Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Department of Pain, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Lab Invest. 2022 Dec;102(12):1389-1399. doi: 10.1038/s41374-022-00806-7. Epub 2022 Aug 17.
Analysis of the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that Kelch-like 17 (KLHL17) is overexpressed in non-small cell lung cancer (NSCLC) including adenocarcinoma (ADC) and squamous cell carcinoma (SCC). We therefore explored the role of KLHL17 in the development and progression of NSCLC. Immunohistochemistry and western blotting showed that KLHL17 expression was significantly higher in the tumor tissues from 173 patients with NSCLC, compared with the corresponding non-neoplastic tissue. In addition, upregulated KLHL17 expression was positively correlated with tumor size, lymph node metastasis and tumor node metastasis (TNM) stage, and affected the overall survival (OS) of patients with NSCLC. Consistent with clinical samples, in vitro studies demonstrated that KLHL17 expression was higher in various cell lines of NSCLC (A549, H1299, H460 and SK cells) as compared to normal human bronchial epithelial cells (HBE cells). Overexpression of KLHL17 in the cell lines of NSCLC with KLHL17-Flag plasmid promoted the proliferation and migration of tumor cells, which was associated with elevated activation of Rat sarcoma/Mitogen-activated protein kinases (Ras/MAPK) signaling and increased expression of cyclin D1, cyclin D-dependent kinases 4 (CDK4), matrix metalloproteinase 2 (MMP2) and Ras homolog gene family member A (RhoA). In contrast, knockdown of KLHL17 in the cell lines of NSCLC using KLHL17 small interfering RNA suppressed the proliferation and migration of tumor cells, in association with reduced activation of Ras/MAPK signaling and decreased expression of cyclin D1, CDK4, MMP2 and RhoA. Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration. These results suggest that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating Ras/MAPK signaling pathway. Therefore, KLHL17 may be a novel therapeutic target for the treatment of NSCLC.
分析基因表达谱交互分析（GEPIA）数据库显示，Kelch-like 17（KLHL17）在非小细胞肺癌（NSCLC）中过表达，包括腺癌（ADC）和鳞状细胞癌（SCC）。因此，我们探讨了 KLHL17 在 NSCLC 发生和发展中的作用。免疫组织化学和 Western blot 显示，与相应的非肿瘤组织相比，173 例 NSCLC 患者的肿瘤组织中 KLHL17 表达明显升高。此外，上调的 KLHL17 表达与肿瘤大小、淋巴结转移和肿瘤淋巴结转移（TNM）分期呈正相关，并影响 NSCLC 患者的总生存期（OS）。与临床样本一致，体外研究表明，KLHL17 在各种 NSCLC 细胞系（A549、H1299、H460 和 SK 细胞）中的表达高于正常人类支气管上皮细胞（HBE 细胞）。用 KLHL17-Flag 质粒过表达 NSCLC 细胞系中的 KLHL17 促进了肿瘤细胞的增殖和迁移，这与 Rat sarcoma/Mitogen-activated protein kinases（Ras/MAPK）信号的激活升高以及细胞周期蛋白 D1、细胞周期蛋白依赖性激酶 4（CDK4）、基质金属蛋白酶 2（MMP2）和 Ras homolog gene family member A（RhoA）的表达增加有关。相反，用 KLHL17 小干扰 RNA 敲低 NSCLC 细胞系中的 KLHL17 抑制了肿瘤细胞的增殖和迁移，与 Ras/MAPK 信号的激活降低以及细胞周期蛋白 D1、CDK4、MMP2 和 RhoA 的表达减少有关。此外，用 Ras 抑制剂 salirasib 处理肿瘤细胞可阻止 KLHL17 诱导的 Ras/MAPK 活性以及肿瘤增殖和迁移。这些结果表明，上调的 KLHL17 在 NSCLC 中通过激活 Ras/MAPK 信号通路促进肿瘤的增殖和迁移。因此，KLHL17 可能是治疗 NSCLC 的新的治疗靶点。
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