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Upregulation of KLHL17 promotes the proliferation and migration of non-small cell lung cancer by activating the Ras/MAPK signaling pathway

Abstract

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.

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Fig. 1: Database information showing high expression of KLHL17 in non-small cell lung cancer.
Fig. 2: KLHL17 is associated with poor prognosis of patients with non-small cell lung cancer.
Fig. 3: KLHL17 is highly expressed in the cell lines of non-small cell lung cancer (NSCLC).
Fig. 4: KLHL17 promotes the proliferation of non-small cell lung cancer cells.
Fig. 5: KLHL17 promotes the migration of non-small cell lung cancer cells.
Fig. 6: KLHL17 regulates the Ras/MAPK signaling pathway.
Fig. 7: Inhibition of Ras/MAPK signaling pathway with Ras inhibitor salirasib prevents KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Editage (www.editage.cn) for their English language editing service.

Funding

This study was supported by Shengjing Hospital of China Medical University and the First Hospital of China Medical University.

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ZL designed the study, conducted experiments, acquired and analyzed data, and wrote the manuscript. MZ, XJ, YZ, SZ, YX, HR, HS, and HW conducted the experiments and acquired data. XQ was responsible for the conception and supervision of the study and wrote the manuscript. All authors corrected drafts and approved the final version of the manuscript.

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Correspondence to Xueshan Qiu.

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The authors declare no competing interests.

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Liu, Z., Zhao, M., Jiang, X. et al. Upregulation of KLHL17 promotes the proliferation and migration of non-small cell lung cancer by activating the Ras/MAPK signaling pathway. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00806-7

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