Dataset Information

Downregulation of HOXC6 by miR-27a ameliorates gefitinib resistance in non-small cell lung cancer

ABSTRACT: Non-small cell lung cancer (NSCLC) is a major type of lung cancer. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), represented by gefitinib (Gef), are targeted drugs used for the treatment of NSCLC. However, NSCLC patients often develop resistance to tyrosine kinase inhibitors, which limits their efficacy. Homeobox gene HOXC6 is dysregulated in many cancers and contributes to chemoresistance in cancer cells. However, the role and mechanism of HOXC6 in the development of Gef resistance in NSCLC remains unclear. In the present study, we found that HOXC6 was highly expressed in Gef-resistant NSCLC cells. Further experiments showed that silencing of HOXC6 ameliorated Gef resistance in PC9/G cells whereas overexpression of HOXC6 promoted Gef resistance in PC9 cells. HOXC6 influenced Gef sensitivity in NSCLC cells by regulating cell proliferation, colony formation, cell apoptosis, cell cycle, cell mobility and other related signaling molecules or pathways. HOXC6 was also found to be a direct target of miR-27a. As expected, overexpression of miR-27a ameliorated Gef resistance by inhibiting HOXC6 expression in vitro and in vivo. Clinical analysis revealed that high HOXC6 levels and low miR-27a levels were significantly correlated with more malignant clinical features and poorer survival of NSCLC patients. In summary, the present study demonstrates that HOXC6 may be a potential therapeutic target for overcoming Gef resistance in NSCLC patients. A combination of Gef and miR-27a agomirs may be an effective intervention for Gef-resistant NSCLC.

SUBMITTER: He W

PROVIDER: S-EPMC8493406 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundFerroptosis is a newly generated regulatory cell death promoted by the accumulated lipid-based reactive oxygen species (ROS). Solute carrier family 7 member 11 (SLC7A11), the cystine/glutamate antiporter, is known as a ferroptosis executor that exhibits a positive correlation with carcinoma progression because of antioxidant function. Nonetheless, it is yet unclear on the understanding of ferroptosis regulation in lung cancer.MethodsDatabase, qRT-PCR, Western-blot (WB), and immunohistochemistry were utilized to determine SLC7A11 expression and function, as well as gene iron related to necrosis in clinical tissue specimens and cells; a ferroptosis inducer, inhibitors, and SLC7A11 lentivirus were used to confirm SLC7A11's biological activity in cell viability, oxidative stress, lipid peroxidation, and iron ion enrichment in non-small cell lung cancer (NSCLC) in different cells; lentivirus was used to infect lung adenocarcinoma cell lines to acquire miR-27a-3p overexpression and knockdown cell lines, and to detect SLC7A11 level through qRT-PCR and WB. The influence of upregulated/downregulated miR-27a-3p on ferroptosis and other related biological characteristics of lung adenocarcinoma cell lines was detected.ResultsUpregulated SLC7A11 was shown in NSCLC patients and cells, and increased SLC7A11 had a relation to the poorly prognostic status of NSCLC patients. Besides, a novel miRNA, miR-27a-3p, was an essential modulator of ferroptosis via directly targeting SLC7A11 in NSCLC cells. Overexpressing miR-27a-3p led to SLC7A11 suppression via directly binding to its 3'-UTR, followed by the reduction of erastin-caused ferroptosis. In contrast, inhibited miR-27a-3p resulted in an increase in NSCLC cells' sensitivity to erastin. Of importance, the accumulated lipid ROS and cell death of iron peptide mediated by anti-miR-27a-3p can be eliminated by impeding the glutamylation process. Our literature collectively uncovered that miR-27a-3p modulated ferroptosis by targeting SLC7A11 in NSCLC cells, illustrating the important role of miRNA in ferroptosis.ConclusionMiR-27a-3p modulates ferroptosis via targeting SLC7A11 in NSCLC cells, implying the significant role of miR-27a-3p/SLC7A11 in ferroptosis.

Dataset Information

Downregulation of HOXC6 by miR-27a ameliorates gefitinib resistance in non-small cell lung cancer

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets