CCN1 suppresses cell proliferation of esophageal squamous cell carcinoma through amyloid precursor protein without DR6 participation

Esophageal cancer is commonly seen as either squamous cell carcinoma (ESCC) or adenocarcinoma (EAC), two very different cancers. CCN1 is a matricellular protein that induces apoptosis in EAC cells through upregulation of DR5, a death receptor, while its role in ESCC is unclear. DR6 is another death receptor, which has been reported to induce apoptosis, necroptosis, or pyroptosis in various cell systems with or without the engagement of its putative ligand amyloid precursor protein (APP). In this study, we found that CCN1 and DR6 were both highly expressed in ESCC but downregulated in EAC. Overexpression of CCN1 in ESCC cells inhibited cell proliferation through upregulation of APP and its association with p53 without DR6 involvement. Overexpression of APP stopped cell growth, but overexpression of DR6 did not affect cell growth or cell death whatsoever. •CCN1 and DR6 are both highly expressed in ESCC but downregulated in EAC compared to their levels in normal cells.•Overexpression of CCN1 in ESCC cells inhibits cell proliferation through APP without DR6 involvement.•Overexpression of APP attenuates ESCC cell growth, but overexpression of DR6 does not.