Hepatitis B virus (HBV) DNA is prone to mutations because of the proofreading deficiencies of HBV polymerase. We have identified hepatocellular carcinoma (HCC) survival-associated HBV mutations in the X protein region of HBV DNA. In the present study, we extend our research to assess HCC survival-associated HBV mutations in the HBV precore/core (PreC/C) region. The PreC/C region was amplified and sequenced and the HBV mutations were identified according to the NCBI database (http://www.ncbi.nlm.nih.gov/genome/5536). The relationships between the mutations in the PreC/C region and HCC survival were analyzed. Survival curves were generated using the Kaplan-Meier method, and comparisons between the curves were made using the log-rank test. Multivariate survival analysis was performed using a Cox proportional hazards model. After adjusting for clinical characteristics, the 1915, 2134, 2221, 2245 and 2288 mutational sites were identified as statistically significant independent predictors of HCC survival by multivariate survival analysis using a Cox proportional hazards model. In addition, the mutational site of 1896 was identified for its association with survival at a borderline significance level. A total of five mutations in the precore/core region were identified as independent predictors of postoperative survival in HCC patients. The analysis of HBV DNA mutations may help identify patient subgroups with poor prognosis and may help refine therapeutic decisions regarding HCC patients.
Autophagy, referring to an evolutionarily conserved, multi-step lysosomal degradation process, has been well-known to be initiated by Unc-51 like kinase 1 (ULK1) with some links to Parkinson’s disease (PD). MicroRNAs (miRNAs), small and non-coding endogenous RNAs 22 ~ 24 nucleotides (nt) in length, have been demonstrated to play an essential role for modulating autophagy. Recently, the relationships between miRNAs and autophagy have been widely reported in PD; however, how microRNAs regulate autophagy still remains in its infancy. Thus, in this study, we computationally constructed the ULK1-regulated autophagic kinase subnetwork in PD and further identified ULK1 able to negatively regulate p70S6K in starvation-induced autophagy of neuroblastoma SH-SY5Y cells. Combination of in silico prediction and microarray analyses, we identified that miR-4487 and miR-595 could target ULK1 and experimentally verified they could negatively or positively regulate ULK1-mediated autophagy. In conclusion, these results may uncover the novel ULK1-p70S6K autophagic pathway, as well as miR-4487 and miR-595 as new ULK1 target miRNAs. Thus, these findings would provide a clue to explore ULK1 and its target miRNAs as potential biomarkers in the future PD therapy.
Aberrant expression of receptor interacting protein kinase 4 (RIPK4), a crucial regulatory protein of Wnt/β-catenin signaling, has recently been reported to be involved in several cancers. Here, we report the potential clinical implication and biological functions of RIPK4 in cervical squamous cell carcinoma (CSCC). One hundred and ninety-eight CSCC cases, 109 low-grade squamous intraepithelial lesions (LSILs), 141 high-grade squamous intraepithelial lesions (HSILs) and 63 chronic cervicitis were collected. The expression of RIPK4 was detected by immunohistochemistry (IHC), and its clinical value and oncogenic functions were further assessed. RIPK4 expression increased significantly with disease progression from 3.2% in chronic cervicitis, 19.3% in LSILs and 85.1% in HSILs to 94.4% in CSCCs (P < 0.001). Moreover, RIPK4 may serve as a useful biomarker to distinguish HSIL from chronic cervicitis/LSIL, which are two different clinical types for therapeutic procedures, with a high sensitivity and specificity (85.1% and 86.6%, respectively) and the performance improved when combined with p16INK4a. Further, RIPK4 overexpression was associated with overall (HR = 2.085, P = 0.038) and disease-free survival (HR = 1.742, P = 0.037). Knockdown of RIPK4 reduced cell migration and invasion via inhibition of Vimentin, MMP2 and Fibronectin expression in cervical cancer cells. RIPK4 might act as a potential diagnostic and independent prognostic biomarker for CSCC patients.
Nasopharyngeal carcinoma (NPC) is a multifactoral and polygenic disease with high prevalence in Southeast Asia and Southern China. Environmental factors and genetic susceptibility play important roles in NPC pathogenesis. In the present study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in nuclear factor-kappa B (NFκB) and its inhibitor (IκBα) conferred consistent risks for NPC. Four putatively functional SNPs (NFκB1: rs28362491del>ins ATTG; NFκB2: rs12769316G>A; IκBα: rs2233406C>T and rs696G>A) were analyzed to evaluate their associations with NPC risk in total 1590 NPC cases and 1979 cancer-free controls. We found that the rs28362491 insATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of NPC (odds ratio [OR] = 1.30, 95% confidence interval [CI] = 1.09–1.55, and P = 2.80 × 10−3) compared with the del/del homozygous genotype. The rs696AA variant in IκBα had an increased risk of NPC (OR = 1.41, 95% CI = 1.20–1.66, and P = 2.28 × 10−5) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a. Furthermore, both adverse genotypes of NFκB/IκBα and their interaction also exerted an increased risk on NPC. Taken together, Our findings indicated that genetic variants in NFκB1 (rs28362491del>ins ATTG) and IκBα (rs696G>A) and their synergistic effect might contribute to NPC predisposition.
A case of epithelioid inflammatory myofibroblastic scarcoma (EIMS) developing in an 8-year-old boy who presented with a bulky intra-abdominal occupying lesion with recurrence undergoing a radical resection was reported. Histologically, the tumor cells arranged in cords, strands or sheets of round-to-epithelioid cells with a vesicular nuclear chromatin pattern, prominent nucleoli and weakly eosinophic or basophilic cytoplasm embedded in the abundant myxoid stroma with lymphocytes infiltration. They were positive for ALK, Desmin, SMA, CD30, but negative for AE1/AE3, LCA, CD2, CD3, CD5, CD7, S-100, CD34, CD31, EMA, MyoD1, and myogenin. An elevated proliferation index was demonstrated by Ki-67 comparing the first and the second lesion. Fluorescence in situ (FISH) showed the presence of chromosomal translocation involving ALK. This case show EIMS is a rare variant of inflammatory myofibroblatic tumor with aggressive biological behavior and unfavourable prognosis. To be familiar with its significant clinicopathologic characteristics could prompt us to take it into consideration when facing the relevant dieases.
Epithelioid inflammatory myofibroblastic scarcoma; soft tissue neoplasm; ALK; FISH
To gain molecular insights of HBV integration that may contribute to HCC tumorigenesis, we performed whole transcriptome sequencing and whole genome copy number profiling of hepatocellular carcinoma (HCC) samples from 50 Chinese patients. We identified a total of 33 HBV-human integration sites in 16 of 44 HBV-positive HCC tissues, which were enriched in HBV genotype C-infected patients. In addition, significantly recurrent HBV-MLL4 integration (18%; 8/44) was found in this cohort of patients. Using long-range PCR and Sanger sequencing, we comprehensively characterized gDNA and cDNA sequences that encode for the HBV-MLL4 transcripts, and we revealed that HBV integration into MLL4 exons led to much higher mRNA expression of MLL4 than the integration into MLL4 introns due to an alternative splicing mechanism. Moreover, the HBV-MLL4 integration occurred almost exclusively in CTNNB1 and TP53 wild-type patients. The integration was also associated with a distinct gene expression profile. In conclusion, this is the first report on the molecular basis of the MLL4 integration driving MLL4 over-expression. HBV-MLL4 integration occurred frequently in Chinese HCC patients, representing a unique molecular segment for HCC with HBV infection.
Oxidative stress contributes to endothelial cell (EC) dysfunction, which is prevalent in ageing and atherosclerosis. MicroRNAs (miRs) are small, non-coding RNAs that post-transcriptionally regulate gene expression and play a key role in fine-tuning EC functional responses, including apoptosis and angiogenesis. MiR-92a is highly expressed in young endothelial cells in comparison with senescent endothelial cells, which exhibit increased oxidative stress and apoptosis. However, the impact of miR-92a treatment on EC viability and angiogenesis under oxidative stress is unknown. Hydrogen peroxide (H2O2) was used to induce oxidative stress in human umbilical vein endothelial cells (HUVEC). Pre-miR-92a treatment decreased H2O2–induced apoptosis of HUVEC as determined by TUNEL assay. Pre-miR-92a treatment enhanced capillary tube formation by HUVEC under oxidative stress, which was blocked by LY294002, an inhibitor of Akt phosphorylation. Interestingly, we also observed that inhibition of miR-92a by anti-miR-92a antisense can also enhance angiogenesis in HUVEC with and without oxidative stress exposure. Our results show that perturbation of miR-92a levels outside of its narrow “homeostatic” range may trigger endothelial cell angiogenesis, suggesting that the role of miR-92a in regulating angiogenesis is controversial and may vary depending on the experimental model and method of regulating miR-92a.
microRNA; angiogenesis; Apoptosis; Oxidative Stress
We report an unusual case of Clostridium perfringens liver abscess formation after transcatheter arterial chemoembolization (TACE) for large hepatocellular carcinoma. Severe deterioration in liver and renal function accompanied with hemocytolysis was found on the 2nd day after TACE. Blood culture found Clostridium perfringens and abdominal computed tomography revealed a gas-containing abscess in the liver. Following antibiotics administration and support care, the infection was controlled and the liver and renal function turned normal. The 2nd TACE procedure was performed 1.5 mo later and no recurrent Clostridium perfringens infection was found.
Transcatheter arterial chemoembolization; Hepatocellular carcinoma; Major complication; Clostridium perfringens; Liver abscess
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.
Systems biology network; Apoptosis; AMPK; ZIPK; Dual-target activator (BL-AD008)
AIM: To investigate transarterial chemoembolization (TACE) with hepatic infusion of oxaliplatin and 5-fluorouracil and Lipiodol chemoembolization in large hepatocellular carcinoma (HCC).
METHODS: In this retrospective study, 132 patients with unresectable HCCs larger than 10 cm were treated with hepatic infusion of oxaliplatin and 5-fluorouracil followed by Lipiodol chemoembolization. The primary endpoint was overall survival (OS). Sixteen-week disease-control rate, time to progression (TTP), and major complications were also studied. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP.
RESULTS: A total of 319 procedures were performed in the 132 patients. Eleven (8.3%) patients received radical resection following TACE treatment (median time to initial TACE 4.3 ± 2.3 mo). The median OS and TTP were 10.3 and 3.0 mo respectively, with a 50.0% 16-wk disease-control rate. Major complications were encountered in 6.0% (8/132) of patients following TACE and included serious jaundice in 1.5% (2/132) patients, aleukia in 1.5% (2/132), and hepatic failure in 3.0% (4/132). One patient died within one month due to serious hepatic failure and severe sepsis after receiving the second TACE. The risk factor associated with TTP was baseline alpha-fetoprotein level, and vascular invasion was an independent factor related to OS.
CONCLUSION: Hepatic infusion of oxaliplatin and 5-fluorouracil followed by lipiodolized-chemoembolization is a safe and promising treatment for patients with HCCs larger than 10 cm in diameter.
Hepatic infusion; Large hepatocellular carcinoma; Oxaliplatin; Transarterial chemoembolization; 5-fluorouracil
Extracellular signal-regulated kinase1/2 (ERK1/2) plays a crucial role in the resistance of apoptosis in carcinogenesis; however, its targeted small-molecule inhibitors still remain to be discovered. Thus, in this study, we computationally and experimentally screened a series of small-molecule inhibitors targeting ERK toward different types of human breast cancer cells. Subsequently, we synthesized some candidate ERK inhibitors, identified a novel ERK inhibitor (BL-EI001) with anti-proliferative activities, and analyzed the BL-EI001/ERK complex. Moreover, we found that BL-EI001 induced breast cancer cell apoptosis via mitochondrial pathway but independent on Ras/Raf/MEK pathway. In addition, we carried out proteomics analyses for exploring some possible BL-EI001-induced apoptotic pathways, and further found that BL-EI001-induced apoptosis affected ERK phosphorylation in breast cancer. Further, we found that BL-EI001 bear anti-tumor activities without remarkable toxicities, and also induced mitochondrial apoptosis by targeting ERK in vivo. Taken together, these results demonstrate that in silico design and experimental discovery of a synthesized small-molecule ERK inhibitor (BL-EI001) as a potential novel apoptosis-inducing drug in the treatment of breast cancer.
Extracellular signal-regulated kinase 1/2 (ERK1/2); ERK inhibitor (BL-EI001); Apoptosis; Mitochondrial pathway; Breast cancer
The present study was designed to investigate the effect of Agaricus brasiliensis extract (ABE) on phenylhydrazine-induced neonatal jaundice in rats. Administration of ABE dose-dependently reduced the elevated bilirubin level induced by phenylhydrazine. It can be somewhat supported from the results of in vitro bilirubin degradation experiment. ABE treatment also reduced the total antioxidant status (TAOS), cascade O2−/SOD, level of NF-κB protein, and adrenomedullin (AM). Overall, the results of this study demonstrated that Agaricus brasiliensis extract may be beneficial to reducing bilirubin level without causing hepatotoxicity in neonatal jaundice.
Cross-presentation is one of the main features of dendritic cells DCs, critically important for the development of spontaneous and therapy-inducible antitumor immune responses. Patients, at early stages of cancer, have normal presence of DCs. However, the difficulties in the development of antitumor responses in patients with low tumor burden raised the question of the mechanisms of DC dysfunction. In this study, we found that, in differentiated DCs, tumor-derived factors blocked the cross-presentation of exogenous antigens without inhibiting the antigen presentation of endogenous protein or peptides. This effect was caused by intracellular accumulation of different types of oxidized neutral lipids: triglycerides, cholesterol esters, and fatty acids. In contrast, the accumulation of non-oxidized lipids did not affect cross-presentation. Oxidized lipids blocked cross-presentation by reducing the expression of peptide-MHC class I complexes on the cell surface. Thus, this study suggests the novel role of oxidized lipids in the regulation of cross-presentation.
Pulsed electromagnetic fields (PEMF) have been shown to promote proliferation and regeneration in the damaged tissue. Here, we examined whether PEMF therapy improved postnatal neovascularization using murine model of hindlimb ischemia, and the underlying cellular/molecular mechanisms were further investigated. Hindlimb ischemia was induced by unilateral femoral artery resection using 6-8 week-old male C57BL6 mice. Then, mice were exposed to extracorporeal PEMF therapy (4 cycles, 8min/cycle, 30 ± 3 Hz, 5 mT) every day until day 14. Our data demonstrated that PEMF therapy significantly accelerated wound healing, decreased prevalence of gangrene and increased postnatal neovascularization. Moreover, the levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in ischemic muscles were markedly enhanced following PEMF therapy. In vitro, PEMF inhibited the process of hypoxia-induced apoptosis and augmented tube formation, migration and proliferative capacities of human umbilical vein endothelial cells (HUVECs). Additionally, PEMF exposure increased VEGF secretion, as well as the eNOS and Akt phosphorylation, and these benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. In conclusion, our data indicated that PEMF therapy enhanced ischemia-mediated angiogenesis, through up-regulating VEGF expression and activating the PI3K-Akt-eNOS pathway. Therefore, PEMF should be a valuable treatment for the patients with critical limb ischemia.
Pulsed electromagnetic fields (PEMF); angiogenesis; hindlimb ischemia; VEGF; eNOS
Induced pluripotent stem cells (iPS) can differentiate into cardiomyocytes (CM) and represent a promising form of cellular therapy for heart regeneration. However, residual undifferentiated iPS derivates (iPSD), which are not fully eliminated by cell differentiation or purification protocols, may form tumors after transplantation, thus compromising therapeutic application. Inhibition of stearoyl-coA desaturase (SCD) has recently been reported to eliminate undifferentiated human embryonic stem cells, which share many features with iPSD. Here, we tested the effects of PluriSin#1, a small-molecule inhibitor of SCD, on iPS-derived CM. We found that plurisin#1 treatment significantly decreased the mRNA and protein level of Nanog, a marker for both cell pluripotency and tumor progression; importantly, we provide evidence that PluriSin#1 treatment at 20 µM for 1 day significantly induces the apoptosis of Nanog-positive iPSD. In addition, PluriSin#1 treatment at 20 µM for 4 days diminished Nanog-positive stem cells in cultured iPSD while not increasing apoptosis of iPS-derived CM. To investigate whether PluriSin#1 treatment prevents tumorigenicity of iPSD after cell transplantation, we intramyocardially injected PluriSin#1- or DMSO-treated iPSD in a mouse model of myocardial infarction (MI). DMSO-treated iPSD readily formed Nanog-expressing tumors 2 weeks after injection, which was prevented by treatment with PluriSin#1. Moreover, treatment with PluriSin#1 did not change the expression of cTnI, α-MHC, or MLC-2v, markers of cardiac differentiation (P > 0.05, n = 4). Importantly, pluriSin#1-treated iPS-derived CM exhibited the ability to engraft and survive in the infarcted myocardium. We conclude that inhibition of SCD holds the potential to enhance the safety of therapeutic application of iPS cells for heart regeneration.
PluriSin#1; iPS; Nanog; tumorigenicity; myocardial infarction
Dysregulation of endocytosis was viewed as an emerging feature of cancer development and progression. A large GTPase dynamin2 plays a significant role in receptor tyrosine kinases (RTKs) endocytosis. The study was designed to investigate its roles in hepatocellular carcinoma (HCC) metastasis and its underlying mechanism. Dynamin2 expression in cancer tissues from HCC patients was assessed by immunohistochemistry and its prognostic significance for the patients was conducted using univariate and multivariate analysis. Its role in tumor invasion and metastasis was evaluated in vitro by gene silence using siRNA-mediated approach and the small molecule inhibitor of Dynasore. EGFR expression in HCC cell lines and EGFR downstream signaling ERK1/2 was evaluated by Western-blot and immunofluorescence analyses after Dynamin2 inhibition. Our data indicated that low expression of dynamin2 was well correlated with invasion characteristics and shorter overall survival. HCC cell migration, colony formation and invasion were significantly increased after the inhibition of dynamin2 in HCC cells. Internalization of EGFR was markedly reduced when dynamin2 was knock down or inhibition. In addition, we observed that dynamin2 regulated EGF mediated EGFR downstream Ras/ERK1/2 signaling and p-ERK1/2 accumulation in nucleus. The results demonstrate a possible mechanism of dynamin involved EGFR endocytosis and modulation of metastasis in HCC. Dynamin2 inhibits the invasion and metastasis of HCC cells by the promotion of EGFR endocytosis and downregulation of ERK1/2 phosphorylation.
Dynamin2; hepatocellular carcinoma; endocytosis; EGFR; ERK1/2
Fructus Sophorae pill, one of the traditional Chinese medicine, was widely used for hemorrhoids, hypertension and odontalgia. This paper describes a sensitive and specific assay for the determination of the 15 active constituents (sophoricoside, genistin, genistein, rutin, quercetin, kaempferol, baicalein, baicalin, naringin, naringenin, hesperidin, neohesperidin, wogonin and cimifugin, prim-O-glucosylcimifugin) in Fructus Sophorae pill.
Materials and Methods:
Chromatographic separation was performed on a C18 column with acidified aqueous methanol gradients at a flow rate of 0.8 mL/min. The identification and quantification of the analytes were achieved by use of a hybrid quadrupole linear ion trap mass spectrometer. Multiple-reaction monitoring scanning was applied to quantification with switching electrospray ion source polarity between positive and negative modes.
The proposed method was used to analyze 40 batches of samples with good linearity (r, 0.9990-0.9999), intraday precisions (RSD, 0.14-2.55%), interday precisions (RSD, 0.51-2.81%), stability (RSD, 0.31-2.65%), and recovery (RSD, 1.29-2.95%) of the 15 compounds. In addition, the hierarchical cluster analysis, including a method called furthest neighbor and nearest neighbor, was employed to classify samples according to characteristics of the 15 constituents.
The results indicated that the analytical method was rapid, reliable, simple and suitable for the quality evaluation of Fructus Sophorae pill.
Dosage form; Fructus Sophorae pill; Hierarchical cluster analysis; HPLC-ESI-MS/MS; Qualitative and quantitative determination
AIM: To assess the effects of 3-field lymphadenectomy for esophageal carcinoma.
METHODS: We conducted a computerized literature search of the PubMed, Cochrane Controlled Trials Register, and EMBASE databases from their inception to present. Randomized controlled trials (RCTs) or observational epidemiological studies (cohort studies) that compared the survival rates and/or postoperative complications between 2-field lymphadenectomy (2FL) and 3-field lymphadenectomy (3FL) for esophageal carcinoma with R0 resection were included. Meta-analysis was conducted using published data on 3FL vs 2FL in esophageal carcinoma patients. End points were 1-, 3-, and 5-year overall survival rates and postoperative complications, including recurrent nerve palsy, anastomosis leak, pulmonary complications, and chylothorax. Subgroup analysis was performed on the involvement of recurrent laryngeal lymph nodes.
RESULTS: Two RCTs and 18 observational studies with over 7000 patients were included. There was a clear benefit for 3FL in the 1- (RR = 1.16; 95%CI: 1.09-1.24; P < 0.01), 3- (RR = 1.44; 95%CI: 1.19-1.75; P < 0.01), and 5-year overall survival rates (RR = 1.37; 95%CI: 1.18-1.59; P < 0.01). For postoperative complications, 3FL was associated with significantly more recurrent nerve palsy (RR = 1.43; 95%CI: 1.28-1.60; P = 0.02) and anastomosis leak (RR = 1.26; 95%CI: 1.05-1.52; P = 0.09). In contrast, there was no significant difference for pulmonary complications (RR = 0.93; 95%CI: 0.75-1.16, random-effects model; P = 0.27) or chylothorax (RR = 0.77; 95%CI: 0.32-1.85; P = 0.69).
CONCLUSION: This meta-analysis shows that 3FL improves overall survival rate but has more complications. Because of the high heterogeneity among outcomes, definite conclusions are difficult to draw.
Oesophagus; Cancer; Lymph node dissection; Survival; Complication
A malignant gastrointestinal neuroectodermal tumor (GNET), a distinctive entity covering the characteristics of clear cell sarcoma (CCS) of gastrointestinal tract described recently, arising primarily in the ileum of a 33-year-old woman is reported. Histologically, the neoplasm involved the full thickness of the intestinal wall. Tumor cells, mainly displayed epithelioid or polygonal appearance with oval or round nuclei, arranged in strand, nested, and solid pattern with prominent pseudopapillary architecture instead of the familiar histological image with multinucleated osteoclast-like giant cells. They were positive for vimentin, S-100, synaptophysin, CD56 and CD99 protein, but negative for AE1/AE3, EMA, CEA, LCA, Desmin, CK7, CK20, Villin, CgA, CD117, Dog-1, GFAP, Melan-A, HMB-45, CD34, CR, WT1, D2-40. Fluorescence in situ hybridization (FISH) showed the presence of chromosomal translocation involving EWSR. The patients lived through a calm period after a tumor resection and 4 cycles of chemotherapy combining ifosfamide and epirubicin. This case demonstrates that GNET is a rare tumor in gastrointestinal tract, and furthermore, various misleading histological characteristics should been taken into consideration in the diagnosis.
Malignant gastrointestinal neuroectodermal tumor; clear cell sarcoma; ileum; pseudopapillary; immunochemistry; FISH
Upregulator of cell proliferation 4 (URG4) has been implicated in the oncogenesis of certain cancers. However, the correlation between URG4 expression and clinicopathological significance in human cancer remains unclear. Therefore, this study investigated its expression and clinicopathological significance in cervical cancer patients.
URG4 expression was examined using quantitative PCR (qPCR) and western blotting in normal cervical epithelial cells, cervical cancer cells, and eight matched pairs of cervical cancer tissues and adjacent noncancerous tissues from the same patient. In addition, immunohistochemistry (IHC) was used to examine URG4 expression in paraffin-embedded tissues from 167 cervical cancer patients (FIGO stages Ib1-IIa2). Statistical analyses were performed to evaluate associations between URG4 expression and prognostic and diagnostic factors.
URG4 was significantly upregulated in the cervical cancer cell lines and tissues compared with the normal cells and adjacent noncancerous cervical tissues. IHC revealed high URG4 expression in 59 out of the 167 (35.13%) cervical cancer specimens. Its expression was significantly correlated with clinical stage (P < 0.0001), tumour size (P = 0.012), T classification (P = 0.023), lymph node metastasis (P = 0.001) and vaginal involvement (P = 0.002). Patients with high URG4 expression, particularly those who received concurrent chemotherapy and radiotherapy (P < 0.0001), showed a shorter overall survival (OS) and disease-free survival (DFS) compared to those with the low expression of this protein. Multivariate analysis revealed that URG4 expression is an independent prognostic factor for cervical cancer patients.
Our results demonstrated that elevated URG4 protein expression is associated with a poor outcome in patients with early-stage cervical cancer. URG4 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-885) contains supplementary material, which is available to authorized users.
URG4; Cervical cancer; Prognosis; Concurrent chemotherapy and radiotherapy; Biomarker
This study was designed to evaluate the effectiveness of radiofrequency ablation in patients with intermediate (BCLC B) stage hepatocellular carcinoma who underwent transcatheter arterial chemoembolization.
Included in this study were 211 patients with intermediate stage HCC who underwent initial transcatheter arterial chemoembolization and were potentially amendable for radiofrequency ablation (single tumor with diameter 5-8 cm, median 6.0 cm; 2–5 multiple nodules with diameter less than 5 cm) between January 2005 and December 2011. According to the inclusion and exclusion criteria, 55 patients were treated with following radiofrequency ablation, and the remaining 156 patients were treated with transcatheter arterial chemoembolization alone. The treatment effectiveness, local tumor control and survival outcome between the two groups were compared.
The complete tumor necrosis rate after treatment was 76.9% in combination group vs. 46.5% in transcatheter arterial chemoembolization alone group (P = 0.02). The major complication rate was 1.8% in combination group vs. 2.6% in transcatheter arterial chemoembolization alone group. Follow-up observation showed that the total tumor control rate was 74.5% in combination group versus 54.5% in transcatheter arterial chemoembolization alone group (P < 0.001). The 1-, 3- and 5-year survival rates in combination group were significantly higher than those in TACE alone group (P = 0.01).
Radiofrequency ablation following initial transcatheter arterial chemoembolization delays tumor progression and prolongs overall survival of patients with intermediate stage HCC tumors.
Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Radiofrequency ablation; Combination therapy; Survival
Zea mays is an economically important crop, but its molecular mechanism of flowering remains largely uncharacterized. The gene, SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), integrates multiple flowering signals to regulate floral transition in Arabidopsis. In this study, ZmSOC1 was isolated from Zea mays. Sequence alignment and phylogenetic analysis demonstrated that the ZmSOC1 protein contained a highly conserved MADS domain and a typical SOC1 motif. ZmSOC1 protein was localized in the nucleus in protoplasts and showed no transcriptional activation activity in yeast cells. ZmSOC1 was highly expressed in maize reproductive organs, including filaments, ear and endosperm, but expression was very low in embryos; on the other hand, the abiotic stresses could repress ZmSOC1 expression. Overexpression of ZmSOC1 resulted in early flowering in Arabidopsis through increasing the expression of AtLFY and AtAP1. Overall, these results suggest that ZmSOC1 is a flowering promoter in Arabidopsis.
Zea mays; ZmSOC1; flowering; Arabidopsis; transcription factor
The homeobox gene, goosecoid (GSC), is a transcription factor that participates in cell migration during embryonic development. Because cell migration during development has characteristics similar to cell invasion during metastasis, we evaluated the potential role of GSC in the metastasis of hepatocellular carcinoma (HCC). GSC expression in HCC cell lines and tissues was evaluated, and its effects on the migration potential of HCC cells were determined by GSC knock-down and overexpression methods. In addition, the prognostic role of GSC expression in the metastasis of cancer cells in HCC patients was determined. Our data showed that GSC was highly expressed in several HCC cell lines, particularly in a highly metastatic HCC cell line. Overexpression of GSC promoted cell migration and invasion of HCC cells in vitro. Gain-of-function induced the epithelial-mesenchymal transition but not collective cell migration, whereas loss-of-function induced the reverse change. High-level expression of GSC correlated closely with poor survival and lung metastasis in HCC patients; lung metastases showed more upregulated GSC expression than the primary tumor. We conclude that GSC promotes metastasis of HCC potentially through initiating the epithelial-mesenchymal transition. GSC is also a prognostic factor for poor survival and metastasis of HCC, which suggests its potential as a therapeutic target for metastatic HCC.
The objective of the study was to investigate the in vitro antioxidation activity of lycium barbarum polysaccharides (LBP). Ultraviolet spectrophotometry was adopted to determine the capability of LBP to clear superoxide anions, hydroxyl radicals, DPPH free radicals and ABTS free radicals. The result showed that the law for LBP to clear superoxide anions, hydroxyl radicals and DPPH free radicals was that the clearance rate increased gradually with the increase of the concentration, and when the concentration reached a certain value, the clearance rate leveled off, while the IC50 for clearing ABTS free radicals was 47.158±6.231 µg/ml. The study concluded that LBP is a good in vitro antioxidant.
LBP; superoxide anion; hydroxyl radical; DPPH; ABTS
Pregnane X receptor (PXR) is an important member of the nuclear receptor superfamily that copes with various endobiotic and xenobiotic stimuli, such as carcinogens by regulating an array of environmental response genes. Low PXR expression has been shown to promote tumor initiation and metastasis. The aim of the current study was to investigate whether the single nucleotide polymorphisms (SNPs) of PXR could alter lung cancer susceptibility in Chinese by affecting the function or expression of PXR. We genotyped three putatively functional SNPs of PXR (i.e., rs3814055C>T, rs3732360C>T, and rs3814058C>T) and analyzed their associations with lung cancer risk in a two-stage case-control study with a total of 1559 lung cancer cases and 1679 controls in the southern and eastern Chinese population. We found that in comparison to the rs3814058CC common genotype, the rs3814058T variants (TC/TT) which is located in the 3'-untranslated region (3'-UTR) of PXR conferred a consistently increased risk of lung cancer in both the southern Chinese (odd ratios (OR) = 1.24, 95% confidence interval (CI) = 1.03−1.49) and the eastern Chinese (OR = 1.33, 95% CI = 1.02−1.75). The variants also significantly interacted with smoking on increasing cancer risk (p = 0.023). Moreover, lung cancer tissues with the rs3814058T variants showed significantly lower PXR expression than those with rs3814058CC genotype in the smokers (p = 0.041). These results suggested that the rs3814058C>T polymorphism of PXR interacts with smoking on increasing lung cancer risk in Chinese smokers, which might be a functional genetic biomarker for lung cancer.
pregnane X receptor (PXR); lung cancer; susceptibility