Association analyses identify six new psoriasis susceptibility loci in the Chinese population.

We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10⁻8) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⁻²¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⁻³ and P = 7.9 × 10⁻³, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⁻³ and P = 1.5 × 10⁻³, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.

Involvement of mTOR and survivin inhibition in tamoxifen-induced apoptosis in human hepatoblastoma cell line HepG2.

Patients with advanced hepatocellular carcinoma (HCC) have shown to benefit from tamoxifen treatment. The mechanisms of tamoxifen effects in HCC, however, are not yet clearly understood. The PI3K/Akt/mTOR signal pathway is involved in cell proliferation, tumorigenesis, and apoptosis. Over-expression of survivin has played an important role in leading to antiapoptosis. The current study investigated changes in mTOR pathway and survivin expression in hepatocarcinoma cell line HepG2 treated with tamoxifen. We detected apoptosis of hepatocarcinoma cells by flow cytometry assay. Survivin transcription level and p70S6k was demonstrated by PCR, dual-luciferase reporter assay and western blot analysis respectively. Our results are showed as follows: tamoxifen leads to apoptosis of the cells, and reduction in survivin expression, as well as a dramatic reduction in the activated form of p70S6 kinase. Twenty micromoles tamoxifen treatment significantly depresses transcription of survivin mRNA. Treating HepG2 cells with rapamycin, a specific mTOR inhibitor, significantly reduce survivin protein level but did not affect survivin transcription, which indicated that tamoxifen and rapamycin were synergistic in regards to down-regulation of survivin expression in hepatocellular carcinoma cells. Our results suggest that tamoxifen down-regulate survivin expression in HepG2 cells is mediated by transcriptional and posttranscriptional level via PI3K/Akt/mTOR pathway to induce apoptosis.

[Expression of livin in gastric cancer and effect of silencing of the livin gene on apoptosis in gastric cancer cells].

OBJECTIVE: The aim of this study was to detect the expression of livin in human gastric carcinoma and analyze the relationship between livin expression and cliniopathologic features. To explore the feasibility of small interference RNA (siRNA) in inhibition of livin gene expression and to investigate the apoptosis susceptibility of SGC-7901 cells by siRNA-mediated silencing of the livin gene. METHODS: The expression of livin at mRNA and protein levels were determined by RT-PCR and Western blot assay, respectively. The relationship between livin expression and clinicopathologic features was analyzed. Two siRNAs specifically targeting livin gene were designed and synthesized in vitro, and were transfected into the gastric cancer SGC-7901 cells. The expression of livin mRNA was assayed by RT-PCR. Cell growth state and 50% inhibition concentration (IC50) of 5-Fu and cisplatin on SGC-7901 cells were determined by MTT method. Cell apoptosis was assessed by flow cytometry (FCM). RESULTS: The expressions of livin mRNA and protein were detected in 19 of 40 gastric carcinoma cases (47.5%). No expression of livin was detected in tumor-adjacent tissues and benign gastric lesion. A positive correlation was found between livin expression and poor differentiation as well as lymph node metastases (P < 0.05). The level of livin mRNA was decreased in the SGC-7901 cells transfected by si-livin1 for 48 hours, with inhibition of cell growth. IC50 of si-livin-treated SGC-7901 cells to 5-Fu and cisplatin was decreased (P < 0.05) and the cells were more susceptible to proapoptotic stimuli (5-Fu and cisplatin) than control groups (P < 0.05). CONCLUSION: Livin is overexpressed in gastric carcinoma with a correlation to tumor differentiation and lymph node metastasis, suggesting that it may be as one of molecular prognostic factors for some cases of gastric cancer. SiRNA can inhibit livin expression of SGC-7901 cells and induce cell apoptosis. Livin might serve as a new target for apoptosis-inducing therapy of gastric cancer. Livin;