Effects of TRAF3 on the proliferation and migration of lung adenocarcinoma depend partly on pyroptosis.

BACKGROUND: Tumor necrosis factor receptor-associated factor 3 (TRAF3) has specific regulatory effects on a wide range of diseases, including tumors. However, the effect and mechanism of TRAF3 on lung adenocarcinoma (LUAD) are still unknown. The aim of the present study was to make clear the role and potential mechanism of TRAF3 in LUAD. METHODS: TIMER2.0 database and western blot were applied to detect the expression of TRAF3 in lung adenocarcinoma tissue. Kaplan-Meier Plotter database was utilized to explore the effect of TRAF3 on the clinical prognosis of lung adenocarcinoma patients. Specific siRNA was used to inhibit the expression of TRAF3 in LUAD cells (A549 and H1299). CCK-8 and EdU assays were performed for assessing LUAD cells proliferation. Wound healing assay and transwell assay were performed for determining cells migration. CCK-8 assay was used to assess the response of the LUAD cells to paclitaxel. TIMER2.0 bioinformatics and western blot were employed to detect the effects of TRAF3 on pyroptosis in LUAD. RESULTS: TRAF3 was highly expressed in lung adenocarcinoma tissues and cell lines. Patients with TRAF3 hyperexpression had a good prognosis compared to those with lower expression. TRAF3 inhibition notably induced proliferation and migration of LUAD cells. Inhibition of TRAF3 also weakened the sensitivity of LUAD cells to paclitaxel. Moreover, bioinformatics results showed that TRAF3 was positively correlated with the expression of pyroptosis-related genes in LUAD. Western blot assays showed that TRAF3 inhibition visibly decreased the expression of apoptosis-associated speck-like protein (ASC), cleaved caspase-1 and matured- IL-1ß. CONCLUSIONS: Inhibition of TRAF3 promotes the proliferation and migration of LUAD cells, and reduces the sensitivity of LUAD cells to paclitaxel. The effects of TRAF3 on LUAD cells were mediated in part by caspase-1-dependent pyroptosis.

Decreased IGF-1 level is associated with restrained amino acid metabolism in NSCLC with diabetes mellitus.

The discovery of a large number of small pulmonary nodules and early diagnosis of lung cancer in the diabetic patients prompt us to re-examine the relationship between diabetes and the occurrence and development of lung cancer. The aim of this study was to explore the underlying metabolites changes in diabetes with NSCLC or benign nodule patients, and further to investigate the association of serum IGF-1 level and differentially expressed metabolites (DEMs). An untargeted metabolomics method was used to detect the changes of metabolism in diabetic patients with NSCLC on the platform of HR-MS. Serum level of IGF-1 was measured by ELISA. The patients were divided to three groups, DM, DLB (nodule), and DLC (cancer). we have identified numerous DEMs, which include amino acid, choline, and fatty acid derivatives. Further analysis of the involved metabolic pathways suggested that linoleate metabolism, tryptophan metabolism, histidine metabolism, putative anti-Inflammatory metabolites formation from EPA, and arachidonic acid metabolism were considered to be the most significant metabolic pathways between groups. Networks analysis suggested that a series of metabolites were associated with serum IGF-1among the three groups, which can be divided into 6 categories. Nine metabolites have been identified as the main DEMs among the DLC, DLB, and DM groups. In conclusion, metabolomics is a powerful and promising tool for the cancer risk evaluation in diabetic patients. Our results suggest that decreased IGF-1 level is associated with restrained amino acid metabolism in NSCLC with diabetes mellitus.

Mining candidate genes for rice cadmium accumulation in the shoot through a genome-wide association study and transcriptomic analysis.

High cadmium (Cd) accumulation in rice is a serious threat to human health. The genetic mechanism of Cd accumulation in rice is highly complicated. To identify the low Cd accumulation in rice germplasm, investigate the genetic mechanism underlying Cd accumulation, and mine the elite genes of significant importance for rice breeding of low Cd accumulation varieties, we performed a genome-wide association study (GWAS) for rice Cd concentration in the shoot. The rice accessions were 315 diverse indica rice accessions selected from the 1568 rice accessions with 700,000 SNPs. Within the high rate of linkage disequilibrium (LD) decay, eight QTLs related to rice Cd accumulation were identified. Transcriptomic analysis showed there were 799 differentially expressed genes (DEGs) in the root and 857 DEGs in the shoot, which are probably considered to be the cause of the significant difference in Cd accumulation between high and low Cd accumulation varieties. In qCd11-1, we detected a crucial candidate gene, LOC_Os11g11050, which encodes an initiation factor, expressed differently in the root between the high and low Cd accumulation varieties. Furthermore, under Cd treatment, the expression levels of LOC_Os11g11050 significantly decreased in both the high and low Cd accumulation varieties. Sequence comparison and qRT-PCR revealed that there were indel sequences and base substitutions in the promoter region of LOC_Os11g11050 correlated with the LOC_Os11g11050 expression level, as well as the phenotype of Cd concentration differences in shoot between the high and low Cd accumulation accessions. LOC_Os11g11050 might play important roles in Cd accumulation. The results of our study provide valuable resources for low Cd accumulation in indica varieties and the candidate functional gene, as well as molecular mechanisms for Cd accumulation in indica rice. The genetic architecture underlying Cd accumulation in indica can be used for further applying the low Cd gene existing in indica for decreasing Cd accumulation in rice.

Wnt signaling may be activated in a subset of Peutz-Jeghers syndrome polyps closely correlating to LKB1 expression.

The premalignant potential of Peutz-Jeghers syndrome (PJS) hamartomas has not been established. The major gene responsible for PJS is LKB1. LKB1 has a complex cellular role, therefore, the exact role of LKB1 in Peutz-Jeghers syndrome hamartomas (PJSs) is particularly difficult to understand. It has recently been found that LKB1 functions in the Wnt pathway in Xenopus during early development. Aberrant beta-catenin expression, the key regulator of the activated Wnt/beta-catenin signaling pathway, appears to stimulate interferon-induced gene 1 (IFITM1) products in intestinal tumorigenesis. Both contribute to intestinal tumor formation and tumor progression. This study was designed to investigate expression of LKB1, beta-catenin and IFITM1 in PJSs, colorectal adenomas (CRAs), colorectal carcinomas (CRCs) and normal colorectal mucosas (NCs) using RT-PCR and immunohistochemistry. Immunofluorescence was used to assess the co-expression characteristics of beta-catenin and IFITM1. Results showed that the expression profiles of LKB1, beta-catenin and IFITM1 in PJSs were similar to those in CRAs both at the mRNA and protein levels. The cytoplasmic level of beta-catenin expression correlated strongly with LKB1 and IFITM1 expression in the tumor cells. The dyregulation of beta-catenin was found in a majority (16/20) of the PJS polyps. Immunofluorescence also revealed co-expression of beta-catenin and IFITM1 in the cytoplasm of the PJSs. These findings suggest that Wnt signaling may be activated in a subset of PJSs, and activation of the Wnt/beta-catenin signaling in PJS polyps may be caused by LKB1 expression. The activated beta-catenin signaling pathway including IFITM1 might play an important role in a subset of PJS polyps.

[Expression and significance of interferon-inducible transmembrane protein-1 gene in Peutz-Jeghers syndrome].

OBJECTIVE: To detect the mRNA and protein expression of interferon-inducible transmembrane protein-1 (IFITM1) in Peutz-Jeghers syndrome (PJS) and investigate the role of IFITM1 in the occurrence, development and carcinogenesis of PJS polyps. METHODS: Reverse transcription-PCR was employed to detect the mRNA expression of IFITM1 in 16 PJS polyp samples, adenomatous polyp tissues, colon adenocarcinoma samples, and normal intestinal mucosal tissues. The protein expression and localization of IFITM1 in these tissues (32 cases for each) were detected with immunohistochemical (IHC) staining. RESULTS: The IFITM1 mRNA expression was detected in all these tissues, and the expression intensity increased in the order of normal intestinal mucosa, PJS polyp, adenomatous polyp, and colon adenocarcinoma (F=92.704, P=0.000). IHC revealed that IFITM1 protein was localized mainly on the cell membrane and in the cytoplasm, with increased expression intensity in the same order as its mRNA and showing significant differences between the tissues by several rank-sum test (Kruskal-Wallis H, chi(2)=37.036, p=0.000). CONCLUSION: The expression level of IFITM1 is associated with the progression of the carcinogenetic process in PJS polyp, and can be used as a sensitive biomarker for diagnosis and prognostic evaluation of PJS.