Knockdown of LRRN1 inhibits malignant phenotypes through the regulation of HIF-1α/Notch pathway in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory and fatal human malignancies. Leucine-rich repeat neuronal protein-1 (LRRN1) plays a crucial role in the development of the nervous system. However, the clinical implications and biological functions of LRRN1 in PDAC remain unclear. We found that LRRN1 expression was upregulated in PDAC tissues compared with paracancerous tissues and normal pancreatic tissues through the different public databases, tissue microarray-based immunohistochemistry, and dimethylbenzanthracene-induced PDAC murine model. The expression level of LRRN1 was closely related to the overall survival and disease-free survival of PDAC patients. Cox multivariate analysis indicated that LRRN1 was an independent adverse prognostic factor. The small hairpin RNA (shRNA)-mediated LRRN1 knockdown remarkably restrained the proliferative, migratory, and invasive capacities, as well as promoted cell apoptosis and increased G0/G1 arrest in PDAC cells. The xenograft murine subcutaneous bearing model and metastasis model verified that silencing of LRRN1 effectively dampened tumor growth and metastasis in vivo. Specifically, LRRN1 exerted its biological functions through the HIF-1α/Notch signaling pathway, and LRRN1 knockdown could dampen Jagged 1-mediated Notch pathway activation. Therefore, LRRN1 could serve as the potential therapeutic or prognostic target for PDAC.

Keywords

• LRRN1
• HIF-1α
• proliferation
• migration
• invasion
• pancreatic ductal adenocarcinoma