Ling-Qiang Zhang

Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1.

Aim:Forkhead box M1 (FoxM1) is a transcription factor that plays important roles in the pathogenesis and progression of human cancers, including hepatocellular carcinoma (HCC). The aim of this study was to examine the involvement of FoxM1 in the anti-cancer action of sorafenib, a multikinase inhibitor, in human HCC cells.Methods:HCC cell lines HepG2 and HuH-7 were tested. Cell viability was examined using MTT assay and cell invasion was determined with Transwell migration assay. The relevant mRNA expression was determined with RT-PCR, and the proteins were detected using Western blotting and immunofluorescence assays. RNA interference was used to modify the expression of p53 and FoxM1. HuH-7 cell line xenograft mice were used for in vivo study, which were treated with sorafenib (40 mg/kg, po) daily for 3 weeks.Results:Sorafenib (2–20 μmol/L) inhibited the proliferation of the cells in dose- and time-dependent manners with an IC50 value of nearly 6 μmol/L at 48 h. Sorafenib (6 μmol/L) markedly suppressed the cell invasion. Furthermore, sorafenib (2−6 μmol/L) dose-dependently decreased the expression of FoxM1, MMP-2, and Ki-67, and up-regulated that of p53 in the cells. Silencing p53 abolished the decrease of FoxM1 and increase of p53 in sorafenib-treated cells. Silencing FoxM1 significantly reduced the expression of MMP-2 and Ki-67, and enhanced the anti-proliferation action of sorafenib in the cells, whereas overexpression of FoxM1 increased the expression of MMP-2 and Ki-67, and abrogated the anti-proliferation action of sorafenib. In the xenograft mice, sorafenib administration decreased the tumor growth by 40%, and markedly increased the expression of p53, and decreased the expression of FoxM1, MMP-2, and Ki-67 in tumor tissues.Conclusion:Sorafenib inhibits HCC proliferation and invasion by inhibiting MMP-2 and Ki-67 expression due to up-regulation of P53 and suppressing FoxM1.

Model based on γ-glutamyltransferase and alkaline phosphatase for hepatocellular carcinoma prognosis

AIM To determine the prognostic value of alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) for hepatocellular carcinoma (HCC) . METHODS We analyzed the outcome of 172 HCC patients who underwent liver resection. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of ALP and GGT. Then, preoperative risk factors for survival were evaluated by multivariate analysis. Based on the significant factors, a prognostic score model was established. RESULTS By ROC curve analysis, ALP > 120 U/L and GGT > 115 U/L were considered elevated. Overall survival (OS) and tumor-free survival (TFS) for patients with elevated ALP and GGT were significantly worse than for patients with ALP and GGT within the normal range. Multivariate analysis showed that the elevated levels of ALP, GGT and tumor size were independent prognostic factors. Giving each positive factor as a score of 1, we established a preoperative prognostic score model. The 5-year OS for patients with a score of 0, 1, 2 and 3 were 84.0%, 45.9%, 44.1% and 0%, respectively, while the TFS was 80.6%, 40.0%, 38.8% and 0%, respectively. When combining patients with scores of 1 and 2 into the middle risk group, and patients with scores of 0 and 3 into the low-risk and high-risk groups, respectively, different outcomes would be significantly distinguished by the risk groups. CONCLUSION Elevated ALP and GGT levels were risk predictors in HCC patients. Our prognostic model might vary the outcomes of patients from different risk groups.

Distinctions between clinicopathological factors and prognosis of alpha-fetoprotein negative and positive hepatocelluar carcinoma patients.

Serum alpha-fetoprotein (AFP) is a significant marker for clinical diagnosis and prognosis evaluation in hepatocellular carcinoma (HCC) patients. However, some proportion of liver cancer patients are AFP-negative (AFP ≤20 ng/ml). In order to study the differences between clinicopathological factors and prognosis of alpha-fetoprotein negative and positive patients, a total of 114 cases (41 AFP-negative and 73 AFP-positive) were selected for our research. By systematically statistical analysis, the results demonstrated that compared with AFP-negative patients, AFP-positive examples were more likely to feature cirrhosis nodules, non-complete neoplasm capsules, and a poor Edmondson-steiner grade. Furthermore, AFP-negative patients demonstrated a favorable long-term prognosis. By univariate analysis and multivariate analysis with Coxs proportional hazards model, multiple tumors were found to be independent risk factors for worse survival of AFP negative patients; however, less tumor-free margins, multiple tumors and Edmondson-steiner grades III/IV, proved to be independent risk factors leading to a poor prognosis of AFP positive cases. Finally, we can infer that high levels of AFP signify a highly malignant tumor and unfavorable prognosis.

Potential Therapeutic Targets for the Primary Gallbladder Carcinoma: Estrogen Receptors

Gallbladder carcinoma, the most frequent malignant neoplasm of the biliary tract system, has always been considered to feature late clinical presentation and diagnosis, limited treatment options and an extremely poor prognosis. In recent years, while the incidence of gallbladder cancer has appeared to be on the increase, the available treatment methods have not greatly improved survival of the affected patients. Thus, exploring new therapeutic targets for this devastating disease is an urgent matter at present. Epidemical studies have demonstrated that the incidence of gallbladder carcinoma exhibits a distinct gender bias, affecting females two to three times more than males, pointing to crucial roles of estrogen. It is well known that estrogen acts on target tissues by binding to estrogen receptors (ERs), which are mainly divided into three subtypes, ERα, ERβ and ERγ. ERα and ERβ appear to have overlapping but also unique even opposite biological effects. As important pathogenic mediators, ERs have been considered to relate to several kinds of tumors. In gallbladder carcinoma tissue, ERs have been shown to be positively expressed, and ERs expression levels are associated with differentiation and prognosis of this cancer. Nevertheless, the exact mechanisms of estrogen inducing growth of gallbladder carcinoma remain poorly understood. On the base of the current investigations, we deduce that estrogen participates in promotion of gallbladder carcinoma by influencing the formation of gallstones, stimulating angiogenesis, and promoting abnormal proliferation. Since ERs mediate the carcinogenic actions of estrogen in gallbladder, and therapy targeting ERs may provide new directions for gallbladder carcinoma. Therefore, it should be stressed that ERs are potential therapeutic targets for gallbladder carcinoma.

Platelet to lymphocyte ratio as a novel prognostic tool for gallbladder carcinoma.

AIM To preliminarily investigate the prognostic significance of the platelet to lymphocyte ratio (PLR) in patients with gallbladder carcinoma (GBC). METHODS Clinical data of 316 surgical GBC patients were analyzed retrospectively, and preoperative serum platelet and lymphocyte counts were used to calculate the PLR. The optimal cut-off value of the PLR for detecting death was determined by the receiver operating characteristic (ROC) curve. The primary outcome was overall survival, which was estimated by the Kaplan-Meier method. The log-rank test was used to compare the differences in survival. Then, we conducted multivariate Cox analysis to assess the independent effect of the PLR on the survival of GBC patients. RESULTS For the PLR, the area under the ROC curve was 0.620 (95%CI: 0.542-0.698, P = 0.040) in detecting death. The cut-off value for the PLR was determined to be 117.7, with 73.6% sensitivity and 53.2% specificity. The PLR was found to be significantly positively correlated with CA125 serum level, tumor-node-metastasis (TNM) stage, and tumor differentiation. Univariate analysis identified carcinoembryonic antigen (CEA), CA125 and CA199 levels, PLR, TNM stage, and the degree of differentiation as significant prognostic factors for GBC when they were expressed as binary data. Multivariate analysis showed that CA125 > 35 U/mL, CA199 > 39 U/mL, PLR ≥ 117.7, and TNM stage IV were independently associated with poor survival in GBC. When expressed as a continuous variable, the PLR was still an independent predictor for survival, with a hazard ratio of 1.018 (95%CI: 1.001-1.037 per 10-unit increase, P = 0.043). CONCLUSION The PLR could be used as a simple, inexpensive, and valuable tool for predicting the prognosis of GBC patients.

FoxM1 as a Novel Therapeutic Target for Cancer Drug Therapy

BACKGROUND Current cancer therapy mainly focuses on identifying novel targets crucial for tumorigenesis. The FoxM1 is of preference as an anticancer target, due to its significance in execution of mitosis, cell cycle progression, as well as other signal pathways leading to tumorigenesis. FoxM1 is partially regulated by oncoproteins or tumor suppressors, which are often mutated, lost, or overexpressed in human cancer. Since sustaining proliferating signaling is an important hallmark of cancer, FoxM1 is overexpressed in a series of human malignancies. Alarge- scale gene expression analysis also identified FoxM1 as a differentially-expressed gene in most solid tumors. Furthermore, overexpressed FoxM1 is correlated with the prognosis of cancer patients, as verified in a series of malignancies by Cox regression analysis. Thus, extensive studies have been conducted to explore the roles of FoxM1 in tumorigenesis, making it an attractive target for anticancer therapy. Several antitumor drugs have been reported to target or inhibit FoxM1 expression in different cancers, and down-regulation of FoxM1 also abrogates drug resistance in some cancer cell lines, highlighting a promising future for FoxM1 application in the clinic.

Prognostic significance of preoperative platelet count in patients with gallbladder cancer

AIM To investigate the prognostic value of preoperative platelet count (PLT) in patients with primary gallbladder cancer (GBC). METHODS The clinical data of 223 GBC patients after surgery was retrospectively reviewed. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cutoff point for PLT. Univariate and multivariate survival analyses were performed to identify the factors associated with the prognosis. RESULTS The ROC curve showed that the optimum cutoff point for PLT was 178 × 10(9)/L, and the entire cohort was stratified into group A with PLT > 178 × 10(9)/L and group B with PLT ≤ 178 × 10(9)/L. Group A had a better survival than group B (P < 0.001). There was an obvious difference between the two groups in terms of the differentiation degree, advanced tumor stage, lymph node metastasis (P < 0.001) and pathological type (P < 0.05). The univariate analysis demonstrated that tumor location, differentiation degree, TNM stage, Nevin stage, lymph node metastasis and PLT were associated with overall survival (P < 0.001). In the multivariate analysis, PLT (P = 0.032), lymph node metastasis (P = 0.007), tumor location (P < 0.001) and TNM stage (P = 0.005) were independent prognostic factors. CONCLUSION PLT is closely correlated with GBC prognosis and could be used to identify the population with a poorer prognosis after surgery.

Exploring the diagnosis markers for gallbladder cancer based on clinical data

Presently, no effective markers are available to facilitate gallbladder cancer (GBC) diagnosis. This study aims to explore available markers for GBC diagnosis. Clinical data of 144 GBC and 116 cholelithiasis patients were retrospectively reviewed. Logistic regression analysis was performed to evaluate GBC risk factors. A receiver operating characteristic (ROC) curve was used to assess the diagnosis value of the risk factors. By comparing the characteristic of GBC and cholelithiasis patients, the following factors exhibited statistical difference: age, gender, gallstones, total bilirubin (TB), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count (PLT), CA125 (carcinoembryonic antigen 125), and CA199 (carbohydrate antigen 199). Logistic regression analysis indicated that age [odds ratio (OR), 1.032; 95%confidence interval (95% CI), 1.004 to 1.061; P = 0.024], gender (OR, 0.346; 95% CI, 0.167 to 0.716; P = 0.004), gallstones (OR, 0.027; 95% CI, 0.007 to 0.095; P < 0.001), ALP (OR, 1.003; 95% CI, 1.000 to 1.006; P = 0.032), TB (OR, 1.004; 95% CI, 1.000 to 1.009; P = 0.042), and CA125 (OR, 1.007; 95% CI, 1.002 to 1.013; P = 0.011) were independent risk factors for GBC. According to the ROC curve, CA125 [area under curve (AUC), 0.720], ALP (AUC, 0.713), TB (AUC, 0.636), and age (AUC, 0.573) were valuable diagnosis markers. Additionally, based on the independent risk factors, the GBC diagnosis model was established. Age, TB, ALP, and CA125 can be used as auxiliary diagnosis factors of GBC. The diagnosis model provides a quantitative tool for GBC diagnosis when comprehensively considering various risk factors.

Survival Analysis of Hepatocellular Carcinoma: A Comparison Between Young Patients and Aged Patients

Background: To compare the clinicopathological features and prognosis between younger and aged patients with hepatocellular carcinoma (HCC). Methods: We analyzed the outcome of 451 HCC patients underwent liver resection, transcatheter arterial chemoembolization and radiofrequency ablation, respectively. Then risk factors for aged and younger patients’ survival were evaluated by multivariate analysis, respectively. Results: The patients who were older than 55 years old were defined as the older group. The overall survival for aged patients was significantly worse than those younger patients. The younger patients had similar liver functional reserve but more aggressive tumor factors than aged patients. Cox regression analysis showed that the elevated levels of aspartate aminotransferase (AST) (Wald &khgr; 2 = 3.963, P = 0.047, hazard ratio [HR] =1.453, 95% confidence interval [CI]: 1.006–2.098), lower albumin (Wald &khgr; 2 = 12.213, P < 0.001, HR = 1.982, 95% CI: 1.351–2.910), tumor size (Wald &khgr; 2 = 8.179, P = 0.004, HR = 1.841, 95% CI: 1.212–2.797), and higher alpha-fetoprotein level (Wald &khgr; 2 = 4.044, P = 0.044, HR = 1.465, 95% CI: 1.010–2.126) were independent prognostic factors for aged patients, while only elevated levels of AST (Wald &khgr; 2 = 14.491, P < 0.001, HR = 2.285, 95% CI: 1.493–3.496) and tumor size (Wald &khgr; 2 = 21.662, P < 0.001, HR = 2.928, 95% CI: 1.863–4.604) were independent prognostic factors for younger patients. Conclusions: Age is a risk factor to determine the prognosis of patients with HCC. Aged patients who have good liver functional reserve are still encouraged to receive curative therapy.

A Causal Role of Genetically Elevated Circulating Interleukin-10 in the Development of Digestive Cancers: Evidence from Mendelian Randomization Analysis Based on 29,307 Subjects.

AbstractRecent studies have observed a high level of circulating interleukin-10 (IL-10) in patients with digestive cancers, yet whether elevated IL-10 is causally associated with digestive cancers so far remained unresolved.We therefore meta-analyzed available observational studies with Mendelian randomization method to explore this causal association by employing IL-10 gene 3 variants (-592C>A, -819C>T, and -1082A>G) as instruments.Data were available from 52 articles encompassing 29,307 subjects. Subgroup analysis by cancer type indicated that -1082A>G was associated with increased risk of gastric cancer (odds ratio [OR] = 1.19; 95% confidence interval [CI]: 1.05–1.35; P = 0.006), and the association was reinforced for intestinal type gastric cancer (OR = 1.26; 95%CI: 1.09–1.44; P = 0.001). By ethnicity, risk estimate for -1082G allele carriers was increased by 21% for digestive cancers in East Asians (95%CI: 1.05–1.40; P = 0.009). As for the genotype–phenotype association, carriers of -1082G allele had an overall 20.21 pg/mL higher IL-10 level than those with -1082AA genotype (P = 0.023). In further Mendelian randomization analysis, the predicted OR for 10 pg/mL increment in IL-10 was 1.14 (95%CI: 1.01–16.99) in gastric cancer.Our findings provided evidence for a causal role of genetically elevated IL-10 in the development of gastric cancer, especially in East Asians and for intestinal type gastric cancer.