MiR-323a-3p Inhibits Tumor Growth and Gefitinib Resistance Acquisition by Targeting EGFR/ErbB3 in Colorectal Cancer

Abstract Background: EGFR-TKIs are prone to develop acquired drug resistance in colorectal cancer and are only applicable in Kras wild type colorectal cancer patients. This study aimed to determine the reasons for the poor treatment efficacy of TKIs in Kras mutant CRC and to improve the treatment effect. Method: The RTK Phosphorylation Membrane array was used to detect and screen changes in phosphorylated protein levels in KRAS mutant-resistant CRC cells. qRT-PCR, western blot and TCGA database were applied for reporting the expression of ERGR and ErbB3 in CRC. Luciferase reporter and western blot examined the network of miR-323a-3p. RTCA, colony formation, CCK-8, caspase-3/7 activity and Flow cytometry probed the impacts of miR-323a-3p on CRC cell growth.Results: We illustrated that ErbB3 and EGFR were activated in gefitinib-resistant Kras mutant colorectal cancer cell lines. ErbB3 is highly expressed in Kras mutant patient tissues, and patients with ErbB3high/EGFRhigh had a poorer prognosis. Mechanically, We found and verified that the tumor suppressor miR-323a-3p simultaneously directly targeted EGFR/ErbB3 and inhibited tumor cell growth by activating the apoptosis pathway. Further functionality studies identified miR-323a-3p synergized with gefitinib to inhibit tumor growth, and this synergy prevented the development of acquired resistance to gefitinib in CRC cell lines.Conclusion: Accordingly, these data indicate that Kras mutant CRC TKI resistance occurs due to the activation of EGFR and ErbB3. Thus, miR-323a-3p has the potential to treat Kras-mutated colorectal cancer by targeting ErbB3/EGFR.