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.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
We are sorry, but there is no personal subscription option available for your country.
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Hong QY, Wu GM, Qian GS, Hu CP, Zhou JY, Chen LA, et al. Prevention and management of lung cancer in China. Cancer, 121 Suppl 17, 3080-8 (2015)
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 71(3), 209-49 (2021)
Ji X, Bosse Y, Landi MT, Gui J, Xiao X, Qian D, et al. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nat Commun, 9(1), 3221 (2018)
Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med, 27(8), 1345-56 (2021)
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin, 67(1), 7-30 (2017)
Hassanein SS, Abdel-Mawgood AL, Ibrahim SA. EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer. Front Oncol, 11, 766659 (2021)
Hassanein SS, Ibrahim SA, Abdel-Mawgood AL. Cell Behavior of Non-Small Cell Lung Cancer Is at EGFR and MicroRNAs Hands. Int J Mol Sci, 22(22), (2021)
Dhanoa BS, Cogliati T, Satish AG, Bruford EA, Friedman JS. Update on the Kelch-like (KLHL) gene family. Hum Genomics, 7, 13 (2013)
Hu H-T, Huang T-N, Hsueh Y-P. KLHL17/Actinfilin, a brain-specific gene associated with infantile spasms and autism, regulates dendritic spine enlargement. J Biomed Sci, 27(1), 103 (2020)
Kang MI, Kobayashi A, Wakabayashi N, Kim SG, Yamamoto M. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A, 101(7), 2046-51 (2004)
Minor DL, Lin YF, Mobley BC, Avelar A, Jan YN, Jan LY, et al. The polar T1 interface is linked to conformational changes that open the voltage-gated potassium channel. Cell, 102(5), 657-70 (2000)
Melnick A, Ahmad KF, Arai S, Polinger A, Ball H, Borden KL, et al. In-depth mutational analysis of the promyelocytic leukemia zinc finger BTB/POZ domain reveals motifs and residues required for biological and transcriptional functions. Mol Cell Biol, 20(17), 6550-67 (2000)
Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol, 5(11), 1001-7 (2003)
Xu L, Wei Y, Reboul J, Vaglio P, Shin TH, Vidal M, et al. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature, 425(6955), 316-21 (2003)
Adams J, Kelso R, Cooley L. The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol, 10(1), 17-24 (2000)
Xu Y, Wang C, Jiang X, Zhang Y, Su H, Jiang J, et al. KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway. Cell Death Dis, 12(6), 556 (2021)
Jiang X, Xu Y, Ren H, Jiang J, Wudu M, Wang Q, et al. KLHL18 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by inhibiting PI3K/PD-L1 axis activity. Cell Biosci, 10(1), 139 (2020)
Titus AJ, Way GP, Johnson KC, Christensen BC. Deconvolution of DNA methylation identifies differentially methylated gene regions on 1p36 across breast cancer subtypes. Sci Rep, 7(1), 11594 (2017)
Zheng X, Xu H, Yi X, Zhang T, Wei Q, Li H, et al. Tumor-antigens and immune landscapes identification for prostate adenocarcinoma mRNA vaccine. Mol Cancer, 20(1), 160 (2021)
Chae HS, Gil M, Saha SK, Kwak HJ, Park HW, Vellingiri B, et al. Sestrin2 Expression Has Regulatory Properties and Prognostic Value in Lung Cancer. J Pers Med, 10(3), (2020)
Zhou H, Cai L, Zhang X, Li A, Miao Y, Li Q, et al. ARHGEF39 promotes tumor progression via activation of Rac1/P38 MAPK/ATF2 signaling and predicts poor prognosis in non-small cell lung cancer patients. Lab Invest, 98(5), 670-81 (2018)
Zhang X, Luo Y, Li Q. TMED3 Promotes Proliferation and Migration in Breast Cancer Cells by Activating Wnt/beta-Catenin Signaling. Onco Targets Ther, 13, 5819-30 (2020)
Park JH, Han HJ. Caveolin-1 plays important role in EGF-induced migration and proliferation of mouse embryonic stem cells: involvement of PI3K/Akt and ERK. Am J Physiol Cell Physiol, 297(4), C935-44 (2009)
Xiang S, Shi X, Chen P, Chen Y, Bing S, Jin X, et al. Targeting Cul3-scaffold E3 ligase complex via KLHL substrate adaptors for cancer therapy. Pharmacol Res, 169, 105616 (2021)
Canning P, Cooper CDO, Krojer T, Murray JW, Pike ACW, Chaikuad A, et al. Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. J Biol Chem, 288(11), 7803-14 (2013)
Shi X, Xiang S, Cao J, Zhu H, Yang B, He Q, et al. Kelch-like proteins: Physiological functions and relationships with diseases. Pharmacol Res, 148, 104404 (2019)
Lin Z, Li S, Feng C, Yang S, Wang H, Ma D, et al. Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility. Nat Genet, 48(12), 1508-16 (2016)
Chen J, Ou Y, Yang Y, Li W, Xu Y, Xie Y, et al. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature, 557(7706), 585-9 (2018)
Chen JC, Alvarez MJ, Talos F, Dhruv H, Rieckhof GE, Iyer A, et al. Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell, 159(2), 402-14 (2014)
Yuan W-C, Lee Y-R, Huang S-F, Lin Y-M, Chen T-Y, Chung H-C, et al. A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell, 20(2), 214-28 (2011)
Liu XR, Wang W, Li HM. KLHL22 promotes malignant melanoma growth in vitro and in vivo by activating the PI3K/Akt/mTOR signaling pathway. Neoplasma, 67(5), 1106-13 (2020)
Han M, Yang HJ, Lin Q. KLHL14, an ovarian and endometrial-specific gene, is over-expressed in ovarian and endometrial cancer. Math Biosci Eng, 17(2), 1702-17 (2019)
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 144(5), 646-74 (2011)
Ward RA, Anderton MJ, Bethel P, Breed J, Cook C, Davies EJ, et al. Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC). J Med Chem, 62(24), 11004-18 (2019)
Vicent S, López-Picazo JM, Toledo G, Lozano MD, Torre W, Garcia-Corchón C, et al. ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br J Cancer, 90(5), 1047-52 (2004)
We would like to thank Editage (www.editage.cn) for their English language editing service.
This study was supported by Shengjing Hospital of China Medical University and the First Hospital of China Medical University.
The authors declare no competing interests.
Ethics approval and consent to participate
This research was approved by the Human Research Ethics Committee of China Medical University, which is accredited by the National Council on Ethics in Human Research.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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