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BACKGROUND AND AIMS: Somatic mutation R249S in TP53 is highly common in hepatocellular carcinoma (HCC). We aim to investigate the effects of R249S in ctDNA on the prognosis of HCC. METHODS: We analysed three cohorts including 895 HCC patients. TP53 mutation spectrum was examined by direct sequencing of genomic DNA from tissue specimens in HCC patients with hepatectomy (Cohort 1, N = 260). R249S and other recurrent missense mutations were assessed for their biological functions and associations with overall survival (OS) and progression-free survival (PFS) of HCC patients in Cohort 1. R249S within circulating tumour DNA (ctDNA) was detected through droplet digital polymerase chain reaction (ddPCR) and its association with OS and PRS was analysed in HCC patients with (Cohort 2, N = 275) or without (Cohort 3, N = 360) hepatectomy. RESULTS: In Cohort 1, R249S occupied 60.28% of all TP53 mutations. Overexpression of R249S induced more serious malignant phenotypes than those of the other three identified TP53 recurrent missense mutations. Additionally, R249S, but not other missense mutations, was significantly associated with worse OS (P = .006) and PFS (P = .01) of HCC patients. Consistent with the results in Cohort 1, HCC patients in Cohorts 2 and 3 with R249S had worse OS (P = 8.291 × 10-7 and 2.608 × 10-7 in Cohorts 2 and 3, respectively) and PFS (P = 5.115 × 10-7 and 5.900 × 10-13 in Cohorts 2 and 3, respectively) compared to those without this mutation. CONCLUSIONS: TP53 R249S mutation in ctDNA may serve as a promising prognosis biomarker for HCC patients with or without hepatectomy.

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A novel bilayer counter electrodes for Dye-sensitized Solar Cells (DSSCs) made of reduced graphene oxide (RGO) and aligned carbon nanotube (ACNT) was developed. The underlayer ACNT severs as a transition layer for RGO. The overlayer of RGO plays the role of catalytic layer. It was demonstrated that the property of graphene counter electrode was adversely affected by aggregation, by adding surfactant, the aggregation of graphene can be inhabited effectively. Moreover, the interface between the RGO and the ACNT can be optimized by surfactant functionalization of RGO. After screening, a cationic surfactant cetylpyridinium chloride (CPC) functionalized RGO, code as CPC-RGO, exhibits the best performance. Compare to the ACNT based counter electrode and other surfactant functionalized RGO/ACNT based bilayer counter electrodes, the CPC-RGO/ACNT reduced interface resistance and improved the double chemical capacitance efficiently, thus uplifting the short circuit current density and fill factor from 7.35 to 8.8 mA cm-2, and 59.87 to 62.79, respectively. Eventually, the CPC-RGO/ACNT based DSSC giving a power conversion efficiency of 3.9%, which is 1.24-fold than that of ANCT based DSSC, because of the best splay degree of CPC/RGO.

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Objectives: To explore the role of mTOR signaling pathway in modulating epileptogenesis in an N-methyl-D-aspartic acid (NMDA)-induced infant spasm (IS) rat model. Methods: After inducing IS successfully, the phosphorylation status of PI3K, Akt, mTOR and S6K of brain and hippocampus tissues was assessed using western blot and immunochemistry analysis, respectively. The possible mechanism of mTOR signaling pathway was evaluated by the, inhibitors for mTOR and PI3K, rapamycin and wortmannin, respectively. The inhibitors were injected into the intraperitoneal space of the rats to examine the effects of PI3K and mTOR in IS rat model. Results: The phosphorylated levels of mTOR and PI3K in hippocampus increased significantly (P < 0.05) 7 days after IS induction in rats. After administration of wortmannin, the phosphorylated levels of PI3K and mTOR decreased. However, only the phosphorylated level of mTOR decreased obviously after rapamycin administration. No obvious neurogenesis was found after IS induction. Discussion: Results of the present study suggest that hippocampal PI3K may be another potential target for IS treatment.

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OBJECTIVE: To investigate the factors in first-time adrenocorticotropic hormone (ACTH) therapy and their influence on spasm control time in infants with infantile spasms. METHODS: A total of 72 infants with infantile spasms who were admitted from January 2008 to October 2013 were enrolled. Their clinical data were collected, and the exposure factors for infantile spasms were selected. A Cox proportional-hazards regression model analysis was performed for these factors to analyze their influence on spasm control time. RESULTS: Clarification of the etiology (known or unexplained etiology), frequency of spasms before treatment, and presence or absence of combination therapy (ACTH used alone or in combination with magnesium sulfate) had a significant influence on spasm control time in infants with infantile spasms. The infants with a known etiology had a significantly shorter spasm control time than those with unexplained etiology, and the infants with a low frequency of spasms before treatment and receiving ACTH combined with magnesium sulfate early had a significantly longer spasm control time than their counterparts (P<0.05). CONCLUSIONS: For infants with infantile spasms at initial diagnosis, etiology should be clarified, which may helpful for evaluating prognosis. A combination of ACTH and magnesium sulfate should be given as soon as possible, which may improve their prognosis.

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Previous studies have identified 8q24 as an important region to prostate cancer (PCa) susceptibility. The aim of this study was to investigate the role of six genetic variants on 8q24 (rs1447295, A; rs6983267, G; rs6983561, C; rs7837688, T; rs10090154, T and rs16901979, A) on PCa risk in Chinese population. Online electronic databases were searched to retrieve related articles concerning the association between 8q24 variants and PCa risk in men of Chinese population published between 2000 and 2014. Odds ratio (ORs) with its 95% correspondence interval (CI) were employed to assess the strength of association. Total eleven case-control studies were screened out, including 2624 PCa patients and 2438 healthy controls. Our results showed that three risk alleles of rs1447295 A (OR=1.35, 95% CI=1.19-1.53, P<0.00001), rs6983561 C (C vs. A: OR=1.41, 95% CI=1.21-1.63, P<0.00001) and rs10090154 T (T vs. C: OR=1.48, 95% CI=1.22-1.80, P<0.00001) on8q24 were significantly associated with PCa risk in Chinese population. Furthermore, genotypes of rs1447295, AA+AC; rs6983561, CC+AC and CC; rs10090154, TT+TC; and rs16901979, AA were associated with PCa as well (P<0.01). No association was found between rs6983267, rs7837688 and PCa risk. In conclusions, variants including rs1447295, rs6983561, rs10090154 and rs16901979 on 8q24 might be associated with PCa risk in Chinese population, indicating these four variations may contribute risk to this disease. This meta-analysis was the first study to assess the role of 8q24 variants on PCa risk in Chinese population.

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OBJECTIVE: This study was performed to investigate the correlation between P15 methylation and hepatocellular carcinoma (HCC) and hepatocirrhosis using a meta-analysis of available case control studies. METHODS: Previous studies have primarily evaluated the incidence of P15 methylation in HCC and corresponding control groups, and compared the incidence of P15 methylation in liver cirrhosis and control groups. Data regarding publication information, study characteristics, and incidence of P15 methylation in both groups were collected from these studies and summarized. RESULTS: Ten studies that assessed P15 gene methylation in 824 HCC tumour tissues and five studies analyzing P15 methylation in 155 liver cirrhosis tissues met our inclusion criteria. Our meta-analysis revealed that the rate of P15 methylation was significantly higher in HCCs than in adjacent non-tumour tissues (OR 9.04, 95% CI 5.80-14.09, P < 0.00001). Moreover, P15 methylation was significantly higher in liver cirrhosis tissues than in control tissues (OR 7.82, 95% CI 3.58-17.07, P < 0.00001). CONCLUSIONS: we found that P15 methylation was associated with an increased risk of HCC and liver cirrhosis. P15 hypermethylation induced the inactivation of the P15 gene, which played an important role in hepatocarcinogenesis.

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UNLABELLED: Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71) ≤ Pmeta ≤ 9.92 × 10(-7) ). CONCLUSION: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.

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The purpose of present study was to investigate the roles of X-linked inhibitor of apoptosis-associated factor l (XAFl) in regulation apoptosis of colorectal cancer (CRC) cells after treatment with cisplatin (DDP). A total of ten paired cancerous and non-cancerous tissues were collected from patients with CRC after surgery. The levels of XAFl protein were detected by Western blot. Primary CRC cells were separated from cancer tissues, and its viability or apoptosis after treatment with DDP was determined with MTT or Annexin V/PI assays, respectively. Furthermore, we either up-regulated transfecting a XAF1 overexpression vector or down-regulated XAF1 by siRNA interference. And then, the XAF1 levels and its sensitivity to cisplatin were assessed. XAFl had a lower expression in the cancerous tissues from samples T1, T2 and T3 than their paired non-cancerous tissues N1, N2 and N3. However, the expression of XAF1 was not detected in samples T4 and N1. XAF1 levels in cancer tissues significantly decreased in comparison with normal tissues. Cell abilities of primary cells were significantly decreased in a dose-dependent manner, after treatment with a series concentrations of cisplatin (2, 5, 10 µg/mL) for 48 h. Although, after down-expression of XAFl by siRNA, cisplatin caused a significant decreases in apoptosis rates in CRC cells. The up-regulation of XAF1 distinctly increased apoptosis in CRC cells administered by cisplatin (P < 0.001). The XAFl could promoted apoptosis and enhanced chemotherapy sensitivity to cisplatin in CRC cells.

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HOXA13 is a member of homeobox genes that encode transcription factors regulating embryonic development and cell fate. Abnormal HOXA13 expression was reported in hepatocellular carcinoma (HCC), but its correlation with tumor angiogenesis and prognosis still remain unclear. This study was aimed to uncover the expression, diagnostic and prognostic significance of HOXA13 in HCC. Immunohistochemistry was performed to detect HOXA13 expression in HCC and corresponding paracarcinomatous tissues from 90 patients. Enzyme-linked immunosorbent assay was used to detect serum HOXA13 in 90 HCC patients and 20 healthy volunteers. Receiver operating characteristics was analyzed to calculate diagnostic accuracy of serum HOXA13, alpha-fetoprotein (AFP) and their combination. Immunoreactivity of HOXA13 was detected in 72.2% of HCC, and 12.2% of adjacent non-cancerous samples. HOXA13 expression was significantly associated with tumor size, microvascular invasion, pathological grade, tumor capsula status, AFP level, tumor-node-metastasis stage and positively correlated with VEGF (p < 0.001) and microvessel density (p < 0.001). The combination of serum HOXA13 and AFP had a markedly higher area under the curve than HOXA13 alone. HOXA13 expression was associated with unfavorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001). Multivariate analysis indicated that patients with HOXA13-expressing tumors had a significantly shorter OS (p = 0.030) and DFS (p = 0.005) than those with HOXA13-negative tumors. Thus, HOXA13 expression possibly plays an important role in tumor angiogenesis, progression and prognosis of HCC. Moreover, we demonstrate that serum HOXA13 may serve as a biomarker for early HCC diagnosing and predicting outcome.

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BACKGROUND/AIMS: Metastasis one of the obstacles before poor prognosis of hepatocellular carcinoma (HCC) is improved. Estrogen receptor alpha (ERalpha) plays an important role in the development and progression of HCC. However, the molecular mechanism of ERalpha in mediating HCC metastasis is still unclear. The aim of the present study was to detect aberrant ERalpha expression in HCC and elucidate its possible mechanisms in HCC metastasis. METHODOLOGY: We detected expression of ERalpha, phospho-estrogen receptor alpha (p-ERalpha), nuclear factor kappa B (NF-kappaB) p65 and Matrix metalloproteinase-9 (MMP-9) between HCC tissues with portal vein tumor thrombus (PVTT) and those without PVTT by immunohistochemical method. Moreover, the expression of above parameters was also determined in HCC cells of different metastatic potential by using immunocytochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) methods. RESULTS: The expression of ERalpha and p-ERalpha was lower in HCC with PVTT than those without PVTT. Meanwhile, the expression pattern of above parameters was also similar in HCC cells of different metastatic potential, whereas, the expression of NF-kappaB p65 and MMP-9 was higher in HCC with PVTT than those without PVTT. The expression of NF-kappaB p65 and MMP-9 in HCC cells was also analogous to the tissues. CONCLUSIONS: These results demonstrated that expression of ERalpha, p-ERalpha, NF-kappaB p65 and MMP-9 correlated with invasion and metastasis in HCC. The mechanism of HCC metastasis may mediate through cross-talk between the NF-KB and ER signaling pathways. Meanwhile, ERa regulated MMP-9 through NF-kappaB indirectly.

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Carcinogenesis is a very complex process involving a series of changes of tumor-related genes. Therefore, genes differentially expressed in tumors have received significant attention. Among them is the tumor differentially expressed (TDE) protein family, which shows no homologue to any other protein families and is unique to eukaryotes. The members of the TDE (also known as Serinc) family are highly conserved, showing approximately 30-80% homologue of their amino acid sequences. Previous reports have shown that both human and mice TDE/Serinc proteins are always upregulated in carcinomatous tissues. However, their precise physiological roles remain unclear. The human TDE2/Serinc1 gene was cloned by our laboratory during the screening for differentially expressed genes in hepatocarcinoma. In the present study, we knocked down the expression of TDE2 with specific siRNA fragments in two human hepatocarcinoma cell lines, and this caused cell cycle arrest at G2. Cell cycle progression is monitored and regulated by several factors. p21, the cdk inhibitor, is a key player and could be transcriptionally activated by many factors including sterol regulatory element-binding proteins (SREBPs). Previous research demonstrated that rat TDE2 could facilitate the cellular sphingolipids biosynthesis in both yeast and mammalian cells. Therefore, we further analyzed the effect of TDE2 knockdown on p21 and SREBP, and found that endogenous p21 expression was upregulated, as was that of SREBPs (-1a and 2). In conclusion, our preliminary results indicated that TDE2 may have an effect on tumor cell growth by influencing the expression of SREBP and p21.

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OBJECTIVE: To explore the effect of human umbilical cord blood mononuclear cells (UCBMC) promoting nerve behavior function and brain tissue recovery of neonatal SD rat with hypoxic ischemic brain injury (HIBI). METHOD: A modified newborn rat model that had a combined hypoxic and ischemic brain injury as described by Rice-Vannucci was used, early nervous reflex, the Morris water maze and walking track analysis were used to evaluate nervous behavioral function, and brain MRI, HE staining to evaluate brain damage recovery. RESULT: Newborn rat Rice-Vannucci model showed significant brain atrophy, obvious hemiplegia of contralateral limbs,e.g right step length [(7.67 ± 0.46) cm vs. (8.22 ± 0.50) cm, F = 1.494] and toe distance [(0.93 ± 0.06) cm vs. (1.12 ± 0.55) cm, F = 0.186] were significantly reduced compared with left side, learning and memory ability was significantly impaired compared with normal control group (P < 0.01); Cliff aversion [(8.44 ± 2.38) s vs.(14.22 ± 5.07) s, t = 4.618] and negative geotaxis reflex time [(7.26 ± 2.00) s vs. (11.76 ± 3.73) s, t = 4.755] on postnatal 14 days of HIBI+ transplantation group were significantly reduced compared with HIBI+NaCl group (P < 0.01) ; the Morris water maze experiment showed escape latency [ (23.11 ± 6.64) s vs. (34.04 ± 12.95) s, t = 3.356] and swimming distance [ (9.12 ± 1.21) cm vs.(12.70 ± 1.53) cm, t = 17.095] of HIBI+transplantation group were significantly reduced compared with those of HIBI+NaCl group (P < 0.01) ; the residual brain volume on postnatal 10 d [ (75.37 ± 4.53)% vs. (67.17 ± 4.08)%, t = -6.017] and 67 d [ (69.05 ± 3.58)% vs.(60.83 ± 3.69)%, t = -7.148]of HIBI+ transplantation group were significantly larger than those of HIBI+NaCl group (P < 0.01); After human UCBMC transplantation, left cortical edema significantly reduced and nerve cell necrosis of HIBI+ transplantation group is not obvious compared with HIBI+NaCl group. CONCLUSION: Human UCBMC intraperitoneal transplantation significantly promoted recovery of injured brain cells and neurobehavioral function development.

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To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, P(meta) = 2.48 × 10(-10), odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, P(meta) = 2.72 × 10(-17), OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (P(trend) = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10(-14)).

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Osteopontin (OPN) has been implicated in tumor development and progression for several years. However, the prognostic value of OPN overexpression in patients with hepatocellular carcinoma (HCC) remains controversial. We performed a meta-analysis to assess the relationship between OPN overexpression and clinical outcome of HCC. A meta-analysis of seven studies (1,158 patients) was carried out to evaluate the association between OPN and overall survival (OS) and disease-free survival (DFS) in HCC patients. The correlation between OPN and tumor vascular invasion or other invasion-related parameters was also assessed. Data were synthesized with random effect model of DerSimonian and Laird, hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Our analysis results indicated that high OPN expression predicted poor OS (HR: 1.37, 95% CI: 1.21-1.55) and DFS (HR: 1.62, 95% CI: 1.24-2.11) of HCC. OPN overexpression tended to be associated with the presence of tumor vascular invasion (OR: 1.93, 95% CI: 0.97-3.84) and advanced tumor grade (OR: 1.74, 95% CI: 0.95-3.18). By this study, we conclude that OPN overexpression indicates a poor prognosis for patients with HCC, it may also have predictive potential for HCC invasion and metastasis.

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Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. Estrogen has recently emerged as a protective factor in the development and progression of HCC, but whether and how it reduces metastasis of HCC remain to be elucidated. We conducted an in vivo highly metastatic rat HCC model in female Sprague-Dawley rats induced by diethylnitrosamine and N-nitrosomorpholine to examine the effects of estrogen on HCC metastasis. Moreover, female rats were randomly distributed into four groups: ovariectomy (OVX), sham operation, ovariectomy followed by 30 µg/kg body weight/day 17α-ethynylestradiol supplementation, and sexually intact control groups. Here, we show that, 60% lung metastasis was observed in the rats of OVX group, whereas 17-25% lung metastasis was found in rats of the other three groups. Furthermore, physiological doses of estrogen, no matter endogenous or exogenous, can suppress metastasis of HCC through decreasing interleukin-6 (IL-6) and hepatocyte growth factor (HGF) expression in the tumor microenvironment. In conclusion, the present study demonstrated that estrogen has the potential to inhibit lung metastasis from rat HCCs in vivo. Its mechanism of action may involve modulation of inflammatory tumor microenvironment by suppression of HGF and IL-6 production.

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BACKGROUND: To examine the expression of signal transducer and activator of transcription 3 (STAT3) and its activated form (p-STAT3), Twist, and E-cadherin in hepatocellular carcinoma (HCC), and explore their correlations with HCC progression and prognosis. MATERIALS AND METHODS: The expression profiles of STAT3, p-STAT3, Twist, and E-cadherin were assessed on 100 clinical HCC samples and 10 normal liver tissues by using an immunohistochemical staining method, and their correlations with clinicopathologic parameters and survival of HCC patients were statistically analyzed. RESULTS: The results demonstrated that the positive rate of STAT3, p-STAT3, and Twist in HCC was significantly higher than that in normal liver tissues; furthermore, 52% of HCC lesions showed reduced E-cadherin expression. Correlation analysis indicated that p-STAT3 was positively correlated with Twist expression, whereas Twist was negatively correlated with E-cadherin expression; p-STAT3, Twist, or E-cadherin expression was significantly associated with HCC invasion and metastasis. Survival analysis showed that HCC patients with p-STAT3, Twist positive expression, or reduced E-cadherin expression had a significantly shorter survival duration than those with p-STAT3, Twist negative expression, or those with normal E-cadherin expression. Multivariate analysis identified p-STAT3, Twist, or E-cadherin expression as an independent prognostic factor for overall survival of HCC patients after surgery. CONCLUSIONS: By this study, we suggest that activated STAT3 signal may associate with Twist and E-cadherin expression and mediate HCC invasiveness and metastasis; abnormal p-STAT3/Twist/E-cadherin signal axis may predict poor prognosis of HCC patients.

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AIM: To investigate the association between TP53 Arg72Pro polymorphism and esophageal cancer (EC) risk using meta-analysis. METHODS: All eligible studies published before March 1, 2010 were selected by searching PubMed using keywords "p53" or "TP53", "polymorphism" or "variation", "esophageal" and "cancer" or "carcinoma". Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for EC risk associated with TP53 Arg72Pro polymorphism using fixed- and random-effects models. RESULTS: Nine case-control studies involving 5545 subjects were included in this meta-analysis. Significantly reduced risk of EC was associated with TP53 genotypes for Arg/Arg + Arg/Pro vs Pro/Pro (OR = 0.73, 95% CI: 0.57-0.94, P = 0.014). Subgroup analyses according to the source of controls and the specimens used for determining TP53 Arg72Pro genotypes or sample size showed that significantly reduced risk was observed only in studies which have population-based controls (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.66, P < 0.001), and use white blood cells or normal tissue to assess TP53 genotypes of cases (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.65, P < 0.001) or include at least 200 subjects (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.65, P < 0.001). Analysis restricted to well-designed studies also supported the significantly decreased risk of EC (Arg/Arg vs Pro/Pro: OR = 0.54, 95% CI: 0.46-0.64, P < 0.001). CONCLUSION: TP53 Arg72 carriers are significantly associated with decreased EC risk. Nevertheless, more well-designed studies are needed to confirm our findings.

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The TP53 gene has an important role in the protection of cells from DNA damage due to UV exposure, and sequence variation in the gene may alter skin cancer susceptibility. To examine the association between the TP53 Arg72Pro polymorphism and skin cancer risk, we undertook a meta-analysis of 15 case-control studies involving 6,362 subjects. The quality of the studies was assessed according to a predefined scale. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for association using a random-effects model. Overall, no evidence of association was observed between TP53 genotypes and the risk of skin cancer in any genetic model (Arg/Arg vs. Pro/Pro: OR=1.05, 95% CI: 0.71-1.55; Arg/Pro vs. Pro/Pro: OR=0.92, 95% CI: 0.68-1.24; Arg/Arg+Arg/Pro vs. Pro/Pro: OR=0.97, 95% CI: 0.70-1.35; Arg/Arg vs. Arg/Pro+Pro/Pro: OR=1.15, 95% CI: 0.91-1.46). Stratified analyses according to ethnicity and quality score of the studies also detected no significant association in any subgroup. Furthermore, no effect of this polymorphism on subtype of skin cancer, such as melanoma, squamous cell carcinoma, and basal cell carcinoma, was observed. In conclusion, this meta-analysis suggests that the TP53 Arg72Pro polymorphism may have little involvement in skin cancer susceptibility.

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Extracellular matrix protein 1 (ECM1) is a glycoprotein involved in a number of biologic processes. To investigate the expression of ECM1 in hepatocellular carcinoma (HCC) and determine its correlation with tumor progression and prognosis, the expression levels of ECM1 in three HCC and one normal liver cell lines, tumor, and corresponding adjacent tissues from 18 HCC patients were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Immunohistochemistry assay was used to determine the expression of ECM1 in HCC and corresponding paracarcinomatous tissues from 77 patients. The results of Western blotting were consistent with the results from RT-PCR analysis of ECM1 mRNA expression. Among the four cell lines, the expression level in HCCLM3, which with the highest metastatic potential, was significantly higher than that with lower (P < 0.05); while ECM1 expression was not detected in normal liver cell line. Expression level of ECM1 was significantly increased in HCC compared with adjacent and normal liver tissues (P < 0.05). Immunohistochemically, the expression of ECM1 in HCC was judged to be positive in 57 (74.0%) cases, significantly higher than that in corresponding paracarcinomatous tissues (P < 0.01), and it was associated with tumor size (P = 0.036), number of tumor nodules (P = 0.048), TNM stage (P = 0.029), and vascular invasion (P = 0.007). In particular, the expression of ECM1 was found to be an independent factor for predicting overall and disease-free survival of HCC. The expression level of ECM1 was associated with metastatic potential of HCC, and its abnormal expression may be used as a predictive factor of unfavorable prognosis and recurrence for HCC after surgery.

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Vasculogenic mimicry (VM), including tubular VM and patterned matrix VM, has been generally recognized as a new pattern of tumor neovascularization. Pilot studies of tubular VM showed that it was present in hepatocellular carcinoma (HCC) and associated with poor clinical prognosis. However, whether patterned matrix VM is clinically significant in HCC is unknown. To elucidate the effects of patterned matrix VM on prognosis of HCC and the mechanisms involved in VM formation, we examined 151 cases of surgically resected human HCC by immunohistochemistry and transmission electron microscopy and conducted hypoxic experiments on human HCC cell line MHCC97-H. We observed 31 of 151 (20.5%) cases exhibited evidence of patterned matrix VM. The expression of patterned matrix VM was associated with larger tumors (P = 0.042), vascular invasion (P = 0.016), high-grade HCC (P = 0.022), and late-stage HCC (P = 0.013). Kaplan-Meier survival analysis revealed that cases of the VM group had lower overall survival (OS) rate (P < 0.001) and disease-free survival (DFS) rate (P = 0.002) than that of the non-VM group. Univariate and multivariate analysis indicated that the presence of patterned matrix VM was independent adverse prognostic factor for both OS (P = 0.004) and DFS (P = 0.011). Expression of hypoxia-inducible factor 1 alpha (HIF-1alpha), matrix metalloproteinase (MMP)-2, and MMP-9 were higher in the VM group than in the non-VM group (P = 0.001, P = 0.030, P = 0.007, respectively). After VM formation was induced by hypoxia, up-regulated expression of HIF-1α, MMP-2, and MMP-9 was also detected in cells cultured under hypoxia condition. Our results indicate that patterned matrix VM exists in HCC, and it might serve as an unfavorable prognostic factor for HCC patients. It is possible that hypoxia via induction of expression of HIF-1alpha, MMP-2, and MMP-9 may enhance VM formation in HCC.

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