Paclitaxel (PTX), a tubulin-binding agent, is widely used and has shown good efficacy in the initial period of treatment for non-small cell lung cancer (NSCLC). However, the relatively rapid acquisition of resistance to PTX treatments that is observed in virtually all cases significantly limits its utility and remains a substantial challenge to the clinical management of NSCLC. The aim of this study was to identify candidate genes and mechanisms that might mediate acquired paclitaxel resistance. In this work, we established paclitaxel-resistant cells (A549-T) from parental cell lines by step-dose selection in vitro. Using methylation chip analysis and transcriptome sequencing, 43,426 differentially methylated genes and 2,870 differentially expressed genes are identified. Six genes (KANK1, ALDH3A1, GALNT14, PIK3R3, LRG1, WEE2), which may be related to paclitaxel resistance in lung adenocarcinoma, were identified. Among these genes, KANK1 exhibited significant differences in methylation and expression between cell lines. Since KANK1 plays an important role in the development of renal cancer and gastric cancer, we hypothesised that it may also play a role in acquired resistance in lung adenocarcinoma. Transient transfection of SiKANK1 significantly reduced the expression of KANK1, reducing apoptosis, increasing cell migration, and enhancing the tolerance of A549 cells to paclitaxel. KANK1 acts as a tumour suppressor gene, mediating the resistance of lung adenocarcinoma A549 to paclitaxel. The reduction of KANK1 expression can increase the paclitaxel resistance of non-small cell lung cancer and increase the difficulty of clinical treatment.

中文翻译：

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KANK1调节肺腺癌A549细胞中的紫杉醇耐药性。

紫杉醇（PTX）是一种微管蛋白结合剂，已被广泛使用，并且在非小细胞肺癌（NSCLC）的治疗初期显示出良好的疗效。但是，几乎在所有情况下都观察到对PTX治疗耐药性的相对较快获得，这极大地限制了其实用性，仍然是NSCLC临床管理的重大挑战。这项研究的目的是确定可能介导获得性紫杉醇耐药性的候选基因和机制。在这项工作中，我们通过体外分步剂量选择从亲本细胞系中建立了抗紫杉醇的细胞（A549-T）。使用甲基化芯片分析和转录组测序，鉴定出43426个差异甲基化基因和2870个差异表达基因。六个基因（KANK1，ALDH3A1，GALNT14，PIK3R3，LRG1，WEE2），鉴定出可能与肺腺癌中紫杉醇耐药性有关。在这些基因中，KANK1在细胞系之间的甲基化和表达方面表现出显着差异。由于KANK1在肾癌和胃癌的发展中起重要作用，因此我们假设它也可能在肺腺癌的获得性耐药中起作用。SiKANK1的瞬时转染显着降低了KANK1的表达，减少了细胞凋亡，增加了细胞迁移，并增强了A549细胞对紫杉醇的耐受性。KANK1作为肿瘤抑制基因，介导肺腺癌A549对紫杉醇的耐药性。KANK1表达的降低可增加非小细胞肺癌对紫杉醇的耐药性，增加临床治疗的难度。