Effects of MLL5 and HOXA regulated by NRP1 on radioresistance in A549

Abstract

Radiotherapy is widely used in the management of lung cancer, and physicians are aware that the effect of radiotherapy is dependent on radiosensitivity. Although a series of blockers and activators targeting molecules related to radioresistance have been developed as radiation sensitizers, compensatory mechanisms or drug resistance limits their clinical efficacy. The identification of a key molecule related to lung cancer cell radioresistance or an effective molecular target is a challenging but important problem in radiation oncology. A previous study found that neuropilin 1 (NRP1) is related to radioresistance in A549 cells and is associated with VEGF, PI3K-Akt, MAPK-ERK, P38, NF-κβ and TGF-β. Inhibition of NRP1 can increase the radiosensitivity of A549 cells. Therefore, NRP1 may be a molecular target for radiotherapy-sensitizing drugs in lung cancer. The present study investigated the key downstream genes of NRP1, verified their regulation and clarified their roles in regulating lung cancer radioresistance. NRP1 positively regulated the downstream homeobox genes (HOXs) HOXA6, HOXA9 and mixed lineage leukaemia 5 (MLL5) in addition to MLL5-regulated HOXA6 and HOXA9, but these genes did not regulate NRP1. MLL5, HOXA6 and HOXA9 levels were decreased in tumour tissues and positively correlated with NRP1. All of these genes were induced by ionizing radiation in vivo and in vitro. NRP1 expression was significantly lower in squamous cell carcinoma compared with that in adenocarcinoma, and lymph node metastasis occurred more often in patients with lung cancer with high MLL5 and NRP1 expression compared with patients with low MLL5 and NRP1 expression. Collectively, these data confirmed that NRP1 is associated with MLL5 and regulates radioresistance through HOXA6 and HOXA9.

Down-regulated long non-coding RNA LHFPL3 antisense RNA 1 inhibits the radiotherapy resistance of nasopharyngeal carcinoma via modulating microRNA-143-5p/homeobox A6 axis

“…HOXA6 encodes a transcription factor that regulates gene expression and cell differentiation. HOXA6 has been identified to play an important role in cell proliferation, differentiation and invasion, and it has been reported that HOXA6 might be radiation‑sensitive [ 21 , 22 ].…”

“…Additionally, in colorectal cancer, HOXA6 overexpression has been confirmed by Lin et al ., who have clarified that HOXA6 ablation abrogates the migration and invasion capacity of colorectal cancer cells [ 18 ]. Furthermore, Shao et al have elucidated that HOXA6 can regulate radiation resistance in A549 cells in lung cancer [ 22 ]. In light of previous findings, the research further illustrated that HOXA6 was high-expressed in NPC cells, and the deletion of HOXA6 could inhibit the growth of radiation-resistant NPC cells.…”

The Nervous System Development Regulator Neuropilin-1 as a Potential Prognostic Marker and Therapeutic Target in Brain Cancer

“…Radiation-resistant cellular models of lung adenocarcinoma show increased NRP1 expression, and the NRP1 inhibitor EG00229 reduces the expression levels and binding capacity of NRP1 [78]. NRP1 regulation of radioresistance in lung cancer involves downstream homeobox genes HOXA6 and HOXA9 [79], and microRNA-9 is able to restore radio-sensitivity in radioresistant lung cancer cells by targeting NRP1 [80]. NRP1 can also promote resistance to molecularly targeted therapies in cancer.…”

GATA3 Exerts Distinct Transcriptional Functions to Regulate Radiation Resistance in A549 and H1299 Cells

“…Previous studies have supported the notion that elevated NRP1 expression in tumors correlates with poor outcomes. On the other hand, NRP1 is associated with radiation resistance [ 19 ]. However, the molecular mechanism through which NRP1 plays a crucial role in the formation of radiation resistance in lung cancer cells is unknown; in particular, more research into transcription factor regulatory mechanisms is needed.…”