Molecular insight of p53/Sp1/MUC5AC axis in the tumorigenesis and progression of lung adenocarcinoma.

The aberrant expression of secretory mucin MUC5AC has been documented during the tumourigenesis and progression of various cancers. However, little is currently known on the function of MUC5AC in lung adenocarcinoma. The present study focused on the tumour‐promoting role of MUC5AC and its regulatory mechanisms in lung adenocarcinoma. Firstly, MUC5AC expression was evaluated in NSCLC tissue microarrays by immunohistochemistry. Kaplan–Meier analysis were used to clarify the prognostic value of MUC5AC. Subsequently, small interfering RNA and small hairpin RNA were used to knockdown MUC5AC in lung ADC cell lines to elucidate its role in tumorigenesis and progression of lung adenocarcinoma via in vitro functional assays and xenograft mouse models. Finally, the regulatory mechanisms underlying p53/Sp1/MUC5AC axis were identified through dual‐luciferase report. We found that MUC5AC was upregulated in lung ADC tissues and cell lines, especially in KRAS‐mutant cases and correlated with poor prognosis. MUC5AC gene silencing resulted in reduced cell proliferation, invasion and migration. Furthermore, knockdown of MUC5AC led to reversion of the epithelial–mesenchymal transition. Additionally, downregulation of MUC5AC reduced tumourigenesis in mouse models. Finally, we found an antagonistic role between Sp1 and p53 in the regulation of MUC5AC gene expression. Our findings suggest that high MUC5AC expression promotes tumourigenesis and progression of lung ADC. Both p53 gene inactivation and Sp1 overexpression in lung ADC may enhance MUC5AC expression, especially in KRAS‐mutated cases. Given the paucity of efficient drug‐targeted approaches of KRAS‐driven lung ADCs, therapies directed at downstream effectors such as MUC5AC could have huge prospects. [ABSTRACT FROM AUTHOR]