LncRNA H19 modulates neuropathic pain through miR-141/GLI2 axis in chronic constriction injury (CCI) rats.

BACKGROUND: The participation of long non-coding RNAs (lncRNAs) in progressions of chronic pain has been evaluated. We explored mechanisms of lncRNA H19 in chronic constriction injury (CCI)-induced neuropathic pain model in vivo. METHODS: The expressions of lncRNA H19, microRNA-141, and GLI Family Zinc Finger 2 (GLI2) in CCI rats were determined by using RT-qPCR. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were used as neuropathic pain index implying mechanical allodynia and thermal hyperalgesia. The protein concentrations of IL-1ß, IL-6 and TNF-α in rats were examined by ELISA assay. RT-qPCR analyzed gene expression changes of lncRNA H19, miR-141 and GLI2. Online bioinformatics predictions supported that the bindings between miR-141 and GLI2 and dual luciferase reporter method, and RNA pull-down assays determined connections within lncRNA H19, miR-141 and GLI2 in HEK 293 cells. RESULTS: LncRNA H19 was upregulated in the tissues of rats. Also, thermal hyperalgesia and mechanical allodynia were inhibited by lncRNA H19 suppression in rats. Moreover, IL-1ß, IL-6 and TNF-α protein concentrations were suppressed by the downregulation of lncRNA H19 in rats. Furthermore, miR-141 was reduced in CCI rats and restored by the lncRNA H19 knockdown, suggesting the potential negative associations of miR-141 with lncRNA H19. GLI2 targeted miR-141 and GLI2 was increased in CCI rats. Additionally, the neuropathic pain was inhibited by the inhibition of GLI2 in rats, which was reversed by the miR-141 inhibitors. CONCLUSION: LncRNA H19 aggravated the neuropathic pain of CCI rats through miR-141/GLI2 axis, implying that lncRNA H19 might be a biomarker for the inflammation-related neuropathic pain.

EGFR-rich extracellular vesicles derived from highly metastatic nasopharyngeal carcinoma cells accelerate tumour metastasis through PI3K/AKT pathway-suppressed ROS.

Nasopharyngeal carcinoma (NPC) is the most common cancer with high metastatic potential that occurs in the epithelial cells of the nasopharynx. Distant metastases are the primary cause for treatment failure and mortality of NPC patients. However, the underlying mechanism responsible for the initiation of tumour cell dissemination and tumour metastasis in NPC is not well understood. Here, we demonstrated that epidermal growth factor receptor (EGFR) was highly expressed in tumour tissues of NPC patients with distant metastases and was associated with a decrease in reactive oxygen species (ROS). We also revealed that extracellular vesicles (EVs) transfer occurred from highly to poorly metastatic NPC cells, mediating cell-cell communication and enhancing the metastatic potential of poorly metastatic NPC cells. Further experiments indicated that EVs derived from highly metastatic NPC cells induced the up-regulation of EGFR and down-regulation of ROS in low metastatic NPC cells. Mechanistically, EGFR-rich EVs-mediated EGFR overexpression down-regulated intracellular ROS levels through the PI3K/AKT pathway, thus promoting the metastatic potential of poorly metastatic NPC cells. Strikingly, treatment with EVs secreted from highly metastatic NPC cells was significantly associated with rapid NPC progression and shorter survival in xenografted mice. These findings not only improve our understanding of EVs-mediated NPC metastatic mechanism but also have important implications for the detection and treatment of NPC patients accompanied by aberrant EGFR-rich EVs transmission.