膜联蛋白A1和Ki67抗原在胰腺癌组织中的表达及其相互关系

[目的]探讨膜联蛋白A1（annexinA1,ANXA1）在胰腺癌中表达及其与细胞核相关抗原Ki67的相关性。[方法]构建胰腺癌组织芯片,在连续的芯片切片上使用免疫组化法检测ANXA1和Ki67蛋白表达情况,分析两者之间表达的相关性。[结果]胰腺癌组织芯片免疫组化结果显示,ANXA1在胰腺癌中表达的阳性率为71.4%（30/42）,明显高于正常胰腺组织中表达的阳性率18.4%（7/38）（P〈0.01）。Ki67在胰腺癌中表达的阳性率为69.5%（27/41）,也明显高于正常胰腺组织中表达的阳性率23.7%（9/38）（P〈0.01）。在胰腺癌中ANXA1与Ki67的表达存在显著的相关性（P〈0.01）。[结论]ANXA1蛋白在胰腺癌中的表达明显升高,与Ki67的表达有着显著的相关性。     

ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation,Regenerative Proliferation,and Poor Prognosis

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S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility

Background:

High levels of S100A6 have been associated with poor outcome in pancreatic cancer patients. The functional role of S100A6 is, however, poorly understood.

Methods:

Immunoprecipitation followed by two-dimensional gel electrophoresis and mass spectrometry were undertaken to identify S100A6 interacting proteins in pancreatic cancer cells. Immunohistochemistry and coimmunofluorescence were performed to examine expression or colocalisation of proteins. siRNA was used to deplete specific proteins and effects on motility were measured using Boyden Chamber and wound healing assays.

Results:

Our proteomic screen to identify S100A6 interacting proteins revealed annexin 11, annexin 2, tropomyosin β and a candidate novel interactor lamin B1. Of these, annexin 2 was considered particularly interesting, as, like S100A6, it is expressed early in the development of pancreatic cancer and overexpression occurs with high frequency in invasive cancer. Reciprocal immunoprecipitation confirmed the interaction between annexin 2 and S100A6 and the proteins colocalised, particularly in the plasma membrane of cultured pancreatic cancer cells and primary pancreatic tumour tissue. Analysis of primary pancreatic cancer specimens (n=55) revealed a strong association between high levels of cytoplasmic S100A6 and the presence of annexin 2 in the plasma membrane of cancer cells (P=0.009). Depletion of S100A6 was accompanied by diminished levels of membrane annexin 2 and caused a pronounced reduction in the motility of pancreatic cancer cells.

Conclusion:

These findings point towards a functional role for S100A6 that may help explain the link between S100A6 expression in pancreatic cancer and aggressive disease.     

Genetic Variants of CYP2D6 Gene and Cancer Risk: A HuGE Systematic Review and Meta-analysis

Objective: Genetic polymorphisms in metabolic enzymes are associated with numerous cancers. A largenumber of single nucleotide polymorphisms (SNPs) in the CYP2D6 gene have been reported to associate withcancer susceptibility. However, the results are controversial. The aim of this Human Genome Epidemiology(HuGE) review and meta-analysis was to summarize the evidence for associations. Methods: Studies focusingon the relationship between CYP2D6 gene polymorphisms and susceptibility to cancer were selected from thePubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data wereextracted by two independent reviewers and the meta-analysis was performed with Review Manager Version 5.1.6and STATA Version 12.0 software. Odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated.Results: According to the inclusion criteria, forty-three studies with a total of 7,009 cancer cases and 9,646healthy controls, were included in the meta-analysis. The results showed that there was a positive associationbetween heterozygote (GC) of rs1135840 and cancer risk (OR=1.92, 95%CI: 1.14-3.21, P=0.01). In addition, wefound that homozygote (CC) of rs1135840 might be a protective factor for cancer (OR=0.58, 95%CI: 0.34-0.97,P=0.04). Similarly, the G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686had negative associations with cancer risk (OR=0.69, 95%CI: 0.48-0.99, P=0.04; OR=0.60, 95%CI: 0.38-0.94,P=0.03; OR=0.50, 95%CI: 0.26-0.95, P=0.03; respectively). Conclusion: This meta-analysis suggests that CYP2D6gene polymorphisms are involved in the pathogenesis of various cancers. The heterozygote (GC) of rs1135840in CYP2D6 gene might increase the risk while the homozygote (CC) of rs1135840, G allele and G carrier (AG+ GG) of rs16947 and heterozygote (A/del) of rs35742686 might be protective factors.     

Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism.

BACKGROUND: Tamoxifen is hydroxylated by cytochrome P450 (CYP) 2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen. PATIENTS AND METHODS: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography-tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR. RESULTS: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N-demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N-demethyltamoxifen were related to SULT1A1 genotype. CONCLUSION: CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.     

CYP2D6 and CYP2E1 Gene Polymorphisms and their Association with Cervical Cancer Susceptibility: A Hospital Based Case-Control Study from South-Western Maharashtra

Background: In last few years several studies all over the world discovered the genetic polymorphisms in different cytochrome P450 genes associated with risk of various cancers, but contradictory outcomes were evidenced in case of cervical cancer risk.  In this case-control study we aimed to see whether the polymorphism of CYP2D6 or CYP2E1 genes may or may not be associated with cervical cancer risk in women of rural Maharashtra. Methods: In this case-control study, the association of CYP2D6 and CYP2E1 gene polymorphism with cervical cancer risk was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The study was conducted with 350 clinically confirmed cervical cancer patients and 350 healthy women in a population of South-Western Maharashtra. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated, where p ≤0.005 was considered as statistically significant. Results: After the analysis of SNP (rs389209) of CYP2D6 and SNPs (rs2031920, rs6413432, rs6413420) of CYP2E1, we noticed that variant allele A of CYP2E1*6 showed significant increase in cervical cancer cases (OR=4.81; 95% CI: 1.57- 14.77; p=0.005). The genotypic distribution of heterozygote G/A genotype of CYP2D6*4 showed negative association with cervical cancer development when age of cancer occurrence (OR=0.41; 95% CI: 0.27- 0.61; p<0.0001) and tobacco history (OR=0.35; 95% CI: 0.20- 0.59; p=0.0001) was considered. Conclusion: The findings from this study supported that rs6413432 SNP of CYP2E1*6 increased cervical cancer risk in the studied rural women population.     

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Cytochrome P450 (CYP) 2A6 and CYP2E1 are enzymes with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogens. The polymorphic CYP2A6 and CYP2E1 have been implicated in increased susceptibility to certain malignancies. In our study, 120 Japanese patients with gastric adenocarcinoma and 158 healthy controls were compared for frequencies of CYP2A6 and CYP2E1 genotypes. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion allele, which causes lack of the enzyme activity, was significantly higher in the gastric cancer patients than in the healthy control subjects (OR = 3.14, 95% confidence interval (95% CI) = 1.05-9.41). Subdividing gastric adenocarcinoma according to tumor differentiation, patients with the well-differentiated type were 4.9-fold more likely to have the CYP2A6 homozygote deletion genotype (OR = 4.91, 95% CI 1.17-20.52). Stratifying by smoking status, we did not find the risk of CYP2A6 gene deletion allele in gastric adenocarcinoma. The CYP2E1 polymorphism detected by RsaI was not significantly different between gastric adenocarcinoma patients (40.8%) and the control population (44.3%). No statistically significant changes were observed when the CYP2E1 genotype was examined relative to tumor differentiation and smoking status. These results suggest that the CTY2A6 deletion is associated with gastric adenocarcinoma among Japanese populations.     

CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients

Background:

We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin.

Methods:

Among MGC patients (n=108), who received S-1 (40 mg m⁻² b.i.d., days 1–14) and cisplatin (60 mg m⁻², day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487).

Results:

Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3% P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death.

Conclusion:

Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.     

Expression profile of COL2A1 and the pseudogene SLC6A10P predicts tumor recurrence in high‐grade serous ovarian cancer

Tumor recurrence, following initial response to adjuvant chemotherapy, is a major problem in women with high‐grade serous ovarian cancer (HGSOC). Microarray analysis of primary tumors has identified genes that may be useful in risk stratification/overall survival, but are of limited value in predicting the >70% rate for tumor recurrence. In this study, we performed RNA‐Seq analysis of primary and recurrent HGSOC to first identify unique differentially expressed genes. From this dataset, we selected 21 archetypical coding genes and one noncoding RNA, based on statistically significant differences in their expression profile between tumors, for validation by qPCR in a larger cohort of 110 ovarian tumors (71 primary and 39 recurrent) and for testing association of specific genes with time‐to‐recurrence (TTR). Kaplan–Meier tests revealed that high expression of collagen type II, alpha 1 (COL2A1) was associated with delayed TTR (HR = 0.47, 95% CI: 0.27–0.82, p = 0.008), whereas low expression of the pseudogene, solute carrier family 6 member 10 (SLC6A10P), was associated with longer TTR (HR = 0.53, 95% CI: 0.30–0.93, p = 0.027). Notably, TTR was significantly delayed for tumors that simultaneously highly expressed COL2A1 and lowly expressed SLC6A10P (HR = 0.21, 95% CI: 0.082–0.54, p = 0.0011), an estimated median of 95 months as compared to an estimated median of 16 months for subjects expressing other levels of COL2A1 and SLC6A10P. Thus, evaluating expression levels of COL2A1 and SLC6A10P at primary surgery could be beneficial for clinically managing recurrence of HGSOC.     

CYP2D6基因G4268C和ERCC1基因C8092A位点的单核苷酸多态性与肺癌遗传易感性

目的：探讨辽宁地区CYP2D6基因G4268C和ERCC1基因C8092A位点的单核苷酸多态性对肺癌发生的影响。方法：采用病例-对照研究方法,选取肺癌患者和健康对照者各200例。应用KI法快速抽提人外周血基因组DNA,PCR-RFLP的方法检测CYP2D6基因G4268C和ERCC1基因C8092A位点的单核苷酸多态性。结果：G4268/G、G4268/C和C4268/C这3种基因型在病例和对照组的分布频率分别为1.50%、58.00%、40.50%和2.50%、44.00%、53.50%,非C4268/C基因型的个体发生肺癌的风险是C4268/C基因型个体的1.73倍（95%CI=1.02-2.95）,在腺癌中OR=2.75（95%CI=1.27-5.94）;按吸烟情况进行分层分析后发现不吸烟者及轻度吸烟者中携带非C4268/C基因型的个体患肺癌的风险显著增高,OR值为2.09（95%CI=1.09-4.25）和3.41（95%CI=1.24-9.93）;非A8092/A基因型的个体发生肺癌的风险是A8092/A基因型个体的0.98倍（95%CI=0.52-2.17）。结论：C4268/C基因型在不吸烟者和轻度吸烟者中可能作为保护因素而降低肺癌的易感性,ERCC1 C8092A多态性与肺癌易感性无相关性。     

Lives and Economic Loss in Brazil due to Lack of Radiotherapy Access in Cervical Cancer: A Cost-Effectiveness Analysis

AimsAmong all malignancies, the use of radiotherapy incurs the highest survival benefit within cervical cancers. Radiotherapy, however, remains underutilised for cervical cancers within the Brazilian public health system (BPHS). The objective of this study was to estimate the potential health and monetary benefits for universal access to radiotherapy and chemoradiotherapy (CRT) for untreated cervical cancer patients in the BPHS.Materials and methodsUsing 2016 data on Brazilian cervical cancer incidence and availability of radiotherapy/CRT in the BPHS, the number of cancer deaths due to radiotherapy/CRT underutilisation was estimated. The incremental effectiveness was calculated by life-year gain. The indirect costs from mortality-related productivity loss (MRPL) were estimated based on life expectancy, wage and labour force participation rate. MRPL was compared with direct medical costs after being adjusted to 2016 US dollars. This study was conducted from the payer's perspective; both costs and effectiveness were discounted at a rate of 3%. The incremental cost-effectiveness ratio (ICER) was calculated to determine the cost-effectiveness of radiotherapy for cervical cancer in Brazil. One-way sensitivity analyses were carried out to assess the robustness of the model.ResultsThe total number of life-years lost due to lack of universal access to radiotherapy and CRT per year were 27 199 and 31 627, respectively. The annual cost to match the radiotherapy gap was $10.5 million, with an additional cost of $3 million to close the CRT gap. The mean years of potential life lost per death was 20.5. The cost per life saved was $7942 for radiotherapy alone (ICER $388/life-year) and $8774 for CRT (ICER $429/life-year). MRPL due to shortage of radiotherapy and CRT were $59 million and $69 million, respectively.ConclusionProviding universal access to radiotherapy/CRT for cervical cancer patients in the BPHS is highly cost-effective and should be prioritised as an impactful public health initiative.     

PRMT6 increases cytoplasmic localization of p21CDKN1A in cancer cells through arginine methylation and makes more resistant to cytotoxic agents

p21^CDKN1A is known as a potent inhibitor of cyclin-dependent kinase (CDK), which regulates cell cycle in response to various stimuli, including DNA damage, on the p53-dependent manner. Here we demonstrate that protein arginine methyltransferase 6 (PRMT6) methylates p21 at arginine 156 and promotes phosphorylation of threonine 145 on p21, resulting in the increase of cytoplasmic localization of p21. The cytoplasmic presence of p21 makes cancer cells more resistant to cytotoxic agents. Our results indicate that PRMT6 appears to be one of the key proteins to dysregulate p21 functions in human cancer, and targeting this pathway may be an appropriate strategy for development of anticancer drugs.