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LCMR1 Promotes Large-cell Lung Cancer Proliferation and Metastasis through Downregulation of HLA Coding Genes

ABSTRACT: Lung cancer is notorious for high morbidity and mortality around the world. We previously cloned the gene LCRM1 from human large-cell lung carcinoma cell line, however whether this gene affect the proliferation and metastasis of large-cell lung carcinoma is yet unknown. To fully identify the biofunction of LCMR1 in lung cancer, we performed pan-cancer and cell line based LCMR1 expression profiling. Our analysis indicated that LCMR1 was expressed at higher levels in most solid tumors, especially in NSCLC. The expression profile of LCMR1 in different NSCLC cell lines revealed the highest level in the large-cell lung cancer cell 95D. Furthermore, our functional studies using lentivirus-based knockdown strategies indicates that LCMR1 is critical for large-cell lung cancer proliferation, migration, and invasion in cultured cells, and blocking this gene significantly reduced the growth of 95D cell xenograft mouse model. In mechanism assay, multiple sequence-based assay revealed that LCMR1 diminished the RNA Pol II occupancy at the promoter of HLA coding genes, thus blocks the transcription of these genes. Also, the correlation assay of TCGA database suggested that the expression level of LCMR1 was negatively related with the HLA coding genes, which plays vital role in cancer-specific antigen presenting and anticancer immunity. In conclusion, our studies showed that LCMR1 is required for large-cell lung cancer cell growth and invasion, suggesting its potential as a valid target in clinical treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234816 | GEO | 2023/08/01

REPOSITORIES: GEO

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Project description:Background: Non-Small Cell Lung Cancer (NSCLC) presents as a highly metastatic disease with Kras and P53 as prevalent oncogenic driver mutations. Endocytosis, through its role in receptor recycling and enrichment, is important for cancer cell proliferation and metastasis. Huntingtin Interacting Protein 1 (HIP1) is a clathrin mediated endocytic adapter protein found overexpressed in different cancers. However, conflicting roles both as a tumour promoter and suppressor are reported. HIP1 expression is found repressed at advanced stages and some HIP1-ALK fusions are reported in NSCLC patients. However, the molecular mechanisms and implications of HIP1 depletion are not completely understood. Methods: HIP1 depletion was performed using siRNA transient transfection and validated using immunoblotting for each experiment. HIP1 depleted A549 cells were analysed for deregulated global proteome using label-free LC-MS. Gene expression dataset was analysed using TCGA, GTeX and GEO to explore HIP1 expression in Lung cancer patients. Kaplan–Meier Plotter database was used to analyse the survival correlation between HIP1 mRNA expression in lung cancer patients. Various functional assays such as matrigel based invasion, trans-well migration, soft agar colony, tube formation are performed after HIP1 depletion. NRF2 inhibitor was used after HIP1 knockdown to assess its effect on invasion and soft agar colony formation. Results: In silico analysis of HIP1 transcript expression reveals that it is reduced in high-grade and metastatic lung cancer patients correlating with poor survival. Global proteome profiling reveals that HIP1 depleted A549 cells are enriched in pathways associated with metabolism, proliferation and survival. Molecular and functional analysis indicate higher invasive ability of HIP1 depleted cells. The secretome from HIP1 depleted cells also increases the angiogenic potential of HUVEC cells. NRF2 inhibition in HIP1 depleted cells reduces invasion of NSCLC cells with different driver mutations. Conclusion: Our study shows that HIP1 depletion leads to activation of various molecular pathways responsible for cell proliferation and survival. Additionally, enhancement of invasion in HIP1 depleted subsets of NSCLC cells is via upregulation of NRF2 and can be reversed by its inhibitor.

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LCMR1 Promotes Large-cell Lung Cancer Proliferation and Metastasis through Downregulation of HLA Coding Genes

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