Int J Pharm. 2021 Mar 3:120446. doi: 10.1016/j.ijpharm.2021.120446. Online ahead of print.
Gastric cancer (GC) presents a challenge for conventional therapeutics due to low targeting specificity and subsequent elicitation of multiple drug resistance (MDR). As an essential enzyme for DNA repair, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) exhibits multiple functions to affect cancer malignancy and is excessively expressed in GC. However, the roles APEX1 and its inhibitor miR-27a-5p play in modulating GC progression and MDR development remains unclear. Here, we verified APEX1 as a target of miR-27a-5p and subsequently established the APEX1-deleted SGC-7901 cell line by CRISPR/Cas9 editing. The roles of the APEX1/miR-27a-5p axis in GC progression, metastasis and doxorubicin (DOX) resistance were explored by the targeted chemotherapy facilitated by a GC-specific peptide (GP5) functionalized liposomal drug delivery formulation (GP5/Lipo/DOX/miR-27a-5p). The results showed that APEX1 deletion distinctly attenuated cell growth and metastatic properties in GC, and also sensitized GC cells to DOX. Notably, miR-27a-5p was validated as a suppressor of APEX1-dependent GC development and DOX resistance by a RAS/MEK/FOS and PTEN/AKT/SMAD2 pathway-dependent manner. The altered expression of epithelial-mesenchymal transition (EMT) signatures and signal pathway proteins in the APEX1-deleted cells implied that APEX1 potentially enhances DOX resistance of GC cells by altering the regulation of MAPK and AKT pathways, leading to compromised efficacy of chemotherapy or by initiating additional DNA damage response pathways. Taken together, these findings revealed that as a novel therapeutic target, APEX1/miR-27a-5p axis plays essential roles in modulating the GC development and MDR, and the GC targeted drug delivery formulation presents a strategic reference for the future designation of chemotherapeutics study.