Clathrin is a major protein component of the cytoplasmic face of intracellular organelles, called coated vesicles and coated pits. These specialized organelles are involved in the intracellular trafficking of receptors and endocytosis of a variety of macromolecules. The basic subunit of the clathrin coat is composed of three heavy chains and three light chains. [provided by RefSeq, Jul 2008]
National Cancer Institute PDQ summaries are written and frequently updated by editorial boards of experts Further info.
CLTC OMIM, Johns Hopkin University Referenced article focusing on the relationship between phenotype and genotype.
CLTC International Cancer Genome Consortium. Summary of gene and mutations by cancer type from ICGC
CLTC Cancer Genome Anatomy Project, NCI Gene Summary
CLTC COSMIC, Sanger Institute Somatic mutation information and related details
CLTC TICdb, Universidad de Navarra Search the database of Translocation breakpoints In Cancer for "CLTC"
CLTC Epigenomics, NCBI Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: CLTC (cancer-related)
Challagundla KB, Wise PM, Neviani P, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
BACKGROUND: How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL). METHODS: Coculture experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts treated with Cisplatin and peritumoral exosomic miR-155 (n = 6 mice per group) CD163, miR-155, and TERF1 levels were assessed in 20 NBL primary tissues by Human Exon Arrays and quantitative real-time polymerase chain reaction. Student's t test was used to evaluate the differences between treatment groups. All statistical tests were two-sided. RESULTS: miR-21 mean fold change (f.c.) was 12.08±0.30 (P < .001) in human monocytes treated with NBL derived exosomes for 48 hours, and miR-155 mean f.c. was 4.51±0.25 (P < .001) in NBL cells cocultured with human monocytes for 48 hours. TERF1 mean luciferase activity in miR-155 transfected NBL cells normalized to scrambled was 0.36 ± 0.05 (P <.001). Mean tumor volumes in Dotap-miR-155 compared with Dotap-scrambled were 322.80±120mm(3) and 76.00±39.3mm(3), P = .002 at day 24, respectively. Patients with high CD163 infiltrating NBLs had statistically significantly higher intratumoral levels of miR-155 (P = .04) and lower levels of TERF1 mRNA (P = .02). CONCLUSIONS: These data indicate a unique role of exosomic miR-21 and miR-155 in the cross-talk between NBL cells and human monocytes in the resistance to chemotherapy, through a novel exosomic miR-21/TLR8-NF-кB/exosomic miR-155/TERF1 signaling pathway.
Kukita K, Tamura Y, Tanaka T, et al. Cancer-Associated Oxidase ERO1-α Regulates the Expression of MHC Class I Molecule via Oxidative Folding. J Immunol. 2015; 194(10):4988-96 [PubMed] Related Publications
ERO1-α is an oxidizing enzyme that exists in the endoplasmic reticulum and is induced under hypoxia. It reoxidizes the reduced form of protein disulfide isomerase that has oxidized target proteins. We found that ERO1-α is overexpressed in a variety of tumor types. MHC class I H chain (HC) has two disulfide bonds in the α2 and α3 domains. MHC class I HC folding is linked to the assembly of MHC class I molecules because only fully disulfide-bonded class I HCs efficiently assemble with β2-microglobulin. In this study, we show that ERO1-α associates with protein disulfide isomerase, calnexin, and immature MHC class I before being incorporated into the TAP-1-associated peptide-loading complex. Importantly, ERO1-α regulates the redox state as well as cell surface expression of MHC class I, leading to alteration of susceptibility by CD8(+) T cells. Similarly, the ERO1-α expression within cancer cells was associated with the expression level of MHC class I in colon cancer tissues. Thus, the cancer-associated ERO1-α regulates the expression of the MHC class I molecule via oxidative folding.
Xu Z, Chen H, Liu D, Huo J Fibulin-1 is downregulated through promoter hypermethylation in colorectal cancer: a CONSORT study. Medicine (Baltimore). 2015; 94(13):e663 [PubMed] Related Publications
Fibulin-1 (FBLN1) is involved in the progression of some types of cancer. However, the role of FBLN1 in colorectal cancer (CRC) has not been examined. The purpose of this study was to understand the molecular mechanisms and clinical significance of FBLN1 inactivation in CRC. The expression of FBLN1 in CRC tissues and adjacent normal tissues was analyzed by immunohistochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Methylation-specific polymerase chain reaction (MSP) and bisulfite sequencing PCR (BSP) were performed to examine the methylation status of the FBLN1 gene promoter. Furthermore, the methylated level of FBLN1 was analyzed with the clinicopathological characteristics. Immunohistochemical analysis and qRT-PCR analysis showed that FBLN1 protein and messenger RNA (mRNA) levels in tumor tissues were both significantly decreased compared with that in adjacent nontumor tissues. The methylation rate of FBLN1 promoter was significantly higher in CRC tissues than that in adjacent nontumor tissues (P < 0.001). In addition, the correlation between FBLN1 hypermethylation, protein expression, and overall survival (OS) was statistically significant. Our results indicated that the FBLN1 gene may be a novel candidate of tumor suppressor gene in CRC, and that promoter hypermethylation of FBLN1 is an important reason for its downregulation and is also a good predictor of OS for CRC.
Xu L, Yang M, Zhao T, et al. The polymorphism of CYP2E1 Rsa I/Pst I gene and susceptibility to respiratory system cancer: a systematic review and meta-analysis of 34 studies. Medicine (Baltimore). 2014; 93(27):e178 [PubMed] Related Publications
The purpose of this articles is to determine whether the cytochrome P450 2E1 (CYP2E1) Rsa I/Pst I gene polymorphism is correlated with respiratory system cancers. Respiratory system cancers included lung cancer, laryngeal cancer, nasopharyngeal cancer, and cancers of other respiratory organs, which are the most common malignant tumors worldwide; the significant relationship between CYP2E1 Rsa I/Pst I gene polymorphism and some respiratory system cancer have been reported, but results of some other studies are controversial. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the association. PubMed, EMBASE, Cochrane Library Databases, China National Knowledge Infrastructure, and Wanfang Database (up to July 20, 2014) were searched for all case-control studies those mainly studied the relationship between CYP2E1 Rsa I/Pst I gene polymorphism and the susceptibility of respiratory system cancer. A total of 332 articles were collected, among which 34 studies that involved 7028 cases and 9822 controls fulfilled the inclusion criteria after being assessed by 2 reviewers. When stratified by cancer site, the C2/C2 polymorphism could increase the risk of nasopharyngeal cancer under the homozygote model (C2C2 vs C1C1: OR = 1.85, 95% CI = 1.20-2.85, P = 0.005) and recessive model (C2C2 vs C1C2/C1C1: OR = 1.89, 95% CI = 1.23-2.89, P = 0.003). Protection effect was found in lung cancer in heterozygote model (C1C2 vs C1C1: OR = 0.82, 95% CI = 0.74-0.91, P < 0.001), dominant model (C1C2/C2C2 vs C1C1: OR = 0.83, 95% CI = 0.76-0.90, P < 0.001), and allele contrast model (C2 vs C1: OR = 0.85, 95% CI = 0.73-1.00, P = 0.045). With regard to ethnicity subgroup analysis, there was significant association in Asian population in heterozygote model (C1C2 vs C1C1: OR = 0.85, 95% CI = 0.78-0.94, P = 0.001), dominant model (C1C2/C2C2 vs C1C1: OR = 0.88, 95% CI = 0.81-0.95, P = 0.001), and recessive model (C2C2 vs C1C2/C1C1: OR = 1.25, 95% CI = 1.01-1.53, P = 0.036). CYP2E1 Rsa I/Pst I gene polymorphism may reduce the risk of respiratory system cancer. Furthermore, significant association was also found in Asian populations.
Fragoso MC, Alencar GA, Lerario AM, et al. Genetics of primary macronodular adrenal hyperplasia. J Endocrinol. 2015; 224(1):R31-43 [PubMed] Related Publications
ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for <2% of all endogenous CS cases; however it is more frequently identified incidentally with sub-clinical cortisol secretion. Recently, cortisol secretion has been shown to be regulated by ectopic corticotropin, which is in turn produced by clusters of steroidogenic cells of the hyperplastic adrenal nodules. Hence, the term 'ACTH-independent' is not entirely appropriate for this disorder. Accordingly, the disease is designated primary macronodular adrenal hyperplasia (PMAH) in this review article. The means by which cortisol production is regulated in PMAH despite the suppressed levels of ACTH of pituitary origin is exceedingly complex. Several molecular events have been proposed to explain the enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH. Nonetheless, the precise sequence of events and the molecular mechanisms underlying this condition remain unclear. The purpose of this review is therefore to present new insights on the molecular and genetic profile of PMAH pathophysiology, and to discuss the implications for disease progression.
Cai H, Liu W, Xue Y, et al. Roundabout 4 regulates blood-tumor barrier permeability through the modulation of ZO-1, Occludin, and Claudin-5 expression. J Neuropathol Exp Neurol. 2015; 74(1):25-37 [PubMed] Related Publications
The blood-tumor barrier (BTB) restricts the delivery of chemotherapeutic drug molecules to tumor tissues. We found that the endothelial cell (EC) receptor molecule Roundabout 4 (Robo4) is endogenously expressed in human brain microvascular ECs and that it is upregulated in a BTB model of glioma cocultured ECs. Knockdown of Robo4 in this BTB model increased permeability; short hairpin RNA targeting Robo4 (shRobo4) led to decreased transendothelial electric resistance values, increased BTB permeability, and downregulated expression of the EC tight junction proteins ZO-1, occludin, and claudin-5. Roundabout 4 influenced BTB permeability via binding with its ligand, Slit2. Short hairpin RNA targeting Robo4 also increased matrix metalloproteinase-9 (MMP-9) activity and expression in glioma cocultured ECs; pretreatment with the MMP inhibitor GM6001 partially blocked the effects of shRobo4 on the transendothelial electric resistance values and ZO-1 and occludin expression. Short hairpin RNA targeting Robo4 also upregulated the phosphorylation of Src and Erk1/2; the Src inhibitor PP2 and the Erk1/2 inhibitor PD98059 blocked shRobo4-mediated alteration in ZO-1 and occludin expression. Together, our results indicate that knockdown of Robo4 increased BTB permeability by reducing EC tight junction protein expression, and that the Src-Erk1/2-MMP-9 signal pathways are involved in this process. Thus, Robo4 may represent a useful future therapeutic target for enhancing BTB permeability.
BACKGROUND: microRNAs (miRNA) are 18-22 nucleotides long non-coding RNAs that regulate gene expression at a post-transcriptional level. Human cytomegalovirus (HCMV) encodes at least 26 known mature miRNAs. hcmv-miR-UL112-3p (miR-UL112-3p) is the most well characterized HCMV miRNA, which is suggested to play role in establishment and maintenance of viral latency. Elevated miR-UL112-3p levels have been reported to be present in plasma of patients with hypertension. OBJECTIVES: In this study, we aimed to quantify miR-UL112-3p levels in the plasma/serum of patients with Diabetes Mellitus (DM; from the DIGAMI-2 cohort), Glioblastoma multiforme (GBM), Rheumatoid Arthritis (RA) and Healthy Controls (HC). STUDY DESIGN: Total RNA was isolated from plasma/serum samples of 87 patients and controls, a TaqMan miRNA assay was performed to detect miR-UL112-3p and the copy numbers were normalized to 10 ng of total RNA. HCMV IgG and IgM were analysed using ELISA. RESULTS: HCMV miR-UL112-3p was detected in 14/27 (52%) of DM, 5/20 (25%) of GBM, 1/20 (5%) of RA patients and in 2/20 (10%) of HC, respectively. Anti-HCMV IgG was detected in 85%, 65%, 75% of patients and 70% of HC, respectively. Anti-HCMV IgM was found only in one GBM patient of 87 examined patients and controls. CONCLUSIONS: A higher prevalence of miR-UL112-3p was detected in DM and GBM patients than in RA patients and HC. Elevated levels of miR-UL112-3p and higher prevalence of HCMV IgG were observed in DM patients. Whether the presence of circulating miR-UL112-3p denotes a biomarker of HCMV latency or active replication in patients warrants further investigation.
BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.
Baragaño Raneros A, Martín-Palanco V, Fernandez AF, et al. Methylation of NKG2D ligands contributes to immune system evasion in acute myeloid leukemia. Genes Immun. 2015 Jan-Feb; 16(1):71-82 [PubMed] Related Publications
Engagement of the activating receptor NKG2D (natural killer group 2 member D) with its ligands (NKG2DL) major histocompatibility complex class I related-A and -B (MICA/B), UL-16 binding protein families (ULBPs 1-6) is important to ensure the innate immunity to tumor cells. However, these cells have developed strategies to downregulate NKG2DL expression and avoid immune recognition. We demonstrate that DNA methylation can contribute to the absence of NKG2DL expression during tumor progression. We analyzed the DNA methylation profiles for each NKG2DL by pyrosequencing in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), hepatocellular carcinoma (HC), breast cancer and colon cancer cell lines. High levels of DNA methylation for NKG2DL were found in some tumor cell lines, mainly in AML cells. This hypermethylation was correlated with the absence of transcription for NKG2DL. Higher DNA methylation levels for MICA, ULBP1 and ULBP2 were observed in AML patients (n=60) compared with healthy donors (n=25). However, no DNA methylation for NKG2DL was found in colon cancer patients (n=44). Treatment with demethylating agents (5-azacytidine and 5-aza-2'-deoxycytidine) restored the expression of NKG2DL on the cell surface of AML cells, leading to an enhanced recognition by NKG2D-expressing cells. Our data suggest that NKG2DL may be aberrantly silenced by DNA methylation as a consequence of tumor development in AML patients.
Xu D, Yi W, Chen Y, et al. Overexpression of Sig1R is closely associated with tumor progression and poor outcome in patients with hilar cholangiocarcinoma. Med Oncol. 2014; 31(12):261 [PubMed] Related Publications
Nonopioid Sigma1 receptor (Sig1R), which regulates various metabolism functions, has been implicated in cancers; yet, its role in hilar cholangiocarcinoma remains unclear. In the present study, we examined Sig1R expression in hilar cholangiocarcinoma (HC) tissues and explored its possible clinical values. Tissue microarray blocks containing 92 HC tissues and matched non-cancerous bile duct tissues were examined immunohistochemically for expression of Sig1R protein. Overexpression of Sig1R was found in 43 (46.7%) of the 92 primary tumor tissues. Overexpression of Sig1R was significantly associated with poor/undifferentiation (P = 0.011), tumor invasion (P = 0.001), lymph node metastasis (P = 0.047), and advanced disease stage (P = 0.024) of HC patients. Kaplan-Meier analysis showed that patients overexpressing Sig1R had an earlier recurrence and worse overall survival than those not overexpressing Sig1R. Cox regression analysis revealed that Sig1R was an independent factor to predict HC recurrence and prognosis of HC patients. Our results suggest that Sig1R is frequently activated in human HC tissue and overexpression of Sig1R might serve as a predictor for tumor recurrence and a prognostic biomarker for HC patients.
Shike M, Doane AS, Russo L, et al. The effects of soy supplementation on gene expression in breast cancer: a randomized placebo-controlled study. J Natl Cancer Inst. 2014; 106(9) [PubMed] Related Publications
BACKGROUND: There are conflicting reports on the impact of soy on breast carcinogenesis. This study examines the effects of soy supplementation on breast cancer-related genes and pathways. METHODS: Women (n = 140) with early-stage breast cancer were randomly assigned to soy protein supplementation (n = 70) or placebo (n = 70) for 7 to 30 days, from diagnosis until surgery. Adherence was determined by plasma isoflavones: genistein and daidzein. Gene expression changes were evaluated by NanoString in pre- and posttreatment tumor tissue. Genome-wide expression analysis was performed on posttreatment tissue. Proliferation (Ki67) and apoptosis (Cas3) were assessed by immunohistochemistry. RESULTS: Plasma isoflavones rose in the soy group (two-sided Wilcoxon rank-sum test, P < .001) and did not change in the placebo group. In paired analysis of pre- and posttreatment samples, 21 genes (out of 202) showed altered expression (two-sided Student's t-test, P < .05). Several genes including FANCC and UGT2A1 revealed different magnitude and direction of expression changes between the two groups (two-sided Student's t-test, P < .05). A high-genistein signature consisting of 126 differentially expressed genes was identified from microarray analysis of tumors. This signature was characterized by overexpression (>2-fold) of cell cycle transcripts, including those that promote cell proliferation, such as FGFR2, E2F5, BUB1, CCNB2, MYBL2, CDK1, and CDC20 (P < .01). Soy intake did not result in statistically significant changes in Ki67 or Cas3. CONCLUSIONS: Gene expression associated with soy intake and high plasma genistein defines a signature characterized by overexpression of FGFR2 and genes that drive cell cycle and proliferation pathways. These findings raise the concerns that in a subset of women soy could adversely affect gene expression in breast cancer.
The present study aimed to compare two different methods of extracting RNA from formalin-fixed paraffin-embedded (FFPE) specimens of diffuse large B-cell lymphoma (DLBCL). We further aimed to identify possible influences of variables--such as tissue size, duration of paraffin block storage, fixative type, primers used for cDNA synthesis, and endogenous genes tested--on the success of amplification from the samples. Both tested protocols used the same commercial kit for RNA extraction (the RecoverAll Total Nucleic Acid Isolation Optimized for FFPE Samples from Ambion). However, the second protocol included an additional step of washing with saline buffer just after sample rehydration. Following each protocol, we compared the RNA amount and purity and the amplification success as evaluated by standard PCR and real-time PCR. The results revealed that the extra washing step added to the RNA extraction process resulted in significantly improved RNA quantity and quality and improved success of amplification from paraffin-embedded specimens.
Chiu M, Tardito S, Pillozzi S, et al. Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts. Br J Cancer. 2014; 111(6):1159-67 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
BACKGROUND: A subset of human hepatocellular carcinomas (HCC) exhibit mutations of β-catenin gene CTNNB1 and overexpress Glutamine synthetase (GS). The CTNNB1-mutated HCC cell line HepG2 is sensitive to glutamine starvation induced in vitro with the antileukemic drug Crisantaspase and the GS inhibitor methionine-L-sulfoximine (MSO). METHODS: Immunodeficient mice with subcutaneous xenografts of the CTNNB1-mutated HCC cell lines HepG2 and HC-AFW1 were treated with Crisantaspase and/or MSO, and tumour growth was monitored. At the end of treatment, tumour weight and histology were assessed. Serum and tissue amino acids were determined by HPLC. Gene and protein expression were estimated with RT-PCR and western blot and GS activity with a colorimetric method. mTOR activity was evaluated from the phosphorylation of p70S6K1. RESULTS: Crisantaspase and MSO depleted serum glutamine, lowered glutamine in liver and tumour tissue, and inhibited liver GS activity. HepG2 tumour growth was significantly reduced by either Crisantaspase or MSO, and completely suppressed by the combined treatment. The combined treatment was also effective against xenografts of the HC-AFW1 cell line, which is Crisantaspase resistant in vitro. CONCLUSIONS: The combination of Crisantaspase and MSO reduces glutamine supply to CTNNB1-mutated HCC xenografts and hinders their growth.
Ling L, Zhao P, Yan G, et al. The frequency of Th17 and Th22 cells in patients with colorectal cancer at pre-operation and post-operation. Immunol Invest. 2015; 44(1):56-69 [PubMed] Related Publications
T helper 17 (Th17) and Th22 cells regulate the development of tumors. However, their roles in the development of colorectal cancer (CRC) are still unclear. A total of 49 patients with CRC and 18 healthy controls (HC) were evaluated for the percentages of circulating Th17 and Th22 cells by flow cytometry. The concentrations of serum interleukin-17A (IL-17A), IL-22 and carcinoembryonic antigen (CEA) were examined. The levels of IL-17A and IL-22 in tumors were determined by real-time PCR. We found that the percentages of Th17 and Th22 cells in the CRC patients were significantly lower than that in the HC and were associated negatively with the pathological stages of CRC. The levels of IL-17A and IL-22 mRNA transcripts were lower in the tumor tissues, particularly in the advanced CRC. After the tumor resection, the percentages of circulating Th17 and Th22 cells increased. These data suggest that decreased Th17 and Th22 responses may be associated with the development of CRC.
Huerta M, Fernández-Márquez J, Cabello JL, et al. Analysis of gene expression for studying tumor progression: the case of glucocorticoid administration. Gene. 2014; 549(1):33-40 [PubMed] Related Publications
BACKGROUND: Glucocorticoids are commonly used as adjuvant treatment for side-effects and have anti-proliferative activity in several tumors but, on the other hand, their proliferative effect has been reported in several studies, some of them involving the spread of cancer. We shall attempt to reconcile these incongruities from the genomic and tissue-physiology perspectives with our findings. METHODS: An accurate phenotype analysis of microarray data can help to solve multiple paradoxes derived from tumor-progression models. We have developed a new strategy to facilitate the study of interdependences among the phenotypes defined by the sample clusters obtained by common clustering methods (HC, SOTA, SOM, PAM). These interdependences are obtained by the detection of non-linear expression-relationships where each fluctuation in the relationship implies a phenotype change and each relationship typology implies a specific phenotype interdependence. As a result, multiple phenotypic changes are identified together with the genes involved in the phenotype transitions. In this way, we study the phenotypic changes from microarray data that describe common phenotypes in cancer from different tissues, and we cross our results with biomedical databases to relate the glucocorticoid activity to the phenotypic changes. RESULTS: 11,244 significant non-linear expression relationships, classified into 11 different typologies, have been detected from the data matrix analyzed. From them, 415 non-linear expression relationships were related to glucocorticoid activity. Studying them, we have found the possible reason for opposite effects of some stressor agents like dexamethasone on tumor progression and it has been confirmed by literature. This hidden reason has resulted in being linked with the type of tumor progression of the tissues. In the first type of tumor progression found, new cells can be stressed during proliferation and stressor agents increase tumor proliferation. In the second type, cell stress and tumor proliferation are antagonists so, therefore, stressor agents stop tumor proliferation in order to stress the cells. The non-linear expression relationships among DUSP6, FERMT2, FKBP5, EGFR, NEDD4L and CITED2 genes are used to synthesize these findings.
Wesołowska-Andersen A, Borst L, Dalgaard MD, et al. Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients. Leukemia. 2015; 29(2):297-303 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin-Frankfurt-Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6-6.3%) for the best group (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.
Li L, Jiang W, Zeng SY, Li L Prospective study of hTERC gene detection by fluorescence in situ hybridization (FISH) in cervical intraepithelial neoplasia 1 natural prognosis. Eur J Gynaecol Oncol. 2014; 35(3):289-91 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate the prognostic significance of human chromosome telomerase gene (hTERC) overexpression in cervical intraepithelial neoplasia grade 1 (CIN1) natural prognosis. MATERIALS AND METHODS: A total number of 2,499 women aged 30-49 years were screened in a population-based cervical cancer screening study from Jiangxi province rural sites. Pathology as the gold standard, 74 CIN1 patients first diagnosed by pathological examination were studied. They were observed by carrying the hybrid capture2 (HC2) and hTERC genetic testing to understand the baseline. All observed women accepted voluntary follow-up. Follow-up for the first time in the first 12 months after screening included hr-HPV HC-2 testing. The second follow-up after screening the first 24 months, included hr-HPV HC-2, colposcopy + pathological examinations. RESULTS: Of the 74 CIN1 cases that were followed-up for 24 months, seven cases (9.5%) progressed; 25 cases (33.8%) persisted, and 42 patients (56.7%) regressed. There was significant difference between hTERC amplification positive and negative group (chi2 = 21.07, p < 0.001). The risk of CIN1 persistence and progression in positive group was 3.24 (1.96-5.37) times higher than that in negative group. There was significant difference between hr-HPV persist positive and turn to negative or persistent negative group (chi2 = 7.645, p = 0.006). There was significant difference between hTERC gene and the initial test of hr-HPV both positive and both negative group (chi2 = 4.544, p = 0.033). CONCLUSION: There was a strong association between prevalence of hTERC gene overexpression and CIN1 natural prognosis. The follow-up results indicated that Hr-HPV required repeat testing and that there was significant difference between hr-HPV persistent positive and turn to negative/persistent negative group (chi2 = 7.645, p = 0.006). hTERC gene overexpression could prognoses cervical intraepithelial neoplasia 1 natural prognosis individually.
Skubitz KM, Skubitz AP, Xu WW, et al. Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas. J Transl Med. 2014; 12:176 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
BACKGROUND: The biologic heterogeneity of soft tissue sarcomas (STS), even within histological subtypes, complicates treatment. In earlier studies, gene expression patterns that distinguish two subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF) were used to separate 73 STS into two or four groups with different probabilities of developing metastatic disease (PrMet). This study was designed to confirm our earlier observations in a larger independent data set. METHODS: We utilized these gene sets, hierarchical clustering (HC), and Kaplan-Meier analysis, to examine 309 STS, using Affymetrix chip expression profiling. RESULTS: HC using the combined AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p = 0.048), and also among the four different clusters defined by the second branch points (p < 0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UPS) (p = 0.0004). HC of both the LipoD and UPS sample sets divided the samples into two groups with different PrMet (p = 0.0128, and 0.0002, respectively). HC of the UPS samples also showed four groups with different PrMet (p = 0.0007). HC found no subgroups of the LMS samples. CONCLUSIONS: These data confirm our earlier studies, and suggest that this approach may allow the identification of more than two subsets of STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management.
Tao J, Calvisi DF, Ranganathan S, et al. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology. 2014; 147(3):690-701 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND & AIMS: Aberrant activation of β-catenin and Yes-associated protein 1 (Yap1) signaling pathways have been associated with the development of multiple tumor types. Yap functions as a transcriptional coactivator by interacting with TEA domain DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis. METHODS: We used immunohistochemical analysis to determine expression of β-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the United States, consisting of 104 hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94 hepatoblastoma samples. We assessed β-catenin and Yap1 signaling and interactions in hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1); proteins were knocked down with small interfering RNAs, and effects on proliferation and cell death were measured. Sleeping beauty-mediated hydrodynamic transfection was used to overexpress constitutively active forms of β-catenin (ΔN90/β-catenin) and Yap1 (YapS127A) in livers of mice; tissues were collected, and histological and immunohistochemical analyses were performed. RESULTS: We observed nuclear localization of β-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples. Yap1 and β-catenin coprecipitated in hepatoblastoma but not hepatocellular carcinoma cells. Small interfering RNA-mediated knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner. Knockdown of Yap1 reduced its ability to coactivate transcription with β-catenin; β-catenin inhibitors inactivated Yap1. Overexpression of constitutively active forms of Yap1 and β-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks. Tumor cells expressed both proteins, and human hepatoblastoma cells expressed common targets of their 2 signaling pathways. Yap1 binding of TEA domain factors was required for tumorigenesis in mice. CONCLUSIONS: β-catenin and the transcriptional regulator Yap1 interact physically and are activated in most human hepatoblastoma tissues; overexpression of activated forms of these proteins in livers of mice leads to rapid tumor development. Further analysis of these mice will allow further studies of these pathways in hepatoblastoma pathogenesis and could lead to the identification of new therapeutic targets.
Yu DC, Liu J, Chen J, et al. GGPPS1 predicts the biological character of hepatocellular carcinoma in patients with cirrhosis. BMC Cancer. 2014; 14:248 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) has been associated with diabetes and obesity, but a possible connection with the metabolic syndrome (MetS) and its potential interaction with hepatitis and cirrhosis are open to discussion. Our previous investigations have shown that GGPPS1 plays a critical role during hyperinsulinism. In this report, the expression and distribution of GGPPS1 in liver cancer, and its clinical significance were investigated. METHODS: 70 patients with hepatocellular carcinoma (HCC) were included in this study. Three different types of tissues from each HCC patient were assembled immediately after surgical resection: tumor-free tissue >5 cm far from tumor edge (TF), adjacent nonmalignant tissue within 2 cm (AT), and tissue from the tumor (TT). Normal liver tissues from 10 liver transplant donors served as healthy control (HC) while 10 patients with liver cirrhosis as cirrhosis control (CC). The expression and distribution of GGPPS1 were detected by immunohistochemistry, western blots, or real-time PCR. The relationship between the expression of GGPPS1 and clinic pathologic index were analyzed. RESULTS: We found that GGPPS1 was intensified mainly in the cytoplasm of liver tumor cells. Both the expression of GGPPS1 mRNA and protein were upregulated in TT comparing to AT or TF. Meanwhile, HCC patients with cirrhosis had relative higher expression of GGPPS1. In addition, many pathologic characters show close correlation with GGPPS1, such as tumor stage, vessel invasion, and early recurrence. CONCLUSION: GGPPS1 may play a critical role during the development of HCC from cirrhosis and is of clinical significance for predicting biological character of HCC.
Papadopoulou A, Krance RA, Allen CE, et al. Systemic inflammatory response syndrome after administration of unmodified T lymphocytes. Mol Ther. 2014; 22(6):1134-8 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Systemic inflammatory response syndrome (SIRS) is a rare systemic inflammatory response associated with fever, tachycardia, profound hypotension, and respiratory distress, which has been reported in cancer patients receiving T cells genetically modified with chimeric antigen receptors to retarget their specificity to tumor-associated antigens. The syndrome usually occurs following significant in vivo expansion of the infused cells and has been associated with tumor destruction/lysis. Analysis of patient plasma has shown elevated cytokine levels, and resolution of symptoms has been reported after administration of steroids and/or antibodies (such as anti-tumor necrosis factor and anti-interleukin (IL)-6 receptor antibodies) that interfere with cytokine responses.To date, SIRS has not been reported in subjects receiving genetically unmodified T cells with native receptors directed against tumor antigens, in which greater physiological control of T-cell activation and expansion may occur. Here, however, we report a patient with bulky refractory Epstein-Barr virus (EBV)-associated lymphoma, who developed this syndrome 2 weeks after receiving T cells directed against EBV antigens through their native receptors. She was treated with steroids and etanercept, with rapid resolution of symptoms. SIRS may therefore occur even when T cells recognize antigens physiologically through their "wild-type" native receptors and should be acknowledged as a potential complication of this therapy.
Rai R, Sharma KL, Sharma S, et al. Death receptor (DR4) haplotypes are associated with increased susceptibility of gallbladder carcinoma in north Indian population. PLoS One. 2014; 9(2):e90264 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND AND AIM: Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis. Hence, the present study aimed to investigate the association of functional SNPs of DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) and FASL (rs763110) with gallbladder cancer (GBC) risk. METHODS: This case-control study included 400 GBC and 246 healthy controls (HC). Genotyping was carried out by Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) to systematically summarize the possible association of SNP with cancer risk. Functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). False discovery rate (FDR test) was used in multiple comparisons. RESULTS: The DR4 C rs20575 A rs20576 A rs6557634, G rs20575 A rs20576 G rs6557634 and G rs20575 C rs20576 G rs6557634 haplotypes conferred two-fold increased risk for GBC. Among these, the DR4 C rs20575 A rs20576 A rs6557634 haplotype emerged as main factor influencing GBC susceptibility as the risk was not modulated by gender or gallstone stratification. Our meta-analysis results showed significant association of DR4 rs6557634 with overall cancer risk, GI cancers as well as in Caucasians. We didn't find any association of FAS and FASL SNPs with GBC susceptibility. CONCLUSIONS: The DR4 haplotype C rs20575 A rs20576 A rs6557634 represents an important factor accounting the patients susceptibility to GBC probably due to decreased apoptosis. However, additional well-designed studies with larger sample size focusing on different ethnicities are required to further validate the results.
Lorenzi L, Cigognetti M, Medicina D, et al. ALK-positive inflammatory myofibroblastic tumor of the abdomen with widespread microscopic multifocality. Int J Surg Pathol. 2014; 22(7):640-4 [PubMed] Related Publications
Inflammatory myofibroblastic tumor (IMT) is a locally aggressive neoplasm, most frequently occurring in the abdominal cavity as multiple recurrent nodules. We report a case of IMT in a 24-year-old male presenting as multiple nodules involving the omentum, the liver, and the colon. Spindle tumor cells expressed ALK with a cytoplasmic granular distribution, the CLTC-ALK fusion gene was demonstrated by reverse-transcriptase polymerase chain reaction analysis, and break-apart fluorescence in situ hybridization (FISH) probes for the ALK gene showed a pathological pattern (single red signal associated with 1/2 normal fused signals) highly suggestive for combined gene fusion and deletion. To reduce the surgically unresectable liver mass, the patient was treated with crizotinib, and after 4 months of treatment the disease was defined stable according to RECIST criteria. Interestingly, ALK and FISH/FICTION analysis revealed that tumor cells were widely dispersed as multiple microscopic foci or as single cells beneath the omental mesothelium. These findings indicate that IMT multifocality might result either from dissemination from the main tumor mass or development of multiple independent neoplastic foci; furthermore, they underline the need of omentectomy in abdominal IMT to obtain surgical radicality.
Nam D, Song J, Kim SM, et al. 8-hydrocalamenene, derived from Reynoutria elliptica, suppresses constitutive STAT3 activation, inhibiting proliferation and enhancing chemosensitization of human multiple myeloma cells. J Med Food. 2014; 17(3):365-73 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The identification of the active compounds of herbal medicines and the molecular targets of those compounds is an attractive therapeutic objective. Reynoutria elliptica has been used for the treatment of various inflammatory diseases as a Korean folk remedy. Based on the evidence that anti-inflammatory agents frequently exert antiproliferative activity, we tested two sesquiterpene derivatives, 8-hydrocalamenene (HC) and 8,14-dihydrocalamenene (DHC), for their ability to induce apoptosis and suppress signal transducer and activator of transcription 3 (STAT3) activation in multiple myeloma (MM) U266 cells. We found that HC inhibited cell viability in U266, but not in peripheral blood mononuclear cells. HC exerted significant cytotoxicity and induced substantial subG1-phase arrest and apoptosis as compared with DHC. HC inhibited the expression of gene products involved in antiapoptosis (Bcl-2 and Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9), all of which are known to be regulated by STAT3. Furthermore, HC up-regulated cyclin-dependent kinase inhibitor p21 and induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. Interestingly, HC blocked constitutive STAT3 activation through the inhibition of activation of upstream kinases Janus-like kinase 1 (JAK1), JAK2, and c-Src and up-regulated PIAS3. Deletion of STAT3 reversed cytotoxic effects and the down-regulation of cyclin D1 and c-myc by HC in MM cells. Finally, this sesquiterpene significantly synergized the cytotoxic and apoptotic effects of bortezomib in U266 cells. Taken together, these results suggest that HC is a novel blocker of STAT3 activation which may have a potential in the prevention and treatment of MM.
Nakanuma Y, Sato Y Hilar cholangiocarcinoma is pathologically similar to pancreatic duct adenocarcinoma: suggestions of similar background and development. J Hepatobiliary Pancreat Sci. 2014; 21(7):441-7 [PubMed] Related Publications
Routine experiences suggest that cholangiocarcinomas (CCAs) show different clinicopathological behaviors along the biliary tree, and hilar CCA apparently resembles pancreatic duct adenocarcinoma (PDAC). Herein, the backgrounds for these similarities were reviewed. While all cases of PDAC, hilar CCA, intrahepatic CCA (ICCA) and CCA components of combined hepatocellular-cholangiocarcinoma (cHC-CCA) were adenocarcinomas, micropapillary patterns and columnar carcinoma cells were common in PDAC and hilar CCA, and trabecular components and cuboidal carcinoma cells were common in ICCA and CCA components of cHC-CCA. Anterior gradient protein-2 and S100P were frequently expressed in perihilar CCA and PDAC, while neural cell adhesion molecule and luminal epithelial membrane antigen were common in CCA components of c-HC-CCA. Pdx1 and Hes1 were frequently and markedly expressed aberrantly in PDAC and perihilar CCA, although their expression was rare and mild in CCA components in cHC-CCA and ICCA. Hilar CCA showed a similar postoperative prognosis to PDAC but differed from ICCA and cHC-CCA. Taken together, hilar CCA may differ from ICCA and CCA components of cHC-CCA but have a similar development to PDAC. These similarities may be explained by the unique anatomical, embryological and reactive nature of the pancreatobiliary tract. Further studies of these intractable malignancies are warranted.
Huang C, Du J, Xie K FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis. Biochim Biophys Acta. 2014; 1845(2):104-16 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Pancreatic cancer is a devastating disease with an overall 5-year survival rate less than 5%. Multiple signaling pathways are implicated in the pathogenesis of pancreatic cancer, such as Wnt/β-catenin, Notch, Hedgehog, hypoxia-inducible factor, signal transducer and activator of transcription, specificity proteins/Krüppel-like factors, and Forkhead box (FOX). Recently, increasing evidence has demonstrated that the transcription factor FOXM1 plays important roles in the initiation, progression, and metastasis of a variety of human tumors, including pancreatic cancer. In this review, we focus on the current understanding of the molecular pathogenesis of pancreatic cancer with a special focus on the function and regulation of FOXM1 and rationale for FOXM1 as a novel molecular target for pancreatic cancer prevention and treatment.
Sheng L, Xiong M, Li C, Meng X Reversing multidrug-resistant by RNA interference through silencing MDR1 gene in human hepatocellular carcinoma cells subline Bel-7402/ADM. Pathol Oncol Res. 2014; 20(3):541-8 [PubMed] Related Publications
Multidrug resistance (MDR) in hepatocellular carcinoma (HC) significantly impedes the effect of chemotherapy and is considered as a primary reason leading to its recurrences and metastasis. The aim of present study was to explore new molecular targets for the reversal of MDR in HC by screening the adriamycin (ADM)-induced, human MDR-resistant HC cell subline Bel-7402/ADM. Small interfering RNAs (siRNAs) of four (MDR1si326, MDR1si1513, MDR1si2631 and MDR1si3071) targeting MDR1 were designed and transfected into Bel-7402/ADM cell strains. The experiments involved the following: mRNA expression of MDR1 gene by RT-PCR, P-glycoprotein (P-gp) expression by Western blot, intracellular ADM accumulation flow cytometry, and IC50 of ADM by a cytotoxic MTT assay. Four siRNAs reversed MDR in HC mediated by MDR1 to varying degrees. The expression level of MDR1 mRNA in cells of MDR1si326 or MDR1si2631 group (0.190 ± 0.038 or 0.171 ± 0.011) was more decreased. The expression level of P-gp in cells of MDR1si326 group was the lowest. The accumulation of ADM in cells of MDR1si326 or MDR1si2631 group (77.0 ± 3.5 or 75.4 ± 2.9) was more increased. The IC50 of cells to ADM was lowest in MDR1si326 group (11.32 ± 0.69 mg/L). Compared with other three siRNAs, MDR1si326 performed the optimal reversal effect of drug resistance in human HC Bel-7402/ADM.
Penna-Martinez M, Epp F, Kahles H, et al. FOXE1 association with differentiated thyroid cancer and its progression. Thyroid. 2014; 24(5):845-51 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Single nucleotide polymorphisms (SNPs) near thyroid transcription factor genes (FOXE1 rs965513/NKX2-1 rs944289) have been shown to be associated with differentiated thyroid cancer (DTC) in Caucasoid populations. We investigated the role of those SNPs in German patients with DTC and also extended our analysis to tumor stages and lymphocytic infiltration of the tumors (ITL). METHODS: Patients with DTC (n=243; papillary, PTC; follicular, FTC) and healthy controls (HC; n=270) were analyzed for the rs965513 and rs944289 SNPs. RESULTS: The case-control analysis for rs965513 SNP showed that the genotypes "AA," "AG," and minor allele "A" were more frequent in patients with DTC than in HC (pronounced in PTC p(genotype)=0.000084, p(allele)=0.006 than FTC p(genotype)=0.29 and p(allele)=0.06). Furthermore, subgroup analysis of the DTC patients stratified for primary tumor stage (T1-T2, T3-T4), the absence or presence of regional lymph node metastases (N0, N1), for distant metastases (M0, M1), as well as for ITL, showed an association of rs965513 with stages T1-T2, T1-T3, N1, and absence of ITL. The NKX2-1 SNP rs944289, however, was not associated with DTC. CONCLUSION: Our results confirm that the FOXE1 rs965513 SNP confers an increased risk for DTC in the German population, particularly allele "A" and the genotypes "AA" and "AG" for PTC. This increased risk was also observed in advanced tumor stages and absence of ITL, which may reflect the course of a more aggressive disease. The NKX2-1 rs944289 SNP, however, appears to play a secondary role in the development of DTC in the German population.
May WA, Grigoryan RS, Keshelava N, et al. Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines. PLoS One. 2013; 8(12):e80060 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.
Nishida N, Arizumi T, Takita M, et al. Reactive oxygen species induce epigenetic instability through the formation of 8-hydroxydeoxyguanosine in human hepatocarcinogenesis. Dig Dis. 2013; 31(5-6):459-66 [PubMed] Related Publications
Chronic hepatitis C (CHC) triggers oxidative stress and contributes to the emergence of hepatocellular carcinoma (HCC). We previously reported that tumor suppressor gene (TSG) methylation is a critical factor during the early stages of hepatocarcinogenesis. In this study, we clarify the association between oxidative stress and epigenetic alterations during hepatocarcinogenesis. We examined DNA oxidation and methylation profiles in 128 liver biopsy samples from CHC patients. The DNA oxidation and methylated TSG numbers were quantified using immunohistochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG) and quantitative PCR for 11 TSGs, respectively. The quantitative chromatin immunoprecipitation-PCR (ChIP-qPCR) assay in HepG2 and fetal liver Hc cells treated with H2O2 was used to quantify trimethyl-H3K4, acetylated-H4K16 (an active chromatin marker), trimethyl-H3K27 (a repressive chromatin marker) and 8-OHdG. We analyzed 30 promoters of 25 different TSGs by qPCR. The high levels of 8-OHdG was the only variable that was significantly associated with the increased number of methylated TSGs in CHC (p < 0.0001). The ChIP-qPCR revealed that after H2O2 treatment of the cell lines, the 8-OHdG-bound promoters showed a modification from an active chromatin (trimethyl-H3K4 and acetylated-H4K16 dominant) to a repressive chromatin (trimethyl-H3K27 dominant) status. We conclude that oxidative stress alters the chromatin status, which leads to abnormal methylation of TSGs, and contributes to hepatocarcinogenesis in CHC patients.