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

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.

Automated summary

The study revealed that HOXC6 is highly expressed in Gef-resistant NSCLC cells and it plays a crucial role in Gef resistance by regulating multiple cellular functions. miR-27a can alleviate Gef resistance by inhibiting HOXC6 expression in NSCLC cells. High levels of HOXC6 and low levels of miR-27a are associated with more malignant clinical features and poorer survival in NSCLC patients.