PA-MSHA exerts potent activity against cetuximab-resistant colorectal cancer through the miR-7-5p/Akt3/Wnt-β-catenin pathway.

Abstract

The prognosis and survival of individuals with cetuximab-resistant colorectal cancer (CRC) remain severely impacted by therapy for this disease. The study investigated the underlying mechanisms of Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA), a type of therapeutic biological product approved in China, for cetuximab-resistant CRC. Cell proliferation, apoptosis, migration and invasion were detected by cell counting kit-8 (CCK-8) assay, flow cytometry, wound healing assay and transwell assay. Massively parallel sequencing of cetuximab-resistant CRC cells with PA-MSHA treatment was used to screen the differential expression profile of miRNAs. The directly target gene of miR-7-5p was revealed by dual luciferase assay. Apoptosis and invasion related proteins were detected by Western blot. PA-MSHA could successfully stop the migrating and invading of cetuximab-resistant CRC cells while also inducing apoptosis. Tumor-bearing experiments in nude mice showed that PA-MSHA slowed tumor growth and lengthened mouse life. The sequencing data showed that miR-7-5p was considerably upregulated after PA-MSHA treatment. As anticipated, miR-7-5p overexpression improved PA-MSHA's anticancer properties both in vitro and in vivo. The target gene of miR-7-5p was confirmed to be Akt3 by dual luciferase assay, and Akt3 silencing undid the inhibition of PA-MSHA efficacy caused by miR-7-5p downregulation. Additionally, PA-MSHA therapy significantly reduced the activation of Wnt-β-catenin pathway, and Akt3 expression was positively linked with several important Wnt-β-catenin pathway genes, including Wnt and CTNNB1. Finally, we discovered that patients with CRC who had developed cetuximab resistance or disease progression had remarkably decreased serum miR-7-5p levels. PA-MSHA controlled the miR-7-5p/Akt3/Wnt-β-catenin pathway to provide substantial efficacy against cetuximab-resistant CRC.