Dataset Information

KLHL18 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by inhibiting PI3K/PD-L1 axis activity.

ABSTRACT:

Background

The expression of Kelch-like protein 18 (KLHL18) in non-small cell lung cancer (NSCLC) is lower than that in normal lung tissue according to the Gene Expression Profiling Interactive Analysis database. KLHL18 is a BTB domain protein and binds cullin 3 (CUL3). However, whether this complex participates in ubiquitination-mediated protein degradation in NSCLC is unclear. Therefore, we aimed to investigate the role of KLHL18 in human NSCLC cells.

Results

We found that KLHL18 is downregulated in cancer cells and is associated with poor prognosis. Further, its expression was significantly associated with tumor node metastasis (TNM) stage, lymph node metastasis, and tumor size. In vitro analysis of NSCLC cells showed that overexpressing KLHL18 inhibited cell proliferation, migration, and invasion. We found that the tumor-inhibitory effect of the KLHL18 protein was achieved by promoting the ubiquitination and degradation of phosphatidylinositol 3-kinase (PI3K) p85α and inhibiting the expression of PD-L1 protein, ultimately preventing tumor cell immune escape.

Conclusions

Our results identified the tumor-suppressive mechanism of KLHL18 and suggested that it is closely related to NSCLC occurrence and development. Further investigation of the underlying mechanism may provide new targets for NSCLC treatment.

SUBMITTER: Jiang X

PROVIDER: S-EPMC7694932 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

KLHL18 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by inhibiting PI3K/PD-L1 axis activity.

Jiang Xizi X Xu Yitong Y Ren Hongjiu H Jiang Jun J Wudu Muli M Wang Qiongzi Q Guan Jingqian J Su Hongbo H Zhang Yao Y Zhang Bo B Guo Yuanzi Y Hu Yujiao Y Jiang Lihong L Liu Zongang Z Wang Huanxi H Cheng Yu Y Sun Limei L Qiu Xueshan X

Cell & bioscience 20201127 1

<h4>Background</h4>The expression of Kelch-like protein 18 (KLHL18) in non-small cell lung cancer (NSCLC) is lower than that in normal lung tissue according to the Gene Expression Profiling Interactive Analysis database. KLHL18 is a BTB domain protein and binds cullin 3 (CUL3). However, whether this complex participates in ubiquitination-mediated protein degradation in NSCLC is unclear. Therefore, we aimed to investigate the role of KLHL18 in human NSCLC cells.<h4>Results</h4>We found that KLHL1 ...[more]

PMID: 33292627

Similar Datasets

Project description:BackgroundFollicular thyroid carcinoma (FTC) is the second most common cancer of the thyroid and easily develops into distant metastasis. PD-L1 is known to be associated with the carcinogenesis and progression of thyroid carcinoma. Our study aimed to investigate the biological functions of PD-L1 and to identify miRNAs that were responsible for modulating the activity of PD-L1.MethodsA total of 72 patients with FTC at The Second Affiliated Hospital of Fujian Medical University were enrolled in this retrospective study. Immunohistochemical (IHC) assay was used to measure PD-L1 expression in FTC. The association between PD-L1 expression and clinicopathologic characteristics was evaluated. Bioinformatics analysis, RT-qPCR and western blotting were used to examine the relationships between miR-199a-5p, PD-L1 and Claudin-1. Cell proliferation, migration and invasion were evaluated by using CCK8 and Transwell migration and invasion assays. Target prediction and luciferase reporter assays were performed to verify the binding between miR-199a-5p and PD-L1. Rescue assay was performed to confirm whether PD-L1 downregulation abolished the inhibitory effect of miR-199a-5p.ResultsAmong 72 pairs of tumor and normal specimens, the proportion of PD-L1 positive samples was higher in FTC tissues than in normal tissues. The results of ESTIMATE and CIBERSORT illustrated that there was a positive correlation between PD-L1 expression and immune infiltration, especially regulatory T cells and M1 macrophages. Prediction of immunotherapy revealed that patients with high PD-L1 expression might benefit from immune checkpoint inhibitors. Transwell migration and invasion assays showed that PD-L1 downregulation in FTC cells could significantly inhibit cell migration and invasion. The bioinformatics analysis and luciferase activity results indicated that PD-L1 was a potential target of miR-199a-5p. Knockdown of PD-L1 reversed the miR-199a-5p inhibitor mediated promotion effect. In addition, we found that PD-L1 expression was positively correlated with Claudin-1 expression and that miR-199a-5p affected the progression of FTC cells through the negative regulation of PD-L1 and Claudin-1.ConclusionsOur study revealed that PD-L1 expression was elevated in FTC and was closely associated with tumor aggressiveness and progression. MiR-199a-5p has a functional role in the progression and metastasis of FTC by regulating PD-L1 and Claudin-1 expression.

Project description:Breast cancer metastasis to the brain, occurring in about 15-25% of cases, represents a major obstacle in the treatment of triple-negative breast cancer (TNBC). The molecular mechanisms driving this form of metastasis are still largely unknown. PD-L1, an immune checkpoint protein, is central to tumor immune evasion and has become a focus for immunotherapy development. While PD-L1 inhibitors have shown success in various cancer types, their effectiveness in TNBC brain metastases remains to be fully investigated. This highlights the urgent need to understand the complex interactions between metastatic brain tumors and the tumor microenvironment in TNBC patients. Gaining insights into these dynamics is crucial for developing new targeted therapies, including those that modulate the PD-L1 pathway, to better manage and treat TNBC brain metastases. We explore the impact of Capsanthin on the tumor microenvironment of brain metastases in triple-negative breast cancer (TNBC). Our results reveal that Capsanthin effectively inhibits the migration of brain metastasis TNBC cells. Furthermore, Capsanthin significantly reduces the expression of EZH2 and N-linked glycosylated PD-L1 proteins and mRNA in TNBC cells, encompassing both primary and metastatic sites, as well as in mesenchymal stem cells (3A6). Data from The Cancer Genome Atlas (TCGA) indicate that elevated expression levels of EZH2 correlate with poorer patient prognosis. Immunoprecipitation assays demonstrate a direct interaction between EZH2 and PD-L1 in brain metastases of TNBC, underscoring the pivotal role of the EZH2-PD-L1 axis. Additionally, Capsanthin was found to suppress the expression of epithelial-mesenchymal transition (EMT) markers in metastatic brain TNBC cells and mesenchymal stem cells. Our results suggest that Capsanthin can modulate the tumor microenvironment and inhibit key pathways involved in cancer progression, offering potential therapeutic benefits for patients with TNBC brain metastases.

Dataset Information

KLHL18 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by inhibiting PI3K/PD-L1 axis activity.

Background

Results

Conclusions

Publications

KLHL18 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by inhibiting PI3K/PD-L1 axis activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets