miR-140-5p mediates bevacizumab-induced cytotoxicity to cardiomyocytes by targeting the VEGFA/14-3-3γ signal pathway

Abstract

Bevacizumab (BVZ) is the first recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGFA) approved by the FDA for the treatment of different kinds of cancers, especially colorectal cancer. Although the anti-tumor effects have been verified, the side effects of BVZ are also noteworthy, among which, cardiotoxicity may be the most serious side effect of BVZ. However, the exact mechanisms of cardiotoxicity induced by BVZ have been little explored. This study was conducted in vitro in a human cardiac myocyte (HCM) model. MTT assay was conducted to determine BVZ-stimulated cell viability. For testing the function and mechanism, the cells were transfected with miR-140-5p mimics, miR-140-5p inhibitor and/or VEGFA small interfering RNA (si-VEGFA). Then, apoptosis of the cells was detected via annexin V/propidium iodide (AV-PI) staining followed by flow cytometry. qRT-PCR and western blot assays were applied to measure gene expression (i.e. mRNA) and protein levels, respectively. The CK, LDH, SOD, CAT and GSH-Px activities and MDA level were determined using commercial kits. ROS levels were determined by DCFH-DA assay. Mitochondrial membrane potential was measured by JC-1 assay. Dual-luciferase reporter assay was used to detect the interaction between miR-140-5p and VEGFA. BVZ could inhibit HCM proliferation and induce apoptosis. miR-140-5p was upregulated in response to BVZ treatment and miR-140-5p restraint could alleviate HCM damage caused by BVZ treatment. In contrast, VEGFA and 14-3-3γ expressions were down-regulated by BVZ, and miR-140-5p could inhibit the expression of 14-3-3γ by directly targeting VEGFA. Moreover, VEGFA suppression enhanced HCM injury stimulated by BVZ and partially reversed the functional role of the miR-140-5p inhibitor in BVZ-treated cells. Taken together, miR-140-5p promoted BVZ-treated cardiomyocyte toxicity by targeting the VEGFA/14-3-3γ signal pathway. Collectively, miR-140-5p mediated the BVZ-induced cytotoxicity to cardiomyocytes by targeting the VEGFA/14-3-3γ signal pathway, indicating that miR-140-5p may be a novel target for treating BVZ-induced cardiotoxicity.

Interferon‐regulatory factor‐1 boosts bevacizumab cardiotoxicity by the vascular endothelial growth factor A/14‐3‐3γ axis

“…5,34 Interestingly, one research has shown that miR-140-5p could mediate BVZ-induced cytotoxicity to cardiomyocytes by targeting the VEGFA/14-3-3γ signalling pathway. 8 In the present study, we revealed that IRF1 accelerated BVZ-induced cardiomyocyte injury by regulating the VEGFA/14-3-3γ axis. IRF1 is involved in immune responses, tumour suppression, and apoptosis in multiple cell types.…”

“…BVZ could induce cardiotoxicity by promoting mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, and ERK inactivation 5,34 . Interestingly, one research has shown that miR‐140‐5p could mediate BVZ‐induced cytotoxicity to cardiomyocytes by targeting the VEGFA/14‐3‐3γ signalling pathway 8 . In the present study, we revealed that IRF1 accelerated BVZ‐induced cardiomyocyte injury by regulating the VEGFA/14‐3‐3γ axis.…”

“…However, the intracellular molecular mechanisms underlying BVZ‐associated cardiotoxicity have yet to be fully understood. A previous study reported that VEGFA was involved in BVZ‐induced cardiomyocyte toxicity 8 . As a vascular bioregulatory substance, VEGFA has been reported to promote angiogenesis, increase blood flow, and play an important role in protecting cardiac function 9 .…”

circGLI3 Inhibits Oxidative Stress by Regulating the miR-339-5p/VEGFA Axis in IPEC-J2 Cells

“…Inhibiting VEGFA gene expression leads to an increase in the ROS level in spinal cord cells and activates the β -catenin signaling pathway [ 40 ]. VEGFA silencing can increase bevacizumab-induced oxidative damage, cardiomyocyte apoptosis, and the ROS level and can change related apoptotic proteins [ 41 ]. Moreover, there is evidence that showed that VEGF effects on epithelial cell migration play an important part in epithelial cell restitution by maintaining mucosal homeostasis after mucosal injury [ 42 ].…”

Non-coding RNAs in cancer therapy-induced cardiotoxicity: Mechanisms, biomarkers, and treatments

“…However, cardiotoxic adverse effects may occur after long-term treatment (164,165). BVZ causes cardiomyocyte mortality that is doseand duration-dependent, leading to cardiac damage, according to a recent study (93). Previously, miR-140-5p was thought to have a role in DOX-caused oxidative stress (35,36).…”