Abstract：
Lung cancer is one of the most frequently diagnosed cancers worldwide, associated with a poor survival rate. Taxol (Paclitaxel) is commonly used as a chemotherapeutic treatment for advanced lung cancers. While Taxol has improved clinical outcomes for lung cancer patients, a significant number of them develop resistance to Taxol, resulting in treatment failure. The role of the long noncoding RNA HCG18 in lung cancer and Taxol resistance has not yet been fully understood. To investigate this, we examined the expression of HCG18 and miR-34a-5p in lung tumors and normal lung tissues using qRT-PCR. We also assessed Taxol resistance through cell viability and apoptosis assays. Through the starBase online service, we analyzed the interactions between lncRNA and mRNA as well as miRNA and mRNA. We further validated the association between lncRNA and miRNA through luciferase and RNA pull-down assays. Our findings demonstrated that HCG18 was significantly upregulated in lung cancer tissues compared to normal lung tissues. Silencing HCG18 increased the sensitivity of lung cancer cells to Taxol. Additionally, our study established a Taxol-resistant cell line and observed a substantial upregulation of HCG18 in Taxol-resistant lung cancer cells. Bioinformatic analysis predicted that HCG18 could bind to miR-34a-5p, forming a competing endogenous RNA network, which was confirmed through luciferase assay. We found that miR-34a-5p was downregulated in lung cancer tissues and negatively correlated with Taxol resistance, as it directly bound to the 3\'UTR region of HDAC1. Further results showed that inhibition of HCG18 significantly increased miR-34a-5p expression and sensitized lung cancer cells to Taxol. This sensitization could be reversed by inhibiting miR-34a-5p. Finally, we demonstrated in a xenograft mouse model that inhibition of HCG18 sensitized Taxol-resistant lung cancer cells to Taxol treatment by modulating the miR-34a-5p-HDAC1 axis. In conclusion, our in vitro and in vivo results uncover a novel molecular mechanism by which HCG18 promotes Taxol resistance through modulation of the miR-34a-5p/HDAC1 axis. These findings contribute to the diagnosis and treatment of chemo-resistant lung cancer.
摘要：
肺癌是全球最常见的癌症之一，与低存活率有关。紫杉醇(紫杉醇)通常用作晚期肺癌的化疗治疗。虽然紫杉醇改善了肺癌患者的临床预后，他们中的许多人对紫杉醇产生抗药性，导致治疗失败。长链非编码RNAHCG18在肺癌和紫杉醇耐药中的作用尚未完全了解。为了调查这一点，我们使用qRT-PCR检测了HCG18和miR-34a-5p在肺肿瘤和正常肺组织中的表达。我们还通过细胞活力和凋亡测定评估了紫杉醇抗性。通过starBase在线服务,我们分析了lncRNA和mRNA以及miRNA和mRNA之间的相互作用。我们通过荧光素酶和RNA下拉法进一步验证了lncRNA和miRNA之间的关联。我们的发现表明，与正常肺组织相比，HCG18在肺癌组织中明显上调。沉默HCG18可增加肺癌细胞对紫杉醇的敏感性。此外,我们的研究建立了一个紫杉醇耐药细胞系,并观察到HCG18在紫杉醇耐药肺癌细胞中显著上调.生物信息学分析预测HCG18可以结合miR-34a-5p，形成竞争的内源性RNA网络，通过荧光素酶测定证实。我们发现miR-34a-5p在肺癌组织中表达下调,与紫杉醇耐药呈负相关。因为它直接绑定到HDAC1的3UTR区域。进一步结果显示HCG18的抑制显著增加miR-34a-5p的表达并使肺癌细胞对紫杉醇敏感。这种致敏作用可以通过抑制miR-34a-5p而逆转。最后,我们在异种移植小鼠模型中证明,抑制HCG18通过调节miR-34a-5p-HDAC1轴,使紫杉醇耐药肺癌细胞对紫杉醇治疗敏感.总之,我们的体内外结果揭示了HCG18通过调节miR-34a-5p/HDAC1轴促进紫杉醇耐药的新分子机制.这些发现有助于化疗耐药肺癌的诊断和治疗。
