Based on the latest studies, we demonstrated that miR-365 could make SGC-7901 and MGC-803 cells become more sensitive to erastin, which is a classic ferroptosis inducer, by inhibiting the expression of Nrf2.
Erastin was firstly ascertained as a inducer of cell death in 2003[24]. As ferroptosis was named by Dixon in 2012[4], Hao S and others[25–27] have shown that the induction of erastin can result in the death of gastric cancer cells, which is suggesting that gastric cancer cells are sensitive to the inducers of ferroptosis. Erastin suppress the synthesis of cysteine-dependent GSH, hence caused the promotion of the toxic ROS accumulation, and lipid oxidation products, MDA[28] [29]. By assessing the changes in these molecules associated with lipid oxidation, erastin induced the oxidation of lipids in gastric cancer cells was observed.
An interesting observation was found during this study. It was revealed that miR-365 significantly enhances erastin-induced cell death. However, it is still unclear about how miR-365 affecting in the pathogenesis of oxidative stress-related retinopathy. Juan Wang et al. believe that miR-365 is associated with Müller cell gliosis through oxidative stress aggravation[30]. Ming Gao et al. found miR-365 served as an intermediate between MT1DP and Nrf2, also at the translation level, it plays an vital role in enhancing Cd‐induced oxidative stress by reducing Nrf2 concentrations [20]. Jia Lin Mo et al. found that upregulation of miR-365 intensifies ischemic neuronal damage through increased oxidative stress by targeting Oxr1. Conversely, silencing miR-365 provided protection against ischemic neuronal injury by activating OXR1-mediated antioxidant signaling [31]. It is revealed that miR-365 not only further enhances the erastin-induced reduction of GSH, but also accumulates the ROS and MDA in gastric cancer cells. Moreover, our findings elucidate the function of miR-365 in stimulating ferroptosis in gastric cancer cells.
It is complicated about the function of Nrf2 in regulating ferroptosis in cancer cells. Nrf2 plays a important role in suppressing cell damage, oxidative stress, and inflammation, which can potentially inhibit tumor initiation. However, strong activation of Nrf2 through genetic alterations or other mechanisms has been observed in various types of cancers. This enhanced Nrf2 activation enables cancer cells to adapt to the microenvironment of hostile, promoting metabolic modifications that support rapid cancer cell proliferation, making tumor grow and invasion [32].Besides, increasing their sensitivity towards chemotherapeutic agents in gastric cancer cells was observed upon the inhibition of Nrf2 [33, 34]. Our experimental data has proved that miR-365 downregulated the transcription of Nrf2 and reduced its protein expression in SGC-7901 and MGC-803 cells which was exposed to erastin. Based on our deduction, the observation that miR-365 enhanced cell death triggered by erastin, suggesting that the downregulation of Nrf2 played a key role in miR-365-induced ferroptosis. Through the deletion of the miR-365 binding site in Nrf2 3’-UTR, we were able to confirm the direct targeting of Nrf2 by miR-365. In this article, it was first time to be unveiled that miR-365 sensitizes gastric cancer cells to ferroptosis inducers by destabilizing Nrf2.
The microenvironment within tumors exhibits a significantly higher level of complexity compared to that of cultured cells. To comprehensively investigate the role of the miR-365-Nrf2 axis in cellular ferroptosis, future studies should include in vivo experiments and the use of additional ferroptosis inducers.