Background: The expression of desmosomal genes in lung adenocarcinoma and lung squamous carcinoma is different. However, the regulatory mechanism of desmosomal gene expression in lung adenocarcinoma and lung squamous carcinoma remains unknown.
Methods: The correlation between expression of desmosomal gene expression and SOX30 expression were analyzed by bioinformatics. The expression of SOX30, DSP, JUP and DSC3 were detected in lung cancer cell lines, lung tissues of mice and patients' tissues by qPCR, WB, Immunofluorescence and Immunohistochemistry. A chromatin Immunoprecipitation assay was used to investigate the mechanisms of the SOX30 regulation on desmosomal gene expression. In vitro proliferation, migration and invasion assays, and an in vivo nude mice model were utilized to assess the important role of desmosomal genes on SOX30-induced tumor suppression. A WB assay and TOP/FOP flash reporter assay was used to investigate the downstream pathway regulated by the SOX30-desmosomal gene axis. A chemical carcinogenic model of SOX30-knockout mice was generated to confirm the role of the SOX30-desmosomal gene axis in tumorigenesis.
Results: The expression of desmosomal genes were upregulated by SOX30 in lung adenocarcinoma but not in lung squamous carcinoma. Further mechanism studies showed that SOX30 acts as a key transcriptional regulator of desmosomal genes by directly binding to the ACAAT motif of desmosomal genes promoter region and activating their transcription in lung adenocarcinoma. Knockdown of the expression of related desmosomal genes by miRNA significantly attenuated the inhibitory effect of SOX30 on cell proliferation, migration and invasion in vitro and on tumor growth and metastasis in vivo. In addition, knockout of SOX30 promotes lung tumor development and loss the inhibition of desmosomal genes on downstream Wnt and ERK signal in urethane-induced lung carcinogenesis in SOX30-knockout mice.
Conclusions: Overall, these findings demonstrate for the first time that SOX30 acts as a master switch of desmosomal genes, inhibits lung adenocarcinoma cell proliferation, migration and invasion by activating the transcription of desmosomal genes. This study provides novel insights on the regulatory mechanism of desmosomal genes in lung adenocarcinoma.
Keywords: Desmosome; ERK; Lung adenocarcinoma; SOX30; Wnt.