Evidence shows that tropomodulin 1 (TMOD1) is a powerful diagnostic marker in the progression of several cancer types. However, the regulatory mechanism of TMOD1 in tumor progression is still unclear. Here, we showed that TMOD1 was highly expressed in acute myeloid leukemia (AML) specimens, and TMOD1-silencing inhibited cell proliferation by inducing autophagy in AML THP-1 and MOLM-13 cells. Mechanistically, the C-terminal region of TMOD1 directly bound to KPNA2, and TMOD1-overexpression promoted KPNA2 ubiquitylation and reduced KPNA2 levels. In contrast, TMOD1-silencing increased KPNA2 levels and facilitated the nuclear transfer of KPNA2, then subsequently induced autophagy and inhibited cell proliferation by increasing the nucleocytoplasmic transport of p53 and AMPK activation. KPNA2/p53 inhibitors attenuated autophagy induced by silencing TMOD1 in AML cells. Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.

Emerging evidence has shown that long non-coding RNAs (lncRNAs) play an important role in inhibiting tumor cell proliferation and inducing differentiation. In this study, integrative analysis of whole transcriptome sequencing data demonstrated that lncRNA-Gm31932 is significantly decreased in all-trans retinoic acid (ATRA)-induced and sodium 4-phenylbutanoate (PB-4)-induced mouse melanoma B16 cells. Silencing lncRNA-Gm31932 could inhibit B16 cell proliferation, with cell cycle arrest at the G0/G1 phase and obvious differentiation characteristics, e.g., increased cell volume, melanin content and tyrosinase (Tyr) activity. Furthermore, a series of experiments (luciferase reporter assay, RNA pull-down assay, and western blotting) showed that lncRNA-Gm3932 down-regulated Prc1 and Nuf2 by competitively sponging miR-344d-3-5p, which subsequently reduced the expression of cell cycle-related proteins CDK2, CDC2, and Cyclin B1, and increased the expression of P21 and P27. Moreover, silencing lncRNA-Gm31932 could significantly inhibit tumor growth in B16 melanoma-bearing mice. Taken together, these results indicate that as a possible signaling pathway for ATRA and PB-4, lncRNA-Gm31932 can induce cell cycle arrest and differentiation via miR-344d-3-5p/Prc1 (and Nuf2) axis.

OBJECTIVESHydroxysafflor yellow B (HSYB) is extracted from the petals of the safflower, a Chinese medicine. Relevant research results have demonstrated that HSYA can suppress the abnormal tumour cell proliferation and induce cell apoptosis. However, the properties of HSYB have rarely been reported, especially its antitumour effects on gastric cancer (GC).METHODSSGC-7901 and BGC-823 cells were treated with different concentrations of HSYB. Cell proliferation inhibition rate was detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation detection. The changes in morphology of cells was observed by Hoechst 33258 staining. Cell apoptosis was evaluated by Annexin V-FITC/PI (fluoresceinisothiocyanate/propidium iodide) double staining. JC-1 was used to detect the level of mitochondrial membrane potential (MMP). The protein levels of cleaved-caspase-3, cleaved-caspase-9, APAF-1, cytoplasmic cytochrome C, BAX and BCL-2 were examined by western blot.KEY FINDINGSHSYB significantly suppressed the proliferation of SGC-7901 and BGC-823 cells. Hoechst 33258 staining assay showed that HSYB treatment triggered apoptotic morphology and the apoptotic rates were significantly increased after being treated with HSYB and the mitochondrial membrane potential was gradually decreased in human GC cells. In addition, Western blot analysis revealed that the levels of cleaved-caspase-3 and cleaved-caspase-9 were remarkably increased in HSYB-treated BGC-823 and SGC-7901 cells. And, the levels of apoptotic protease activating factor-1 (APAF-1) and cytoplasmic cytochrome C were remarkably up-regulated in HSYB-treated cells. At the same time, HSYB could up-regulate the level of BAX and down-regulate the level of BCL-2.CONCLUSIONSOur data suggest that HSYB could induce GC cell apoptosis via the mitochondrial pathway.

Insulin is a key hormone for maintaining glucose homeostasis in organisms. In general, deficiency of insulin synthesis and secretion results in type I diabetes, whereas insulin resistance leads to type 2 diabetes. Cell division cycle 42 (CDC42), a member of Rho GTPases family, has been shown as an essential regulator in the second phase of glucose-induced insulin secretion in pancreatic islets β cells in vitro. However, the effect of CDC42 on insulin expression has not been explored. Here we reported that the glucose-induced insulin expression and secretion were significantly inhibited in mice lacking CDC42 gene in pancreatic β cells (Rip-CDC42cKO) in vivo and in vitro. Deletion of CDC42 gene in pancreatic β cells did not affect survival or reproduction in mice. However, the Rip-CDC42cKO mice showed the systemic glucose intolerance and the decrease of glucose-induced insulin secretion without apparent alterations of peripheral tissues insulin sensitivity and the morphology of islets. Furthermore, we demonstrated that deletion of CDC42 gene in pancreatic β cells significantly attenuated the insulin expression through inhibiting the ERK1/2-NeuroD1 signaling pathway. Taken together, our study presents novel evidence that CDC42 is an important modulator in glucose-induced insulin expression as well as insulin secretion in pancreatic β cells.

Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls (P < 0.001), with the power to detect this significance of being over 99.9%. Moreover, the above two polymorphisms increased the risk of developing hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P < 0.001) and dominant (OR = 1.75; 95% CI: 1.23-2.50; P = 0.002) models after adjusting for body mass index, smoking and drinking. Haplotype analysis showed that the T-C-T haplotype (rs1045411-rs2249825-rs1415125) in HMGB1 gene was associated with a 2.47-fold (95% CI: 1.41-4.34; P = 0.002) increased risk of hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.

This study purported to investigate the impact of interleukin-10 (IL-10) gene 4 polymorphisms (-1082G>A, -819T>C, -592A>C and 210T>C) on peripheral blood IL-10 variation and prostate cancer (PCa) risk, with a special consideration given to various origins of between-study heterogeneity. 2 researchers independently fulfilled literature retrieval, quality assessment and information collection. Sub-grouped analyses per ethnicity, continent, design type, control source, genotyping procedure, genotype validation, age-matched status, study sample size, quality score and controls' mean age were conducted, respectively. Total 17 unduplicated studies (patients/controls: 7561/8101) were assessable for PCa risk, and 4 unduplicated studies (1189 subjects) for peripheral blood IL-10 variation. Pooling all assessable studies identified a marginally significant association between the -1082A allele and increased PCa risk (odds ratio (OR)=1.10, 95% confidence interval [CI]: 1.00 to 1.21) (Heterogeneity I2=64.3%), and no significance was detected in sub-grouped analyses of this polymorphism. Contrastingly, the -592C allele was significantly associated with reduced PCa risk in both prospective (OR=0.85, 95% CI: 0.77 to 0.95) and population-based (OR=0.92, 95% CI: 0.84 to 1.00) studies (Heterogeneity I2=0.0% and 18.1%). Moreover, carriers of combined -592CA/CC genotypes had a significant higher level of peripheral blood IL-10 than the -592AA genotype carriers (weighted mean difference=0.45 and 0.54 mg/dL, 95% CI: 0.23 to 0.67 and 0.30 to 0.39). The above comparisons possessed a low probability of publication bias. In sum, our findings suggested that IL-10 gene -592A>C polymorphism may represent a promising candidate locus for the occurrence of PCa, and further signified a contributing role of this polymorphism in prostate carcinogenesis.