Abstract
NRAS plays a pivotal role in progression of various kinds of somatic malignancies; however, the correlation between NRAS and lung adenocarcinoma is less known. We aim to analyze the prognostic value of NRAS expression in lung adenocarcinoma, and explore the relationship between NRAS and tumor immune microenvironment. We obtained the transcriptome profiles and clinical data of LUAD from The Cancer Genome Atlas database and three Genome Expression Omnibus datasets. Specimens from 325 patients with completely resected lung adenocarcinoma were collected for immunohistochemical assays of NRAS, PD-L1, PD-1 and TIM-3. Then, we performed gene set enrichment analysis to investigate cancer-related and immune-related signaling pathways. TIMER algorithms were performed to evaluate tumor immune infiltrating cells and immune-related biomarkers. Compared with adjacent non-tumor tissue, NRAS expression was significantly upregulated in LUAD tissue. NRAS expression was significantly correlated with more advanced stage and positive lymph nodes. Kaplan-Meier curves and Cox analysis suggested that high NRAS expression led to a poor prognosis, and could be an independent prognostic factor in LUAD patients. Besides, NRAS expression was positively correlated with CD8+ T cells, macrophages, and neutrophils, and negatively correlated with B cells and CD4+ T cells. The expression level of NRAS was positively correlated with PD-L1, PD-1, and TIM-3 both at RNA and protein level. To conclude, we found NRAS is a novel prognostic biomarker in LUAD. Besides, the expression level of NRAS may influence the prognosis of LUAD via various kinds of cancer-related pathways and remodeling TIM.
Highlights
Lung cancer remains the leading cause of cancer-related death and has the highest incidence rate worldwide. (Bray et al, 2018)
The expression level of Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) may influence the prognosis of lung adenocarcinoma (LUAD) via various kinds of cancer-related pathways and remodeling tumor immune microenvironment (TIM)
IHC staining images were achieved from the Human Protein Atlas (HPA) in order to validate the expression of NRAS in LUAD and adjacent non-tumor tissues.(Uhlén et al, 2015) Both the tumor tissues and normal tissues were stained by Antibody CAB010157
Summary
Lung cancer remains the leading cause of cancer-related death and has the highest incidence rate worldwide. (Bray et al, 2018). Among all the histological subtypes of lung cancer, lung adenocarcinoma (LUAD) is the one which dominant, with an average 5-year survival rate of 15%. Numerous large-scale studies have demonstrated that different genetic subtypes have distinctive survival rates in malignancies. Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) was originally identified as the third RAS family member following KRAS and HRAS in human neuroblastoma and fibrosarcoma cell lines. The mutation of RAS gene family occurs in nearly 30 % of human cancers. (Whitwam et al, 2007) The mutation of NRAS leads to continuous activation of Ras-GTP, which promotes tumorigenesis and metastasis. It has been proved that NRAS acts as a negative prognosis predictor in numerous somatic malignancies, such as melanoma, colorectal cancer and hepatocellular carcinoma. It has been proved that NRAS acts as a negative prognosis predictor in numerous somatic malignancies, such as melanoma, colorectal cancer and hepatocellular carcinoma. (Banys-Paluchowski et al, 2020; Bertoli, Giavarra, Vitale, & Minisini, 2019; Dietrich et al, 2019; Hu et al, 2018)
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