCL18-promoting effects in oral cancer cells. Taken together, these results evidenced a mechanism of CCL18 action in OSCC mediated through the LINC00319/miR-199a-5p/FZD4 signaling pathway, which may comprise a potential target for OSCC therapeutic development.
长链非编码 RNA（lncRNA）可能受趋化因子调节，是包括口腔鳞状细胞癌（OSCC）在内的许多癌症的关键调节因子。对于参与趋化因子（CC 基序）配体 18（CCL18）诱导的 OSCC 促进的 lncRNA 的理解仍不清楚。本研究使用 lncRNA 测序发现，在受 rCCL18 刺激的 OSCC 细胞中，LINC00319 显著上调。此外，发现 LINC00319 敲低可减弱 CCL18 在 OSCC 中的致癌作用，降低 OSCC 增殖、转移、上皮-间充质转化（EMT）和血管生成。LINC00319 被证明在 OSCC 中作为 ceRNA 起作用，它直接响应 miR-199a-5p，并挽救 miR-199a-5p 对 FZD4 的抑制作用。功能上，体外和体内实验表明，LINC00319 通过下调 miR-199a-5p 和上调 FZD4 促进 OSCC 生长和转移。体外挽救实验表明，miR-199a-5p 抑制剂或 FZD4 过表达逆转了 OSCC 中 LINC00319 沉默的作用。重要的是，miR-199a-5p 和 FZD4 的表达被发现由 CCL18 介导，miR-199a-5p 模拟物抑制了口腔癌细胞中 CCL18 的促进作用。总之，这些结果证明了 CCL18 在 OSCC 中的作用机制是通过 LINC00319/miR-199a-5p/FZD4 信号通路介导的，这可能成为 OSCC 治疗开发的潜在靶点。
