Heavy Ion-Responsive lncRNA EBLN3P Functions in the Radiosensitization of Non-Small Cell Lung Cancer Cells Mediated by TNPO1

SIMPLE SUMMARY: Heavy-ion radiotherapy (HIRT) is associated with higher tumor cure rates compared with conventional radiotherapy (CRT). However, considering the high cost of HIRT, most tumor patients are still treated with CRT. The aim of this study was to elucidate the tumor inhibitory mechanism of HIRT by exploring gene expression signatures after heavy-ion exposure. We confirmed that the carbon ion-responsive long non-coding RNA endogenous bornavirus-like nucleoprotein 3, pseudogene (EBLN3P), is significantly decreased in carbon-ion irradiated non-small cell lung cancer (NSCLC) cells. The combination therapy of LNC EBLN3P-inhibition and X-ray irradiation can delay the progression of NSCLC both in vitro and in vivo, indicating the potential role of LNC EBLN3P as a target of radiosensitization in CRT. ABSTRACT: In recent decades, the rapid development of radiotherapy has dramatically increased the cure rate of malignant tumors. Heavy-ion radiotherapy, which is characterized by the “Bragg Peak” because of its excellent physical properties, induces extensive unrepairable DNA damage in tumor tissues, while normal tissues in the path of ion beams suffer less damage. However, there are few prognostic molecular biomarkers that can be used to assess the efficacy of heavy ion radiotherapy. In this study, we focus on non-small cell lung cancer (NSCLC) radiotherapy and use RNA sequencing and bioinformatic analysis to investigate the gene expression profiles of A549 cells exposed to X-ray or carbon ion irradiation to screen the key genes involved in the stronger tumor-killing effect induced by carbon ions. The potential ceRNA network was predicted and verified by polymerase chain amplification, western blotting analysis, colony formation assay, and apoptosis assay. The results of the experiments indicated that lncRNA EBLN3P plays a critical role in inhibiting carbon ion-induced cell proliferation and inducing apoptosis of NSCLC cells. These functions were achieved by the EBLN3P/miR-144-3p/TNPO1 (transportin-1) ceRNA network. In summary, the lncRNA EBLN3P functions as a ceRNA to mediate lung cancer inhibition induced by carbon ion irradiation by sponging miR-144-3p to regulate TNPO1 expression, indicating that EBLN3P may be a promising target for increasing the treatment efficacy of conventional radiotherapy for NSCLC.