Mechanism and molecular network of RBM8A-mediated regulation of oxaliplatin resistance in hepatocellular carcinoma via EMT

Abstract

Epithelial-mesenchymal transition (EMT) has been shown to be closely associated with Oxaliplatin (OXA) resistance. Previous study found that RBM8A is highly expressed in HCC and induce EMT, suggesting that it may be involved in the regulation of OXA resistance in HCC. However, the accurate mechanism has not been concluded. In our study, ectopic expression and silencing of RBM8A were performed to explore its function. The OXA resistance potential of RBM8A and its downstream pathway was investigated using in vitro and in vivo models. The results showed that RBM8A overexpression induced EMT in OXA-resistant HCC cells, thereby affecting cell proliferation, apoptosis, migration, and invasion and promoting OXA resistance in vivo and in vitro. Moreover, whole-genome microarrays combined with bioinformatics analysis revealed that RBM8A has a wide range of transcriptional regulatory capabilities in drug-resistant HCC, including the ability to regulate several important tumor-related signaling pathways. Histone deacetylase 9 (HDAC9) is an important mediator of RBM8A activity related to OXA resistance. These data suggest that RBM8A and its related regulatory pathway represent potential markers of OXA resistance and therapeutic targets in HCC. BackgroundHepatocellular carcinoma (HCC) is a highly lethal cancer; although it has the sixth highest incidence of malignant tumors globally, its mortality rate ranks second among all cancers [1]. The advent of the molecularly targeted drug sorafenib has opened the door to advanced HCC drug therapies, but the objective response rate (ORR) and progression-free survival (PFS) for first-line therapies are limited and expensive to administer[2]. HCC is extremely complicated and refractory, and the difficulty in successfully treating it also highlights the necessity and importance of multiple methods and multidisciplinary comprehensive treatments, including systemic chemotherapy.The EACH trial and subsequent basic experiments and clinical trials have confirmed that OXA-based systemic chemotherapy for Asian patients with advanced HCC can improve the objective efficiency and has good tolerance and safety, a high cost-effectiveness ratio and easy clinical promotion; therefore, OXA is recognized as the most effective chemotherapy for HCC [3,4]. Even so, the effectiveness of OXA against HCC is still less than 20%, which is unsatisfactory. OXA resistance has 4 become a tremendous obstacle in the treatment of HCC. Identifying key targets affecting oxaliplatin resistance and its related signaling pathways and understanding their mechanism of action have become key issues to be solved urgently.Epithelial-mesenchymal transition (EMT) refers to the biological process by which epithelial cells gradually lose cell-cell adhesions and undergo a specific transformation to obtain characteristics of a strong mesenchymal phenotype, such as movement and migration; this process is closely related to the occurrence and development of a variety of tumors [5]. Ma et al.[6] reported that OXA-resistant HCC cells sh...