Lung squamous cell carcinoma and lung adenocarcinoma differential gene expression regulation through pathways of Notch, Hedgehog, Wnt, and ErbB signalling

Abstract

Lung malignancies comprise lethal and aggressive tumours that remain the leading cancer-related death cause worldwide. Regarding histological classification, lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) account for the majority of cases. Surgical resection and various combinations of chemo- and radiation therapies are the golden standards in the treatment of lung cancers, although the five-year survival rate remains very poor. Notch, Hedgehog, Wnt and Erbb signalling are evolutionarily conserved pathways regulating pivotal cellular processes such as differentiation, proliferation, and angiogenesis during embryogenesis and post-natal life. However, to date, there is no study comprehensively revealing signalling networks of these four pathways in LUSC and LUAD. Therefore, the aim of the present study was the investigation profiles of downstream target genes of pathways that differ between LUSC and LUAD biology. Our results showed a few co-expression modules, identified through weighted gene co-expression network analysis (WGCNA), which significantly differentiated downstream signaling of Notch, ErbB, Hedgehog, and Wnt in LUSC and LUAD. Among co-expressed genes essential regulators of the cell cycle, DNA damage response, apoptosis, and proliferation have been found. Most of them were upregulated in LUSC compared to LUAD. In conclusion, identified downstream networks revealed distinct biological mechanisms underlying cancer development and progression in LUSC and LUAD that may diversify the clinical outcome of the disease.

Figure 1

Signalling pathways enriched in lung squamous cell carcinoma and lung adenocarcinoma. Enrichment plots present (A) Notch pathway, (B) Wnt pathway, (C) Hh pathway, and (D) ErbB pathway.

Figure 2

Differential expression of Notch downstream targets vastly characterizing lung cancer subtypes within turquoise and brown modules. These groups were mostly correlated with trait of interest (A,B) and showed the highest importance of genes within the particular module (C,D).

Figure 3

Differential expression of Hh downstream targets vastly characterizing lung cancer subtypes within purple, brown, red and blue modules. These groups were mostly correlated with trait of interest (A,B) and showed the highest importance of genes within the particular module (C–F).

Figure 4

Differential expression of ErbB downstream targets vastly characterizing lung cancer subtypes within purple and brown modules. These groups were mostly correlated with trait of interest (A,B) and showed the highest importance of genes within the particular module (C,D).

Figure 5

Differential expression of Wnt downstream targets vastly characterizing lung cancer subtypes within blue module. This group was mostly correlated with trait of interest (A,B) and showed the highest importance of genes within the blue module (C).

Figure 6

Molecular profiles of (A) Notch (brown module), (B) Hh (brown module), (C) Wnt (blue module), (D) ErbB (turquoise module) pathway downstream targets that differentiate lung squamous cell carcinoma from lung adenocarcinoma.

Figure 7

Dimensional partitioning of lung squamous cell carcinoma and lung adenocarcinoma patients according to the resultant expression of the most significant WGCNA modules of (A) Notch, (B) Hh, (C) Wnt and (D) ErbB pathway effectors.