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BACKGROUND: Accumulating evidence has indicated that aberrant RNA modifications are associated with malignant progression and the immune microenvironment in various tumors. However, the function of RNA modification regulators in testicular germ cell tumors (TGCTs) remains to be discovered. This study aimed to investigate the biological functions of RNA modification regulators in testicular germ cell tumors and identify their potential clinical predictive value. METHODS: Expression level of 75 RNA modification regulators was acquired to generate differential expression patterns. RNA modification regulatory genes were applied to construct a progression-free survival (PFS) risk model. Meanwhile, three RNA modification clusters were identified using consensus clustering. Subsequently, the infiltration characteristics of cells in the microenvironment as well as the antitumor drug candidates have been further analyzed. Finally, to further validate our results, we examined the expression and biological behavior of seven selected RNA modification regulators both in TGCT cell lines and clinical tissues. RESULTS: We collected the differentially expressed regulators of RNA modification. RNA modification risk signature was developed to stratify the prognosis of TGCT patients. Furthermore, we found significant differences in immune microenvironment between subgroups. Ultimately, seven selected RNA modification regulators were further verified. CONCLUSIONS: We generated and validated a risk signature related to RNA modification which could accurately predict the relapse risk in TGCT patients. This risk signature was correlated with immune cells infiltration among tumor microenvironments. Furthermore, we screened antitumor drug candidates and evaluated the sensitivity and efficacy of class chemotherapeutic drugs, which could provide reference for clinical drug use.
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BACKGROUND: Recent evidence has indicated that long non-coding RNAs (lncRNAs) were emerged as key molecules in clear cell renal cell carcinoma (ccRCC). TCGA database showed that the expression level of lncRNA NLGN1-AS1 was up-regulated in ccRCC; However, whether NLGN1-AS1 implicated in the malignant progression of ccRCC remained unclear. METHODS: Based on TCGA database, candidate lncRNAs were selected and quantitative real-time PCR (qRT-PCR) was utilized to verify the expression levels of candidate lncRNAs in human ccRCC tissues. Loss-of-function experiments were performed to examine the biological functions of NLGN1-AS1 both in vitro and in vivo. According to bioinformatics analysis, fluorescence reporter assays and rescue experiments, the underlying mechanisms of NLGN1-AS1 in ccRCC cell lines were so clearly understood. RESULTS: As a novel lncRNA, NLGN1-AS1 was up-regulated in ccRCC cell lines and associated with poor prognosis of and ccRCC patients, which was correlated with the progression of ccRCC. Functionally, the down-regulation of NLGN1-AS1 significantly decreased the proliferation of ccRCC cells both in vitro and in vivo. Bioinformatics analysis and luciferase report assays identified that miR-136-5p was a direct target of NLGN1-AS1. We also determined that FZD4 were inhibitory targets of miR-136-5p, and that Wnt/ß-catenin signaling was inhibited by both NLGN1-AS1 knockdown and miR-136-5p over-expression. In addition, we found that the suppression of proliferation and the inhibition of Wnt/ß-catenin pathway induced by NLGN1-AS1 knockdown would require the over-expression of FZD4. CONCLUSIONS: Our findings suggested that lncRNA NLGN1-AS1 could promote the progression of ccRCC by targeting miR-136-5p/FZD4 and Wnt/ß-catenin pathway, and might serve as a novel potential therapeutic target to inhibit the progression of ccRCC.
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OBJECTIVE: To explore the effect of up-regulation of KA1 subunit of the kainate receptor on endoplasmic reticulum stress (ERS)-induced excitotoxic neurodegeneration in mouse hippocampus. METHODS: Seventy adult male KM mice were subjected to microinjections into the hippocampus of kainic acid (KA) or 500, 1000, or 2000 µg/ml tunicamycin (TM). At 1, 2, 3, 4, 5, 8, and 12 h after the injections, the mice were assessed for Bederson scores and sacrificed for FJB staining and immunofluorescence observation of the brain slices. RESULTS: At 3, 4, 5, and 8 h after KA injection and at 4 and 5 h after of 2000 µg/ml TM injection, the mice showed severe central nervous system dysfunction, and FJB staining revealed increased cell death in the hippocampus, where up-regulated expressions of KA1 receptor and ERS marker P-eIF2α were found by immunofluorescence staining (P<0.05). CONCLUSION: Microinjection of KA or TM into the hippocampus causes neuronal death and ERS with up-regulated expression of KA1. In this process of neuronal apoptosis, the membrane receptor KA1 receives the apoptosis signal and transfers it to the inside of the cells to cause cell endoplasmic reticulum dysfunction and ERS response, which ultimately leads to neuronal death.