RETRACTED: Exosomes From Cancer-Associated Mesenchymal Stem Cells Transmit TMBIM6 to Promote the Malignant Behavior of Hepatocellular Carcinoma via Activating PI3K/AKT Pathway

Abstract

ObjectiveCancer-associated mesenchymal stem cells (MSCs) regulate the progression of cancers through exosome-delivered components, while few studies are conducted on hepatocellular carcinoma (HCC). This study aimed to evaluate the effect of exosomes from HCC-associated MSCs (HCC-MSCs) on HCC cellular functions and the potential regulatory mechanism.MethodsHCC cells (Huh7 and PLC) were cultured normally or co-cultured with HCC-MSCs, HCC-MSCs plus GW4869, or HCC-MSC-derived exosomes; then mRNA sequencing and RT-qPCR validation were conducted. Subsequently, candidate genes were sorted out and modified in HCC cells. Next, TMBIM6-modified HCC-MSCs were used to treat HCC cells.ResultsBoth HCC-MSCs and their derived exosomes promoted proliferation, invasion, sphere formation ability but suppressed apoptosis in HCC cells (all p < 0.05); however, the effect of HCC-MSCs on these cellular functions was repressed by exosome inhibitor (GW4869). Subsequently, TMBIM6, EEF2, and PRDX1 were sorted out by mRNA sequencing and RT-qPCR validation as candidate genes implicated in the regulation of HCC cellular functions by HCC-MSC-derived exosomes. Among them, TMBIM6 had a potent effect (all p < 0.05), while EEF2 and PRDX1 had less effect on regulating HCC cell viability and invasion. Next, direct silencing TMBIM6 repressed viability, sphere formation, invasion, epithelial–mesenchymal transition (EMT), and PI3K/AKT pathway but promoted apoptosis in HCC cells; however, overexpressing TMBIM6 showed the opposite effect. Furthermore, incubating with exosomes from TMBIM6-modified HCC-MSCs presented a similar effect as direct TMBIM6 modification in HCC cells.ConclusionHCC-MSC-derived exosomes transmit TMBIM6 to promote malignant behavior via PI3K/AKT pathway in HCC.

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

“…TMBIM6, also named as transmembrane Bax inhibitor motif containing-6, is an inhibitor of Bax-induced apoptosis [48]. Growing evidences has indicated that TMBIM6 exert an oncogenic role in multiple cancers, including squamous cervical, non-small cell lung, breast, nasopharyngeal, hepatocellular, glioblastoma, and laryngeal squamous cell carcinoma [29,37,45,[49][50][51][52][53]. Our study implied that TMBIM6 was modified by m6A in the transcription level and interacts with IGF2BP3 and STRIP2, resulting in the stabilization of TMBIM6.…”

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

“…TMBIM6, also named as transmembrane Bax inhibitor motif containing-6, is an inhibitor of Bax-induced apoptosis [47] . Growing evidences has indicated that TMBIM6 exert an oncogenic role in multiple cancers, including squamous cervical, non-small cell lung, breast, nasopharyngeal, hepatocellular, glioblastoma, and laryngeal squamous cell carcinoma [28,36,44,[48][49][50][51][52] . Our study implied that TMBIM6 was modi ed by m6A in the transcription level and interacts with IGF2BP3 and STRIP2, resulting in the stabilization of TMBIM6.…”

Mesenchymal stem cell-derived exosomes as new tools for delivery of miRNAs in the treatment of cancer

“…In hepatocellular carcinoma (HCC) cells, MSC-derived exosomes increase proliferation, invasion, sphere formation ability and suppress apoptosis through TMBIM6. As a result of silencing TMBIM6, viability, sphere formation, invasion, epithelial mesenchymal transition and PI3K/AKT signaling pathway are suppressed, and apoptosis is triggered ( Shang et al, 2022 ). Adipocyte-derived exosomes differentiated from MSC in breast cancer promote cell proliferation and migration, and also inhibit apoptosis via the Hippo signaling pathway.…”