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Abstract Background Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. Methods Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. Results The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. Conclusions Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance. Graphical Abstract

Considerable attention has been raised on crizotinib- and sunitinib-induced hepatotoxicity, but the underlying mechanisms need further examination. In addition, limited therapeutic strategies exist to reduce the liver damage caused by crizotinib and sunitinib. This study investigated the mechanisms of crizotinib- and sunitinib-induced hepatotoxicity and the potential mitigation through ROS and Nrf2 signaling. Firstly, crizotinib and sunitinib reduced cell viability in human liver cells (L02 cells) and triggered dramatic liver injury in mice. Subsequently, we found that crizotinib and sunitinib activated the oxidative stress response (decreased level of GPx and SOD, and increased MDA content) in vivo. Crizotinib and sunitinib also stimulated hepatocyte mitochondrial apoptosis and necrosis in L02 cells in a dose-dependent manner. In vivo studies further confirmed that crizotinib and sunitinib decreased mitochondrial membrane potential and activated apoptosis-associated proteins (cleaved-PARP, cleaved caspase3, cytochrome c, Bcl2 and Bax). Furthermore, mechanistic investigations demonstrated that crizotinib and sunitinib accumulated ROS and inhibited Nrf2 signaling, and that ROS scavenger NAC and Nrf2 agonist tBHQ alleviated the extent of cell damage and the mitochondrial apoptosis during crizotinib- and sunitinib-induced hepatotoxicity in L02 cells. Collectively, these findings indicated that NAC and tBHQ play the crucial roles in crizotinib- and sunitinib-induced mitochondrial apoptosis via the regulation of oxidative stress.

Circular RNA (circRNA) abnormal expression and regulation are involved in the occurrence and development of a variety of tumors. However, the role of circRNAs still remains unknown in gastrointestinal stromal tumors (GISTs). In the present study, the differential circRNA expression profile of GISTs was screened by human circRNAs chip and verified by qRT-PCR. The circRNA–miRNA–mRNA regulatory network was constructed using the cytoHubba plugin based on the Cytoscape software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore circRNA functions. Six significantly differential circRNAs were also verified in 20 pairs of GISTs and adjacent tissues by qRT-PCR. The result showed that a total of 543 differentially expressed circRNAs were identified in GISTs, of which 242 were up-regulated and 301 were down-regulated. Additionally, the circRNA–miRNA–mRNA network contained six circRNAs, 30 miRNAs, and 308 mRNAs, and the targeted mRNAs were associated with “regulation of biological process,” “intracellular organelle,” “protein binding,” and enriched in Wnt signaling pathway. Furthermore, qRT-PCR demonstrated that hsa_circRNA_061346, hsa_circRNA_103114, and hsa_circRNA_103870 were significantly up-regulated in GISTs (n = 20), and hsa_ circRNA_405324, hsa_circRNA_406821, and hsa_circRNA_000361 were dramatically down-regulated in GISTs (n = 20). In addition, all of these circRNAs were shown to have high diagnostic values, and most of them were significantly associated with tumor size, mitotic figure, and malignant degrees in GISTs (P < 0.05). Therefore, we concluded that circRNAs were abnormally expressed in GISTs, and the circRNA–miRNA–mRNA regulatory network plays an important role in the occurrence and development of GISTs. Also, the identified six candidate circRNAs might be critical circRNAs and may present as potential diagnostic biomarkers for GISTs.

Taurine has positive effects on bone metabolism. However, the effects of taurine on osteoblast apoptosis in vitro have not been reported. The aim of this study was to investigate the activity of taurine on apoptosis of mouse osteoblastic MC3T3-E1 cells. The data showed that 1, 5, 10, or 20 mM taurine resulted in 16.7, 34.2, 66.9, or 63.75% reduction of MC3T3-E1 cell apoptosis induced by the serum deprivation (serum-free α-MEM), respectively. Taurine (1, 5, or 10 mM) also reduced cytochrome c release and inhibited activation of caspase-3 and -9, which were measured using fluorogenic substrates for caspase-3/caspase-9, in serum-deprived MC3T3-E1 cells. Furthermore, taurine (10 mM) induced extracellular signal-regulated kinase (ERK) phosphorylation in MC3T3-E1 cells. Knockdown of the taurine transporter (TAUT) or treatment with the ERK-specific inhibitor PD98059 (10 μM) blocked the activation of ERK induced by taurine (10 mM) and abolished the anti-apoptotic effect of taurine (10 mM) in MC3T3-E1 cells. The present results demonstrate for the first time that taurine inhibits serum deprivation-induced osteoblast apoptosis via the TAUT/ERK signaling pathway.