Suppression of rhomboid domain-containing 1 produces anticancer effects in pancreatic adenocarcinoma through affection of the AKT/GSK-3ß/ß-catenin pathway.

ABSTRACT

The protumor role of rhomboid domain-containing 1 (RHBDD1) has been observed in multiple cancers. However, the relationship between RHBDD1 and pancreatic adenocarcinoma has not been addressed. This project focused on the potential relevance of RHBDD1 in pancreatic adenocarcinoma. Bioinformatic analysis by publicly available data revealed that RHBDD1 was abundantly expressed in pancreatic adenocarcinoma. We further verified that RHBDD1 was expressed highly in clinical specimens of pancreatic adenocarcinoma. The Kaplan-Meier curve demonstrated that high-RHBDD1 expression was associated with poor prognosis in pancreatic adenocarcinoma patients. The functional studies revealed that depletion of RHBDD1 produced in vitro anticancer effects in pancreatic adenocarcinoma cells, including retardation of proliferation, reduction of metastatic potential, and induction of cell-cycle arrest at the G0/G1 phase and apoptosis. Mechanistic studies indicated that loss of RHBDD1 affected the activation of ß-catenin via regulation of AKT. Forced expression of ß-catenin reversed the RHBDD1-loss-induced anticancer effects in pancreatic adenocarcinoma cells. Crucially, depletion of RHBDD1 retarded the growth of pancreatic adenocarcinoma xenografts in vivo, a phenomenon associated with the AKT/ß-catenin pathway. Collectively, these findings delineated that restraint of RHBDD1 displayed remarkable anticancer effects in pancreatic adenocarcinoma by affecting the AKT/ß-catenin pathway. Our work unveils a pivotal role of RHBDD1 in pancreatic adenocarcinoma and proposes it as a novel candidate target for anticancer therapy of pancreatic adenocarcinoma.