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

Abstract The treatment of cetuximab-resistant colorectal cancer (CRC) remains a major problem. The study was to assess the potential effects of Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA), a type of therapeutic biological product approved in China, on cetuximab-resistant CRC and further explore the underlying mechanism. MiRNA sequencing was used to screen the differential expression profile of miRNAs. Cell proliferation, apoptosis, migration and invasion were detected by cell counting kit-8, flow cytometry, wound healing and transwell assays, respectively. PA-MSHA drastically inhibited the migration and invasion, and induced the apoptosis of cetuximab-resistant CRC cells. PA-MSHA also potently inhibited tumour growth and increased the survival time of mice in vivo. These results indicated that PA-MSHA exerted potent activity against cetuximab-resistant CRC. The sequencing data showed that miR-7-5p was markedly upregulated after PA-MSHA treatment, and miR-7-5p overexpression positively enhanced the anticancer activities of PA-MSHA in vitro and in vivo. Luciferase reporter assay confirmed that Akt was the targeted gene of miR-7-5p, and Akt silencing could reverse the PA-MSHA efficacy inhibited by miR-7-5p downregulation. In addition, PA-MSHA treatment markedly inhibited the activation of Wnt-β-catenin pathway, a downstream signaling of Akt. Moreover, Akt silencing inhibited the Wnt-β-catenin pathway activated by miR-7-5p downregulation in PA-MSHA-treated HCT116-R cells. Finally, we found that serum miR-7-5p levels were significantly lower in CRC patients with cetuximab resistance or disease progression. Overall, our data showed that PA-MSHA exerted potent activity against cetuximab-resistant CRC by regulating miR-7-5p/Akt/Wnt-β-catenin pathway. These results indicate that PA-MSHA may be a novel and effective chemotherapeutic agent against cetuximab-resistant CRC.