DNA repair/recombination protein 54L promotes the progression of lung adenocarcinoma by activating mTORC1 pathway.

Abstract

Lung adenocarcinoma (LUAD) is the most prevalent form of lung cancer and has a poor prognosis. RAD54L is a DNA repair protein upregulated in several cancer types, but its role in LUAD progression remains unclear. The objective of this study was to characterise the molecular pathways that oncogenic RAD54L modulates to drive LUAD progression. The Cancer Genome Atlas (TCGA)‒LUAD dataset was analysed to compare the RAD54L mRNA expression in LUAD tumours to that in normal lung tissue. RAD54L and E2F7 mRNA expression was confirmed in human cancer cell lines using RT-qPCR. Bioinformatics tools were used to predict the target genes and downstream signalling pathways of RAD54L. Proteins related to RAD54L, apoptosis, migration, and the mTORC1 pathway were assessed by Western blotting. Using the TCGA‒LUAD dataset, we found that RAD54L was higher in LUAD tumours compared to that in non-cancerous lung tissue, and RAD54L levels were significantly correlated with pathological TNM stage and unfavourable prognosis in patients with LUAD. RAD54L was ubiquitously upregulated in LUAD cells (NCI-H1975, H1299, H23 and A549). Furthermore, RAD54L silencing decreased cell proliferation, invasion, and migration, and induced cell apoptosis and G1 cell cycle phase arrest in H1299 and H23 human lung cancer cell lines. E2F7 was predicted as a target gene of RAD54L. E2F7 overexpression restored malignant cell behaviour in si-RAD54L-treated H1299 cells. Bioinformatic analysis suggested that the mTORC1 signalling pathway is downstream of RAD54L. Rapamycin treatment impaired RAD54L-mediated malignant cell behaviour in H1299 cells. Additionally, RAD54L promoted the progression of xenograft tumours and metastasis in vivo. In conclusion, the E2F7-RAD54L axis promotes the progression of LUAD through the mTORC1 signalling pathway.