REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling.

Abstract

Background: Regenerating family member 3A (REG3A) is involved in the development of multiple malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). However, any role of REG3A in PDAC remains controversial due to its unclear tissue localization or direct receptors, and complex downstream signal transductions.

Methods: Morphological analysis and public multi-omics data retrieval were was utilized to elucidate the tissue localization of REG3A in PDAC. To ascertain the pro-oncogenic role of secreted REG3A, experiments were conducted using in vitro PDAC cell lines and in vivo tumor formation assays in nude mice. A battery of investigative techniques, including RNA sequencing, phospho-kinase arrays, western blot analyses, in silico docking simulations, gene truncation strategies, and co-immunoprecipitation, were employed to delve into the downstream signaling transduction pathways induced by REG3A.

Results: In this study, we confirmed an association between increased serum levels of REG3A and poor prognosis in patients with PDAC. Morphological staining and bioinformatic analysis showed that REG3A was mainly expressed in peritumoral acinar cells that were spatially close to tumor region, while it was almost negative in PDAC tumor cells. Peritumoral REG3A expression levels, but not tumoral REG3A, were highly correlated with PDAC progression. Further in vitro experiments including RNA sequencing and molecular biological assays revealed that secreted REG3A could directly bind to the epidermal growth factor receptor (EGFR), an important pro-oncogene involved in cellular proliferation, and subsequently activate the downstream mitogen-activated protein kinase (MAPK) signals to promote PDAC tumor cell growth.

Conclusion: Taken together, our data indicated that increased expression of REG3A in peritumoral acinar cells acts as a specific event to indicate PDAC progression, and verified EGFR as a possible target of REG3A, providing mechanistic insights into the role of REG3A, the diagnostic method and therapeutic strategy of PDAC.