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1.
Int J Mol Sci ; 24(22)2023 Nov 09.
Article in English | MEDLINE | ID: mdl-38003293

ABSTRACT

Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 (SLC12A1) and glutamate ionotropic AMPA type subunit 4 (GRIA4), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, SLC12A1 expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by GRIA4, were elevated in patients with a worse prognosis. Our results suggest a potential link between SLC12A1 gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance.


Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Membrane Transport Proteins , Neoadjuvant Therapy , Retrospective Studies , Solute Carrier Family 12, Member 1
2.
Oncol Rep ; 39(1): 349-357, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29138851

ABSTRACT

Tumor-initiating cells possess the capacity for self-renewal and to create heterogeneous cell lineages within a tumor. Therefore, the identification and isolation of cancer stem cells is an essential step in the analysis of their biology. The aim of the present study was to determine whether the cell surface protein neuropilin 1 (NRP1) can be used as a biomarker of stem-like cells in lung cancer tumors. For this purpose, NRP1-negative (NRP1-) and NRP1-positive (NRP1+) cell subpopulations from two lung cancer cell lines were sorted by flow cytometry. The NRP1+ cell subpopulation showed an increased expression of pluripotency markers OCT-4, Bmi-1 and NANOG, as well as higher cell migration, clonogenic and self-renewal capacities. NRP1 gene knockdown resulted not only in a decreased expression of stemness markers but also in a decrease in the clonogenic, cell migration and self-renewal potential. In addition, the NRP1+ cell subpopulation exhibited dysregulated expression of epithelial-to-mesenchymal transition-associated genes, including the ΔNp63 isoform protein, a previously reported characteristic of cancer stem cells. Notably, a genome-wide expression analysis of NRP1-knockdown cells revealed a potential new NRP1 pathway involving OLFML3 and genes associated with mitochondrial function. In conclusion, we demonstrated that NRP1+ lung cancer cells have tumor-initiating properties. NRP1 could be a useful biomarker for tumor-initiating cells in lung cancer tumors.


Subject(s)
Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Neoplastic Stem Cells/cytology , Neuropilin-1/genetics , Neuropilin-1/metabolism , A549 Cells , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Lung Neoplasms/genetics , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Phenotype , Tumor Cells, Cultured
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