Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal lungs, as expected for an oncogene. Intriguingly, the predicted binding miR-378a-3p showed a significant inverse correlation with JPX expression. The lncRNA/miRNA physical interaction was validated by reporter vectors. Then, the oncogenic activity of JPX, the tumor-suppressive role of miR-378a-3p, and the contribution of their functional interaction to cancer hallmarks were demonstrated using assays for cell proliferation, migration, invasion, and 3D-spheroid formation. Finally, molecular circuits were investigated by boosting the expression of both JPX and miR-378a-3p, singularly and in combination, demonstrating that JPX counteracted miR-378a-3p silencing activity toward its oncogenic targets GLUT1, NRP1, YY1, and Wnt5a. Overall, the data unveil a novel ceRNET (competing endogenous RNA network), wherein JPX acts as a ceRNA by binding to miR-378a-3p, thus reducing the miRNA silencing activity toward its downstream targets, and eliciting oncogenic pathways driving lung cancer. The knowledge of the network may pave the way to develop new diagnostic panels, and innovative RNA-targeted and RNA-based therapeutic strategies.
肺癌是全球癌症相关死亡的主要原因。非编码RNA在癌症的发生和发展中扮演着关键角色。对三个不同数据集的分析显示，与正常肺组织相比，长链非编码RNA JPX在肺腺癌组织中过度表达，符合其作为癌基因的预期。值得注意的是，预测与JPX结合的miR-378a-3p的表达水平与JPX呈显著负相关。通过报告载体实验验证了该长链非编码RNA与miRNA的物理相互作用。随后，通过细胞增殖、迁移、侵袭及三维球体形成实验，证实了JPX的促癌活性、miR-378a-3p的抑癌作用以及二者功能互作对癌症特征的贡献。最后，通过分别及联合增强JPX和miR-378a-3p的表达，研究了其分子调控环路，证明JPX能够拮抗miR-378a-3p对其致癌靶点GLUT1、NRP1、YY1和Wnt5a的沉默活性。总体而言，本研究揭示了一个新的竞争性内源RNA网络，其中JPX作为ceRNA与miR-378a-3p结合，从而减弱该miRNA对其下游靶点的沉默作用，并激活驱动肺癌发生的致癌通路。对该网络的认知可能为开发新的诊断工具以及创新的RNA靶向和基于RNA的治疗策略奠定基础。
A Novel ceRNET Relying on the lncRNA JPX, miR-378a-3p, and Its mRNA Targets in Lung Cancer
肿瘤(癌症)患者之家