Identification of a Three-Gene Signature Based on Epithelial-Mesenchymal Transition of Lung Adenocarcinoma Through Construction and Validation of a Risk-Prediction Model.

Epithelial-mesenchymal transition (EMT) process, which is regulated by genes of inducible factors and transcription factor family of signaling pathways, transforms epithelial cells into mesenchymal cells and is involved in tumor invasion and progression and increases tumor tolerance to clinical interventions. This study constructed a multigene marker for lung predicting the prognosis of lung adenocarcinoma (LUAD) patients by bioinformatic analysis based on EMT-related genes. Gene sets associated with EMT were downloaded from the EMT-gene database, and RNA-seq of LUAD and clinical information of patients were downloaded from the TCGA database. Differentially expressed genes were screened by difference analysis. Survival analysis was performed to identify genes associated with LUAD prognosis, and overlapping genes were taken for all the three. Prognosis-related genes were further determined by combining LASSO regression analysis for establishing a prediction signature, and the risk score equation for the prognostic model was established using multifactorial COX regression analysis to construct a survival prognostic model. The model accuracy was evaluated using subject working characteristic curves. According to the median value of risk score, samples were divided into a high-risk group and low-risk group to observe the correlation with the clinicopathological characteristics of patients. Combined with the results of one-way COX regression analysis, HGF, PTX3, and S100P were considered as independent predictors of LUAD prognosis. In lung cancer tissues, HGF and PTX3 expression was downregulated and S100P expression was upregulated. Kaplan-Meier, COX regression analysis showed that HGF, PTX3, and S100P were prognostic independent predictors of LUAD, and high expressions of all the three were all significantly associated with immune cell infiltration. The present study provided potential prognostic predictive biological markers for LUAD patients, and confirmed EMT as a key mechanism in LUAD progression.

Comprehensive Bioinformatics Analysis to Identify the Gene HMMR Associated With Lung Adenocarcinoma Prognosis and Its Mechanism of Action in Multiple Cancers.

BACKGROUND: Lung cancer is the third most frequently diagnosed cancer in the world, with lung adenocarcinoma (LUAD) as the most common pathological type. But studies on the predictive effect of a single gene on LUAD are limited. We aimed to discover new predictive markers for LUAD. METHODS: Differentially high-expressed genes at each stage were obtained from the TCGA and GTEx databases. The functions of these genes were investigated through GO enrichment and KEGG pathway analyses. Then, the key genes were selected by applying whole gene overall survival time. The expression of the key gene was studied in LUAD, and survival analysis was performed using Kaplan-Meier mapper, followed by univariate and multifactorial COX analysis. Finally, the gene expression and its prognostic significance in the pan-cancer were examined. RESULTS: A total of 10,106 DEGs were obtained from the two datasets. The top 266 differentially upregulated genes intersected with the top 1,497 overall survival-related genes, and 87 key genes were identified. High-expressed HMMR was associated with a poor prognosis of LUAD. Univariate and multifactorial Cox analysis showed that HMMR was an independent prognostic factor for LUAD patients. A high HMMR expression was strongly associated with the overall survival (OS) and disease-specific survival (DSS) in 11 cancer types and with poorer OS, DSS, and PFI in 10 cancer types. CONCLUSION: HMMR may be an independent prognostic indicator and an important biomarker in diagnosing and predicting the survival of LUAD patients. Also, HMMR may be a key predictor of a variety of cancers.

FL118 inhibits viability and induces apoptosis of colorectal cancer cells via inactivating the CIP2A/PP2A axis.

AIMS: FL118, a novel camptothecin analogue, has been extensively studied for its superior antitumor potency. The aim of this research study is to explore its potential mechanism of action in anti- colorectal cancer (CRC). MAIN METHODS: The effect of FL118 on CRC cell proliferation was assessed using CCK-8 assay, while apoptosis was detected using Hoechst staining and Flow cytometry assays. The expression levels of CIP2A were analyzed using qRT-PCR. The expression of CIP2A, PP2A-C, Bax, cleaved caspase-3 and PARP were analyzed using western blotting analysis. The expressions of related proteins in CRC tissues were detected using immunohistochemical staining. TUNEL assay was used to detect apoptosis of tissue. Toxicity of FL118 in primary organs were examined using H&E staining. KEY FINDINGS: The results show that FL118 can inhibit the proliferation and clonogenic potential of CRC cells and increase the expression of pro-apoptosis proteins, Bax, cleaved caspase-3 and PARP. Microarray analyses found that FL118 treatment significantly decreases cancerous inhibition of protein phosphatase 2A (CIP2A). Further validation found that CIP2A is aberrantly upregulated in CRC tissues, and is positively correlated with the progression of CRC. In vitro findings confirm that FL118 mediates the downregulation of CIP2A, at both protein and mRNA levels. Co-treatment with Okadaic acid (OA) (a PP2A inhibitor) partially abolishes the anti-proliferative and pro-apoptotic effect of FL118. Consistently, in vivo experiment demonstrates that FL118 can effectively suppress tumorigenesis without any obvious toxic effects. SIGNIFICANCE: Collectively, these findings exhibit the anti-neoplastic effects of FL118 against CRC through the down regulation of CIP2A, which subsequently enhances the activity of PP2A.

PRC1 promotes cell proliferation and cell cycle progression by regulating p21/p27-pRB family molecules and FAK-paxillin pathway in non-small cell lung cancer.

BACKGROUND: This study aimed to demonstrate the function and molecular mechanism of protein regulator of cytokinesis 1 (PRC1) in the carcinogenesis of non-small cell lung cancer (NSCLC). METHODS: Bioinformatics analysis was performed. Cell culture and plasmid construction were conducted for cell transfection. mRNA and protein expression, cell proliferation, migration, and cell cycle were detected. Mice models were also constructed. The relationship between PRC1 and the prognosis of NSCLC patients was analyzed. RESULTS: PRC1 expression was higher in tumor tissues than adjacent non-tumor tissues (P<0.05). Cells transfected with the high-expression PRC1 plasmid (TOPO-PRC1 group) had the stronger ability of proliferation and migration (P<0.05) along with a lower incidence of stay at the G2/M phase (P<0.05) than the low-expression PRC1 plasmid. Mice models showed tumors obtained from mice in the TOPO-PRC1 group significantly grew faster, larger, and heavier (P<0.05) than the low-expression PRC1 group. Among the 150 NSCLC patients, patients with the higher PRC1 expression were more likely to have lymph node metastasis occur (P<0.05) and progress into an advanced stage (P<0.05), and showed shorter survival (P<0.05). Moreover, the TOPO-PRC1 group had a lower phosphorylation level, and a lower expression of Cip1/p21 (P<0.05) and Kip1/p27 (P<0.01). CONCLUSIONS: PRC1 could promote cell proliferation and cell cycle progression through FAK-paxillin pathway molecules and the regulation of the phosphorylation level of p21/p27-pRB family molecules. PRC1 might be a new and promising therapeutic target for NSCLC.

[Association of RNASET2 gene polymorphisms and haplotypes with Graves disease in Han Chinese population from coastal regions of Shandong].

OBJECTIVE: To assess the association of RNASET2 gene polymorphisms and haplotypes with Graves disease (GD) in Han Chinese population from coastal regions of Shandong Province. METHODS: A total of 471 GD patients and 472 controls were enrolled. Genotypes of single nucleotide polymorphisms (SNPs) in RNASET2 gene were determined with a Taqman probe on a Fluidigm EPl platform. Haplotypes and their frequencies were analyzed with a SHEsis online software. RESULTS: There was a significant difference in allele frequencies of rs3777722, rs3777723 and rs9355610 between the GD patients and the controls (P=0.018; P=0.028; P=0.021).Allele frequencies of rs3777722 and rs9355610 were significantly lower in GD than in the controls (P=0.018, P=0.021). Haplotypes A-A-C-A and A-A-T-A were significantly more common in the control group compared with the GD group (P=0.046, OR=0.448, 95%CI:0.200-1.006; P=0.049, OR=0.823, 95%CI:0.678-0.999). The frequency of C-G-C-G haplotype was significantly higher in GD patient group than the control group (P=0.018). CONCLUSION: RNASET2 gene polymorphisms and haplotypes are associated with GD in Han population from coastal areas of Shandong Province. rs3777722 and rs9355610 may contribute to the risk for GD.