No abstract

Objective: To investigate the effect of long noncoding RNA GM16343 on interleukin 36β promotion of CD8+T cells in tumor microenvironment regulation. Methods: The differentially expressed long noncoding RNA in interleukin 36β-stimulated mouse CD8+T cells was screened by gene chip technology, and the significant differentially expressed long noncoding RNAs were verified by real-time polymerase chain reaction. The lentiviral vector that overexpresses or knockdown GM16343 was constructed, transfected into CD8+T cells, and stimulated with interleukin 36β, and the amount of interferon γ secreted was detected by enzyme-linked immunosorbent assay. A mouse subcutaneous xenograft model that stably express interleukin 36β was established, and the tumor size and mouse survival time were observed by stimulation with CD8+T cells overexpression or knockdown of GM16343. Results: A total of 12 long noncoding RNAs with significant differences were screened by gene chip analysis. Real-time polymerase chain reaction showed that the difference in GM16343 was larger, and the difference between the groups was observed to be the most significant. Compared to control group, CD8+T cells overexpressing GM16343 increased the secretion of interferon γ, and the tumor diameter of the mice after stimulation showed significant reduction, and the survival time showed significant prolongation. Compared to control group, the CD8+T cells after GM16343 were knocked down. The interferon γ secretion was decreased, and no significant change in tumor diameter and survival time was observed. Conclusion: Interleukin 36β may enhance antitumor immune response of CD8+T cells by regulating GM16343.

Dysregulation of RNA binding proteins (RBPs) is closely associated with tumor events. However, the function of RBPs in hepatocellular carcinoma (HCC) has not been fully elucidated. The RNA sequences and relevant clinical data of HCC were retrieved from the The Cancer Genome Atlas (TCGA) database to identify distinct RBPs. Subsequently, univariate and multivariate cox regression analysis was performed to evaluate the overall survival (OS)-associated RBPs. The expression levels of prognostic RBP genes and survival information were analyzed using a series of bioinformatics tool. A total of 365 samples with 1,542 RBPs were included in this study. One hundred and eighty-seven differently RBPs were screened, including 175 up-regulated and 12 down-regulated. The independent OS-associated RBPs of NHP2, UPF3B, and SMG5 were used to develop a prognostic model. Survival analysis showed that low-risk patients had a significantly longer OS and disease-free survival (DFS) when compared to high-risk patients (HR: 2.577, 95% CI: 1.793–3.704, P < 0.001 and HR: 1.599, 95% CI: 1.185–2.159, P = 0.001, respectively). The International Cancer Genome Consortium (ICGC) database was used to externally validate the model, and the OS of low-risk patients were found to be longer than that of high-risk patients (P < 0.001). The Nomograms of OS and DFS were plotted to help in clinical decision making. These results showed that the model was effective and may help in prognostic stratification of HCC patients. The prognostic prediction model based on RBPs provides new insights for HCC diagnosis and personalized treatment.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. More than 30% of patients with diagnosed HCC have abnormally high expression of fibroblast growth factor receptor 4 (FGFR4). Currently, clinical trials for a variety of FGFR4-specific inhibitors have started. However, the effect of these inhibitors is not ideal, and it is necessary to find a drug combination to synergistically exert anti-tumor effects. We found strong correlations between FGFR4 and HCC clinicopathological characteristics in the present study. After grouping patients according to FGFR4 expression, the key gene signatures were inputted the drug-gene related databases, which predicted several potential drug candidates. More importantly, to achieve the reliable and high throughput drug cytotoxicity assessment, we developed an efficient and reproducible agarose hydrogel microwells to generate uniform-sized multicellular tumor spheroids, which provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates’ effects. Using high content screening, we quickly evaluated the enhanced anti-tumor effects of these combinations. Finally, we demonstrated that Parthenolide is a potential drug that can significantly enhance the clinical efficacy of FGFR4 receptor inhibitors. In general, we offered a new therapeutic way for FGFR4 positive HCC patients.

Radiotherapy is one of the main adjuvant treatments for gastric cancer (GC) that can effectively reduce local recurrence and improve survival rates. However, radiotherapy may result in cytotoxicity and not benefit all patients. This highlights the requirement for identifying potential radiosensitivity genes in GC. The current study investigated the association between tripartite motif containing 36 (TRIM36) status and the prognosis of patients with GC receiving radiotherapy. A total of 371 patients with GC were selected from The Cancer Genome Atlas and randomly divided into test and the validation groups. The results revealed that TRIM36 expression was not associated with the overall survival (OS) rate. Patients who received radiotherapy with high TRIM36 expression had an improved OS rate compared with patients who did not receive radiotherapy in the test group, as demonstrated by univariate analysis [hazard ratio (HR), 0.062; 95% confidence interval (CI), 0.008–0.462; P=0.007] and multivariate analysis (HR, 0.095; 95% CI, 0.012–0.748; P=0.025). In the validation group, patients with high TRIM36 expression had decreased mortality risk when they received radiotherapy compared with patients who did not receive radiotherapy, as determined by univariate analysis (HR, 0.190; 95% CI, 0.067–0.540; P=0.002) and multivariate analysis (HR, 0.075; 95% CI, 0.020–0.276; P<0.001). However, for patients with low expression, no significant difference was identified in the overall survival rates between the radiotherapy and non-radiotherapy groups. Chi-squared analysis revealed that the expression status of TRIM36 was an independent factor and was not associated with clinicopathological factors. The results indicated that patients with high TRIM36 expression receiving radiotherapy exhibited an improved OS rate. TRIM36 may therefore be an important factor affecting the clinical prognosis of patients with GC receiving radiotherapy and may be considered as a potential radiosensitivity gene signature.