NGX6 inhibits AP-1 and Ets-1 expression and down-regulates cyclin D1 in human colorectal cancer

Colorectal cancer (CRC) is a common malignant tumor that is associated with an increased incidence of morbidity and mortality. Nasopharyngeal carcinoma-associated gene 6 (NGX6) is a novel candidate suppressor gene of tumor metastasis, which is down-regulated in CRC. In the present study, we constructed a colorectal tissue microarray to examine the expression profiles of NGX6, phospho-c-Jun N-terminal kinase (p-JNK), and phospho-extracellular signal-regulated kinase (p-ERK ) in CRC tissues. We found that the NGX6 expression was lower in CRC tissues and metastatic lymph nodes, whereas the expressions of p-JNK and p-ERK were higher in CRC tissues, than in normal intestinal mucosa. The expressions of NGX6, p-JNK, and p-ERK were associated with the clinical pathological features of colorectal tissues. NGX6 overexpression inhibited the activation and nuclear translocation of JNK1, which led to an accumulation of p-JNK in the cytoplasm, but did not inhibit the activation and nuclear translocation of ERK1/2. NGX6 also inhibited the expression of the transcription factors AP-1 (c-jun and c-fos) and Ets-1. In addition, NGX6 overexpression decreased the expression of cyclin D1 and dramatically suppressed the transcriptional efficiency of the cyclin D1 promoter. We propose that NGX6 expression is lost in the multi-step process of human colorectal carcinogenesis. Its overexpression can inhibit the expression of transcription factors AP-1 and Ets-1, and down-regulate the transcriptional activity of the cyclin D1 promoter in human CRC.