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Human Cancers (human + cancers)
Kinds of Human Cancers Selected AbstractsExpression of EMMPRIN and matriptase in esophageal squamous cell carcinoma: Correlation with clinicopathological parametersDISEASES OF THE ESOPHAGUS, Issue 6 2006M.-F. Cheng SUMMARY., Extracellular matrix metalloproteinase inducer (EMMPRIN) and the type II transmembrane serine protease, matriptase, are expressed in several human cancers and play an important role in tumor progression. The aim of the present study was to investigate the immuno-staining patterns of EMMPRIN and matriptase in patients with esophageal squamous cell carcinomas (SCC) and correlate the percentage tumor staining with tumor differentiation and clinical parameters. EMMPRIN and matriptase immunoreactivity was seen on the cell membrane and in the cytoplasm of tumor cells in all 41 cases of esophageal SCC evaluated. The percentage tumor staining of EMMPRIN was 48 ± 3% for well differentiated, 73 ± 3% for moderately differentiated, and 92 ± 3% for poorly differentiated esophageal SCC. Higher percentage tumor staining with EMMPRIN correlated significantly with poorly differentiated esophageal SCC (P < 0.05). The percentage tumor staining with matriptase correlated significantly with tumor differentiation (52 ± 3% for well differentiated, 85 ± 2% for moderately differentiated, and 88 ± 3% for poorly differentiated esophageal SCC). Additionally, higher percentage tumor staining with matriptase was significantly correlated with the advanced N and M stages (P < 0.05). Our results demonstrate that EMMPRIN and matriptase are over-expressed in esophageal SCC and are correlated with advanced clinicopathological stages. Pharmacological agents targeting EMMPRIN and matriptase expressions may be beneficial in the treatment of esophageal SCC. [source] Telomerase activity in small cell esophageal carcinomaDISEASES OF THE ESOPHAGUS, Issue 2 2001V. Chow Small cell carcinoma of the esophagus is a rare and aggressive malignant tumor. Telomerase activation is common in human cancers. There is a lack of data on telomerase activity in esophageal small cell cancers. The present report studied the role of telomerase activity in esophageal small cell carcinoma. The clinicopathologic data of five patients with small cell carcinoma of the esophagus who underwent primary surgical treatment between 1991 and 2000 were studied. Telomeric repeat amplification protocol assays were used to investigate telomerase activity in these tumors. The proliferative activity (MIB-1) and p53 expression of these tumors were also studied using immunohistochemistry and correlated with the telomerase activity. All five small cell carcinomas showed detectable telomerase activity in the primary tumor. Two out of the five morphologically normal esophageal mucosae adjacent to the primary tumor had detectable telomerase activity. There was no correlation between the p53 expression, tumor stage, survival of patients, and the presence of telomerase activity. High MIB-1 expression in esophageal small cell carcinomas was associated with high telomerase activity. Telomerase activation is common in small cell carcinoma of the esophagus. This fact may find application in anti-telomerase treatment for this aggressive tumor. [source] Human telomeric G-quadruplex: The current status of telomeric G-quadruplexes as therapeutic targets in human cancerFEBS JOURNAL, Issue 5 2010Stephen Neidle The 3,-ends of human chromosomal DNA terminate in short single-stranded guanine-rich tandem-repeat sequences. In cancer cells, these are associated with the telomere-maintenance enzyme telomerase together with the end-binding protein hPOT1. Small molecules that can compete with these proteins and induce the single-stranded DNA to form quadruplex,ligand complexes are, in effect, able to expose these 3,-ends, which results in the activation of a DNA damage response and selective inhibition of cell growth. Several of these G-quadruplex binding molecules have shown promising anticancer activity in tumour xenograft models, which indicate that the approach may be applicable to the treatment of a wide range of human cancers. This minireview summarizes the available data on these compounds and the challenges posed for drug discovery. [source] Gene position within chromosome territories correlates with their involvement in distinct rearrangement types in thyroid cancer cellsGENES, CHROMOSOMES AND CANCER, Issue 3 2009Manoj S. Gandhi Chromosomal rearrangements in human cancers are of two types, interchromosomal, which are rearrangements that involve exchange between loci located on different chromosomes, and intrachromosomal, which are rearrangements that involve loci located on the same chromosome. The type of rearrangement that typically activates a specific oncogene may be influenced by its nuclear location and that of its partner. In interphase nuclei, each chromosome occupies a distinct three-dimensional (3D) territory that tends to not overlap the territories of other chromosomes. It is also known that after double strand breaks in the genome, mobility of free DNA ends is limited. These considerations suggest that loci located deep within a chromosomal territory might not participate in interchromosomal rearrangements as readily as in intrachromosomal rearrangements. To test this hypothesis, we used fluorescence in situ hybridization with 3D high-resolution confocal microscopy to analyze the positions of six oncogenes known to be activated by recombination in human cancer cells. We found that loci involved in interchromosomal rearrangements were located closer to the periphery of chromosome territories as compared with the loci that were involved in intrachromosomal inversions. The results of this study provide evidence suggesting that nuclear architecture and location of specific genetic loci within chromosome territories may influence their participation in intrachromosomal or interchromosomal rearrangements in human thyroid cells. © 2008 Wiley-Liss, Inc. [source] Expression and mutational analysis of MET in human solid cancersGENES, CHROMOSOMES AND CANCER, Issue 12 2008Patrick C. Ma MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) regulate a variety of cellular functions, many of which can be dysregulated in human cancers. Activated MET signaling can lead to cell motility and scattering, angiogenesis, proliferation, branching morphogenesis, invasion, and eventual metastasis. We performed systematic analysis of the expression of the MET receptor and its ligand HGF in tumor tissue microarrays (TMA) from human solid cancers. Standard immunohistochemistry (IHC) and a computerized automated scoring system were used. DNA sequencing for MET mutations in both nonkinase and kinase domains was also performed. MET was differentially overexpressed in human solid cancers. The ligand HGF was widely expressed in both tumors, primarily intratumoral, and nonmalignant tissues. The MET/HGF likely is functional and may be activated in autocrine fashion in vivo. MET and stem cell factor (SCF) were found to be positively stained in the bronchioalevolar junctions of lung tumors. A number of novel mutations of MET were identified, particularly in the extracellular semaphorin domain and the juxtamembrane domain. MET-HGF pathway can be assayed in TMAs and is often overexpressed in a wide variety of human solid cancers. MET can be activated through overexpression, mutation, or autocrine signaling in malignant cells. Mutations in the nonkinase regions of MET might play an important role in tumorigenesis and tumor progression. MET would be an important therapeutic antitumor target to be inhibited, and in lung cancer, MET may represent a cancer early progenitor cell marker. © 2008 Wiley-Liss, Inc. [source] Unscheduled DNA replication origin activation at inserted HPV 18 sequences in a HPV -18/MYC ampliconGENES, CHROMOSOMES AND CANCER, Issue 8 2007Chiara Conti Oncogene amplification is a critical step leading to tumorigenesis, but the underlying mechanisms are still poorly understood. Despite data suggesting that DNA replication is a major source of genomic instability, little is known about replication origin usage and replication fork progression in rearranged regions. Using a single DNA molecule approach, we provide here the first study of replication kinetics on a previously characterized MYC/papillomavirus (HPV18) amplicon in a cervical cancer. Using this amplicon as a model, we investigated the role DNA replication control plays in generating amplifications in human cancers. The data reveal severely perturbed DNA replication kinetics in the amplified region when compared with other regions of the same genome. It was found that DNA replication is initiated from both genomic and viral sequences, resulting in a higher median frequency of origin firings. In addition, it was found that the higher initiation frequency was associated with an equivalent increase in the number of stalled replication forks. These observations raise the intriguing possibility that unscheduled replication origin activation at inserted HPV -18 viral DNA sequences triggers DNA amplification in this cancer cell line and the subsequent overexpression of the MYC oncogene. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. © 2007 Wiley-Liss, Inc. [source] Microcell-mediated transfer of chromosome 4 into HeLa cells suppresses telomerase activityGENES, CHROMOSOMES AND CANCER, Issue 2 2001Claudia Backsch Telomerase activity can be detected in most human cancers and immortal cell lines. In contrast, the lack of telomerase activity in normal diploid fibroblasts has been correlated with progressive reduction of telomere lengths to critically short sizes followed by the cessation of cell division and the onset of senescence. Several investigators have provided evidence for the localization of a telomerase suppressor gene on chromosome 3. The aim of our study was to determine whether other chromosomes are involved in telomerase repression. Beside human chromosome 3 (serving as positive control), chromosomes 4, 6, and 11 were introduced into HeLa cells via microcell-mediated chromosome transfer. Telomerase activity from different hybrid cell lysates was determined at an early time point after fusion using a Telomerase ELISA kit. Strong repression of telomerase activity was only found in a subset of HeLa hybrids in which chromosome 3 or chromosome 4 had been introduced. Telomerase suppression induced by chromosome 3 or 4 transfer was paralleled by a high frequency (30% or 43%, respectively) of a senescent-like phenotype. Chromosomes 6 and 11, the functional loss of which is also implicated in cervical cancer, had no effect. These results indicate that normal human chromosomes 3 and 4 carry a gene or genes that suppress telomerase activity and induce cellular senescence in HeLa cells.©2001 Wiley-Liss, Inc. [source] Nutrition and pharyngeal cancer: Results from a case-control study in SpainHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 9 2002Ana Escribano Uzcudun MD Abstract Background Oropharyngeal and hypopharyngeal cancer is increasing all over the world, frequently affecting more and more women and younger individuals and not only the typical 50- to 60-year-old heavy smoker and drinking man. In addition, 5-year overall survival rate remains poor (30% to 40% in most series), despite advances in treatment. Therefore, it is crucial to understand as accurately as possible the risk factors for these malignancies to improve primary prevention. Methods We report the results from a case-control study of pharyngeal cancer risk factors conducted in Spain involving 232 consecutive patients who were gender- and age-matched with 232 controls. Data were collected by interviewer-administered personal interview. Results Our results show that low intake of fruit, fruit juice, uncooked vegetables, dietary fiber,containing foods (legume and cereals), fish, milk, and dairy products is an independent risk factor for pharyngeal cancer and that high consumption of meat and fried foods also increases the risk once data are adjusted for tobacco smoking and alcohol drinking. Conclusions Although findings for fruit, juice, and uncooked vegetables are in accordance with those from other authors and can be explained on a biologic basis, the relationship between pharyngeal cancer and dietary excess of saturated fatty acids needs experimental investigation. Findings for milk, dairy products, and fish also warrant more detailed epidemiologic research because of conflicting data reported in the literature and because of the reportedly ambiguous role of retinol in human cancers. No conclusive explanations for the protective effect of dietary fiber,containing foods can be put forward today. Our results are uniquely attributable to oropharyngeal and hypopharyngeal cancers because of the small size of our nasopharyngeal cancer subsample. © 2002 Wiley Periodicals, Inc. Head Neck 24: 830,840, 2002 [source] Human papillomavirus infection and cyclin D1 gene amplification in laryngeal squamous cell carcinoma: Biologic function and clinical significance,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 6 2002Giovanni Almadori MD Abstract Background Human papillomavirus (HPV) infection is suspected to be a risk factor for head and neck, and in particular for laryngeal, carcinogenesis. Cyclin D1 gene (CCND1) overexpression and amplification have been shown to play a role as prognostic factors in many human cancers, among which are head and neck cancers. Methods A literature review of the role in head and neck cancers of HPV infection and CCND1 overexpression and amplification was undertaken. We have evaluated the extent of the current knowledge in this field under the light of recent acquisitions, in particular, about a correlation between HPV infection, a suspected risk factor, and CCND1 amplification, a frequent mutation (about 20% of laryngeal cancers) and a prognostic factor in laryngeal SCC. Results and Discussion The significant correlation between HPV infection and CCND1 amplification supports the hypothesis of the involvement of HPV infection in laryngeal carcinogenesis and suggests that HPV positive laryngeal cancers may constitute a different subset of tumors with a peculiar molecular pattern and thus with a different clinical behavior. HPV infection may be considered a synergistic risk factor with smoking and/or alcohol consumption to be investigated in heavy smokers and drinkers, thus contributing to the identification of patient at high-risk for the development of laryngeal cancer who should undergo strict follow-up and primary and secondary prevention. © 2002 Wiley Periodicals, Inc. Head Neck 24: 597,604, 2002 [source] Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database,,HUMAN MUTATION, Issue 6 2007Audrey Petitjean Abstract The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest. Hum Mutat 28(6), 622,629, 2007. Published 2007 Wiley-Liss, Inc. [source] m.6267G>A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors,HUMAN MUTATION, Issue 6 2006M. Esther Gallardo Abstract Complete sequencing of the mitochondrial genome of 13 cell lines derived from a variety of human cancers revealed nine novel mitochondrial DNA (mtDNA) variations. One of them, m.6267G>A, is a recurrent mutation that introduces the Ala122Thr substitution in the mitochondrially encoded cytochrome c oxidase I (MT-CO1): p.MT-CO1: Ala122Thr (GenBank: NP_536845.1). Biochemical analysis of the original cell lines and the transmitochondrial cybrids generated by transferring mitochondrial DNAs to a common nuclear background, indicate that cytochrome c oxidase (COX) activity, respiration, and growth in galactose are impaired by the m.6267G>A mutation. This mutation, found twice in the cancer cell lines included in this study, has been also encountered in one out of 63 breast cancer samples, one out of 64 colon cancer samples, one out of 260 prostate cancer samples, and in one out of 15 pancreatic cancer cell lines. In all instances the m.6267G>A mutation was associated to different mtDNA haplogroups. These findings, contrast with the extremely low frequency of the m.6267G>A mutation in the normal population (1:2264) and its apparent absence in other pathologies, strongly suggesting that the m.6267G>A missense mutation is a recurrent mutation specifically associated with cancer. Hum Mutat 27(6), 575,582, 2006. © 2006 Wiley-Liss, Inc. [source] Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN-215) and a bombesin antagonist (RC-3095)INTERNATIONAL JOURNAL OF CANCER, Issue 8 2010Sandra Sotomayor Abstract Bombesin (BN) and gastrin-releasing peptide (GRP) have been shown to stimulate the growth of human prostate cancer in vivo and in vitro by mechanisms initiated by binding of the peptide to BN/GRP receptor (GRPR). GRPR is overexpressed in a variety of human cancers, including human prostatic carcinoma. This led us to evaluate the effectiveness of blocking GRPR and of chemotherapy targeted to GRPR in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cells, which exhibit different features of disease progression. Thus, we used a cytotoxic BN/GRP analog, AN-215, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to BN-like carrier peptide, and a BN/GRP receptor antagonist, RC-3095. Semiquantitative RT-PCR and Western blotting revealed that mRNA and protein levels for GRPR increased in prostate cancer cells as compared with nonneoplastic RWPE-1 cells. Immunofluorocytochemistry and Western blot assays revealed that AN-215 was the most effective analog decreasing both the expression of epidermal growth factor receptor family members and the activation of epidermal growth factor receptor and HER-2, which are associated to a poor prognosis. Furthermore, analogs targeted to BN/GRP receptors, AN-215 and RC-3095, blocked the effect of BN on cell growth in RWPE-1, LNCaP and PC-3 cells. These findings shed light on the mechanisms of action of these analogs and support the view that the use of AN-215 and RC-3095 for blocking BN/GRP receptors for targeted therapy may be of benefit for treatment of advanced prostate cancer. [source] Annexin-A7 protects normal prostate cells and induces distinct patterns of RB-associated cytotoxicity in androgen-sensitive and -resistant prostate cancer cells,INTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Yelizaveta Torosyan Abstract The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(+/,)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicityin androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased low-molecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC. [source] Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotypeINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Andreas Weigert Abstract A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor-associated macrophages (TAMs), which are polarized towards an anti-inflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti-cancer strategies along this line. One potential immune modulating compound, sphingosine-1-phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P-producing enzymes for tumor progression. The growth of SphK2-deficient MCF-7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors was comparable. However, TAMs from SphK2-deficient tumors displayed a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-,, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization. © 2009 UICC [source] IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Marie-Christine Brezak Abstract CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent. © 2008 Wiley-Liss, Inc. [source] TP53 mutation signature supports involvement of aristolochic acid in the aetiology of endemic nephropathy-associated tumoursINTERNATIONAL JOURNAL OF CANCER, Issue 4 2009Tatiana Nedelko Abstract The proposal has been put forward that the primary cause of Balkan endemic nephropathy (BEN) is exposure to food crops contaminated with seeds of Aristolochia spp, which contain high levels of aristolochic acids (AA). Recently, tumour DNA samples from patients with BEN were found to harbour principally A to T mutations in the TP53 tumour suppressor gene (Grollman et al., Proc Natl Acad Sci USA 2007;104:12129,34). Using a novel mutation assay in which we can induce and select mutations in human TP53 sequences in vitro by exposure of cultured cells to a mutagen, we found that A to T mutations were elicited by aristolochic acid at sites in TP53 rarely mutated in human cancers in general, but which were observed in the BEN patients. This concordance of specific mutations in patient tumours and aristolochic acid I-exposed cultures supports the argument that AA has a direct role in the aetiology of BEN-associated cancer. © 2008 Wiley-Liss, Inc. [source] Frequent inactivation of SPARC by promoter hypermethylation in colon cancersINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Eungi Yang Abstract Epigenetic modification of gene expression plays an important role in the development of human cancers. The inactivation of SPARC through CpG island methylation was studied in colon cancers using oligonucleotide microarray analysis and methylation specific PCR (MSP). Gene expression of 7 colon cancer cell lines was evaluated before and after treatment with the demethylating agent 5-aza-2,-deoxycytidine (5Aza-dC) by oligonucleotide microarray analysis. Expression of SPARC was further examined in colon cancer cell lines and primary colorectal cancers, and the methylation status of the SPARC promoter was determined by MSP. SPARC expression was undetectable in 5 of 7 (71%) colorectal cancer cell lines. Induction of SPARC was demonstrated after treatment with the demethylating agent 5Aza-dC in 5 of the 7 cell lines. We examined the methylation status of the CpG island of SPARC in 7 colon cancer cell lines and in 20 test set of colon cancer tissues. MSP demonstrated hypermethylation of the CpG island of SPARC in 6 of 7 cell lines and in all 20 primary colon cancers, when compared with only 3 of 20 normal colon mucosa. Immunohistochemical analysis showed that SPARC expression was downregulated or absent in 17 of 20 colon cancers. A survival analysis of 292 validation set of colorectal carcinoma patients revealed a poorer prognosis for patients lacking SPARC expression than for patients with normal SPARC expression (56.79% vs. 75.83% 5-year survival rate, p = 0.0014). The results indicate that epigenetic gene silencing of SPARC is frequent in colon cancers, and that inactivation of SPARC is related to rapid progression of colon cancers. © 2007 Wiley-Liss, Inc. [source] Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancersINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Kunitoshi Tomii Abstract Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. © 2006 Wiley-Liss, Inc. [source] Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Zhe Zhang Abstract RASSF2 can bind directly to K-Ras and function as a negative effector of Ras protein. RASSF2A is the only isoform of RASSF2 that contains CpG islands in its promoter and it has been reported to be inactivated by its promoter methylation in several human cancers. In the present study, we investigated the correlation of RASSF2A expression with its promoter methylation in nasopharyngeal carcinoma (NPC). Expression of RASSF2A was down-regulated in 80% (4/5) of NPC cell lines. Decreased RASSF2A expression was also observed in NPC primary tumors compared with normal nasopharyngeal epithelia. Promoter methylation of RASSF2A could be detected in all the RASSF2A -silenced cell lines (4/5) of the NPC cell lines and 50.9% (27/53) of primary tumors, but not in any of the normal epithelia. RASSF2A -methylated cases showed a significantly lower level of RASSF2A expression than unmethylated cases. Loss of RASSF2A expression can be greatly restored by the methyltransferase inhibitor 5-aza-dC in NPC cell lines. In addition, patients with methylated RASSF2A presented a higher frequency of lymph node metastasis (p < 0.05). Ectopic expression of RASSF2A in RASSF2A -silenced and -methylated NPC cell line CNE2 shows that RASSF2A could inhibit cell cycle progression, colony formation and cell migration, which provided further evidence that RASSF2A is a candidate tumor suppressor gene. In conclusion, RASSF2A, a candidate tumor suppressor gene (TSG), is frequently inactivated by its promoter methylation and this aberrant methylation correlates with lymph node metastasis in NPC. © 2006 Wiley-Liss, Inc. [source] Severe pulmonary metastasis in obese and diabetic miceINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Akinori Mori Abstract Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. © 2006 Wiley-Liss, Inc. [source] Cigarette smoking, elevated fasting serum glucose, and risk of pancreatic cancer in Korean menINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Ji Eun Yun Abstract Pancreatic cancer is one of the most fatal human cancers and continues to be a major unsolved health problem. The goal of this study was to estimate the independent effects and interactions between cigarette smoking and diabetes on the risk of pancreatic cancer in Korean male population. Cigarette smoking and the risk of incidence and death from pancreatic cancer were examined in a 10-year prospective cohort study of 446,407 Korean men aged 40 to 65 years who received health insurance from the National Health Insurance Corporation and who had a medical evaluation in 1992. Relative risks (RR) and 95% confidence intervals (CI) were calculated using a Cox proportional hazards model after adjusting for age, body mass index, exercise and alcohol use. Current smoking was associated with an increased risk of incidence (RR = 1.7, 95% CI = 1.6,1.9) and mortality (RR = 1.6, 95% CI = 1.4,1.7) from pancreatic cancer. The RR for pancreatic cancer increased with both duration and amount of smoking. Diabetes was also associated with an increased risk of both incidence (RR = 1.8, 95% CI = 1.5,2.2) and mortality (RR = 1.7, 95% CI = 1.4,2.1) from pancreatic cancer. There was no interaction between smoking and fasting serum glucose in terms of pancreatic cancer risk. Thus, our prospective study has demonstrated that cigarette smoking and elevated fasting serum glucose are independently associated with an increased risk of pancreatic cancer in a large cohort of Korean males. © 2006 Wiley-Liss, Inc. [source] Osteoprotegerin (OPG),a potential new role in the regulation of endothelialcell phenotype and tumour angiogenesis?INTERNATIONAL JOURNAL OF CANCER, Issue 8 2006Simon S. Cross Abstract The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n = 512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n = 178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours. © 2005 Wiley-Liss, Inc. [source] Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma,INTERNATIONAL JOURNAL OF CANCER, Issue 3 2005Joseph Kwong Abstract Tazarotene-induced gene 1 (TIG1) and Tazarotene-induced gene 3 (TIG3) are retinoid acid (RA) target genes as well as candidate tumor suppressor genes in human cancers. In our study, we have investigated the expression of TIG1 and TIG3 in nasopharyngeal carcinoma (NPC). Loss of TIG1 expression was found in 80% of NPC cell lines and 33% of xenografts, whereas TIG3 was expressed in all NPC samples and immortalized nasopharyngeal epithelial cells. In order to elucidate the epigenetic silencing of TIG1 in NPC, the methylation status of TIG1 promoter was examined by genomic bisulfite sequencing and methylation-specific PCR (MSP). We have detected dense methylation of TIG1 5,CpG island in the 5 TIG1 -negative NPC cell lines and xenograft (C666-1, CNE1, CNE2, HONE1 and X666). Partial methylation was observed in 1 NPC cell line HK1 showing dramatic decreased in TIG1 expression. Promoter methylation was absent in 2 TIG1 -expressed NPC xenografts and the normal epithelial cells. Restoration of TIG1 expression and unmethylated alleles were observed in NPC cell lines after 5-aza-2,-deoxycytidine treatment. Moreover, the methylated TIG1 sequence was detected in 39 of 43 (90.7%) primary NPC tumors by MSP. In conclusion, our results showed that TIG1 expression is lost in the majority of NPC cell lines and xenografts, while promoter hypermethylation is the major mechanism for TIG1 silencing. Furthermore, the frequent epigenetic inactivation of TIG1 in primary NPC tumors implied that it may play an important role in NPC tumorigenesis. [source] SV40 and human cancersINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Mauro Tognon No abstract is available for this article. [source] SV40 in human cancers: ResponseINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Harald zur Hausen No abstract is available for this article. [source] Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Umadevi V. Wesley Abstract Lung cancer is the leading cause of cancer death. Lung cancers produce a variety of mitogenic growth factors that stimulate tumor cell proliferation and migration. The cell surface protease, dipeptidyl peptidase IV (DPPIV), is involved in diverse biologic functions, including peptide-mediated cellular growth and differentiation. DPPIV is expressed in various normal tissues, including lung tissue, and its expression is lost in many types of human cancers. DPPIV expression and its enzymatic activity are detected in normal bronchial and alveolar epithelium but different histologic subtypes of lung carcinomas lose DPPIV expression. To investigate the role of DPPIV in lung carcinoma, we examined the expression of DPPIV at both mRNA and protein levels in non small cell lung cancer (NSCLC) cell lines and normal human bronchial epithelial cells. DPPIV expression was detectable in normal lung epithelial cells, but was absent or markedly reduced in all NSCLC cell lines at both mRNA and protein levels. Restoration of DPPIV expression in NSCLC cells resulted in profound morphologic changes, inhibition of cell proliferation, anchorage-independent growth, in vitro cell migration and tumorigenicity in nude mice. DPPIV reexpression also correlated with increased p21 expression, leading to induction of apoptosis and cell cycle arrest in G1 stage. These effects were accompanied by increased expression of cell surface proteins, fibroblast-activating protein (Fap,) and CD44 that are associated with suppression of tumor growth and metastasis. Thus, DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells. © 2004 Wiley-Liss, Inc. [source] Sv40 in human cancers,An endless tale?INTERNATIONAL JOURNAL OF CANCER, Issue 5 2003Harald zur Hausen Editor-in-Chief No abstract is available for this article. [source] Changes in retinoblastoma gene expression during cervical cancer progressionINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 6 2002Mauricio Salcedo Summary. The role of tumour suppressor genes in the development of human cancers has been studied extensively. In viral carcinogenesis, the inactivation of suppressor proteins such as retinoblastoma (pRb) and p53, and cellular oncogenes overexpression, such as c-myc, has been the subject of a number of investigations. In uterine-cervix carcinomas, where high-risk human papillomavirus (HPV) plays an important role, pRb and p53 are inactivated by E7 and E6 viral oncoproteins, respectively. However, little is known about the in situ expression of some of these proteins in pre-malignant and malignant cervical tissues. On the other hand, it has also been demonstrated that c-myc is involved in cervical carcinogenesis, and that pRb participates in the control of c-myc gene expression. By using immunostaining techniques, we investigated pRb immunodetection pattern in normal tissues, squamous intraepithelial lesions (SILs) and invasive carcinomas from the uterine cervix. Our data show low pRb detection in both normal cervical tissue and invasive lesions, but a higher expression in SILs. C-Myc protein was observed in most of the cellular nuclei of the invasive lesions, while in SILs was low. These findings indicate a heterogeneous pRb immunostaining during the different stages of cervical carcinogenesis, and suggest that this staining pattern could be a common feature implicated in the pathogenesis of uterine-cervix carcinoma. [source] Transcriptional and post-transcriptional control of DNA methyltransferase 3B is regulated by phosphatidylinositol 3 kinase/Akt pathway in human hepatocellular carcinoma cell linesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2010Chuanzhong Mei Abstract DNA methyltransferases (DNMTs) are essential for maintenance of aberrant methylation in cancer cells and play important roles in the development of cancers. Unregulated activation of PI3K/Akt pathway is a prominent feature of many human cancers including human hepatocellular carcinoma (HCC). In present study, we found that DNMT3B mRNA and protein levels were decreased in a dose- and time-dependent manner in HCC cell lines with LY294002 treatment. However, we detected that LY294002 treatment did not induce increase of the degradation of DNMT3B protein using protein decay assay. Moreover we found that Akt induced alteration of the expression of DNMT3B in cells transfected with myristylated variants of Akt2 or cells transfected with small interfering RNA respectively. Based on DNMT3B promoter dual-luciferase reporter assay, we found PI3K pathway regulates DNMT3B expression at transcriptional level. And DNMT3B mRNA decay analysis suggested that down-regulation of DNMT3B by LY294002 is also post-transcriptional control. Furthermore, we demonstrated that LY294002 down-regulated HuR expression in a time-dependent manner in BEL-7404. In summary, we have, for the first time, demonstrate that PI3K/Akt pathway regulates the expression of DNMT3B at transcriptional and post-transcriptional levels, which is particularly important to understand the effects of PI3K/Akt and DNMT3B on hepatocarcinogenesis. J. Cell. Biochem. 111: 158,167, 2010. © 2010 Wiley-Liss, Inc. [source] Role of hypoxia in the hallmarks of human cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2009Kai Ruan Abstract Hypoxia has been recognized as one of the fundamentally important features of solid tumors and plays a critical role in various cellular and physiologic events, including cell proliferation, survival, angiogenesis, immunosurveillance, metabolism, as well as tumor invasion and metastasis. These responses to hypoxia are at least partially orchestrated by activation of the hypoxia-inducible factors (HIFs). HIF-1 is a key regulator of the response of mammalian cells to oxygen deprivation and plays critical roles in the adaptation of tumor cells to a hypoxic microenvironment. Hypoxia and overexpression of HIF-1 have been associated with radiation therapy and chemotherapy resistance, an increased risk of invasion and metastasis, and a poor clinical prognosis of solid tumors. The discovery of HIF-1 signaling has led to a rapidly increasing understanding of the complex mechanisms involved in tumor hypoxia and has helped greatly in screening novel anticancer agents. In this review, we will first introduce the cellular responses to hypoxia and HIF-1 signaling pathway in hypoxia, and then summarize the multifaceted role of hypoxia in the hallmarks of human cancers. J. Cell. Biochem. 107: 1053,1062, 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||