Hypoxia upregulates the expression of lncRNA H19 in non-small cell lung cancer cells and induces drug resistance.

BACKGROUND

The incidence of lung cancer is extremely high. For treatment, the chemotherapy of lung cancer is low, and drug resistance and recurrence are frequently observed, in which hypoxic tumor microenvironments play a key role. We investigated the upregulation of long non-coding ribonucleic acid (lncRNA) H19 expression and the induction of drug resistance in non-small cell lung cancer (NSCLC) cells under hypoxic conditions.

METHODS

We used cobaltous chloride (CoCl2) to create hypoxic culture environments for the A549 and H1650 cells, and they were divided into normoxia and hypoxia groups. We used real-time quantitative PCR detecting system (qPCR) to detect the messenger RNA (mRNA) expressions of lncRNA H19, hypoxia-inducible factor 1-α (HIF1-α), multi-drug resistant associated protein 1 (MRP1), and heme oxygenase-1 (HO-1), and western blot to detect the protein expressions of HIF1-α, MRP1, HO-1, and P-glycoprotein (P-gp). We performed cell migration and invasion assays. Annexin V-Allophycocyanin (APC) and flow cytometry were used to detect the apoptotic rates.

RESULTS

We found that the expression levels of lncRNA H19, HIF1-α, HO-1, multi-drug resistant associated protein 1 (MRP1), and P-glycoprotein increased significantly in the NSCLC cell lines (A549 and H1650) under hypoxic conditions, as determined by the qPCR and western blot analyses. In NSCLC cells cultured under hypoxic conditions, the invasion and migration ability of tumor cells increased significantly, resistance to cisplatin increased, and cisplatin-induced apoptosis decreased considerably. In addition, chemoresistance was also induced in tumor cells under hypoxic conditions.

CONCLUSIONS

These results indicate that hypoxia increased the expression levels of lncRNA H19 and induced chemoresistance in tumor cells.