International Journal of Cancer
Wiley InterScience : International Journal of Cancer

Role for transcription factor TFII-I in the suppression of SSeCKS/Gravin/Akap...
by Yahao Bu, Lingqiu Gao, Irwin H. Gelman
21 Jun 2010 at 7:36am
The SSeCKS/Gravin/AKAP12 gene, encoding a kinase scaffolding protein with metastasis-suppressing activity, is transcriptionally downregulated in Src-transformed cells through the recruitment of HDAC1 to a Src-responsive proximal promoter site charged with Sp1, Sp3 and USF1. However, the ectopic expression of these proteins formed a suppressive complex in Src-transformed but not in parental NIH3T3 cells, suggesting the involvement of additional repressor factors. Transcription factor II-I (TFII-I) [general transcription factor 2i (Gtf2i)] was identified by mass spectrometry as being associated with the SSeCKS promoter complex in NIH3T3/Src cells, and moreover, the Src-induced tyrosine phosphorylation of TFII-I significantly increased its binding to the SSeCKS proximal promoter. siRNA-mediated knockdown of TFII-I or the expression of TFII-IY248/249F caused the derepression of SSeCKS in NIH3T3/Src cells. Taken with previous data showing that the tyrosine phosphorylation of TFII-I facilitates its nuclear translocation, these data suggest that Src-family kinase-mediated phosphorylation converts a portion of TFII-I into a transcriptional repressor.
p53 status influences response to tamoxifen but not to fulvestrant in breast ...
by Lynnette Fernandez-Cuesta, Suresh Anaganti, Pierre Hainaut, Magali Olivier
14 Jun 2010 at 8:42am
Mutations in the tumor suppressor gene TP53 are associated with poor prognosis in breast cancer. This prognostic value may rely in part on the fact that p53 plays a role in the antiproliferative and apoptotic activities of chemotherapy regimens used to treat breast tumors. However, some studies suggested that p53 may also influence response to antihormone treatments. Here we investigate how p53 may affect response to antihormonal treatments, using estrogen-dependent breast cancer cell-lines with different p53 status. We show that p53 mutated cells were more resistant to cytotoxic effects of 4-hydroxy-tamoxifen (OHT) compared to p53 wild-type cells. In contrast, p53 status did not significantly impact on response to fulvestrant. p53 mutated cells were also hypersensitive to proliferative effects of estradiol. Interestingly, OHT at doses in the low range had proliferative activities in p53 mutated cells (120-150% proliferation rate under 1 [mu]M OHT treatment in low estrogen conditions). Using gene silencing or specific tyrosine kinase inhibitors, we show that the proliferative effects of OHT were estrogen receptor dependent and could be abrogated by the inhibition of EGFR and/or HER2 kinases. These findings suggest that loss of p53 function may increase cross-talks between estrogen receptor and EGFR/HER2 pathways, contributing to a proliferative effect of OHT. These results bring new insights into the prognostic role of p53 in breast cancer and into possible mechanisms underlying tamoxifen resistance.
The ARF tumor suppressor: Structure, functions and status in cancer
by Peggy Ozenne, Beatrice Eymin, Elisabeth Brambilla, Sylvie Gazzeri
14 Jun 2010 at 8:42am
The INK4b-ARF-INK4a locus encodes two members of the INK4 family of cyclin-dependent kinase inhibitors, p15INK4b and p16INK4a, and a completely unrelated protein called ARF. ARF is a nucleolar protein with unusual structure that exhibits tumor suppressive functions. There is growing evidence that ARF signaling is complex, and involves p53-dependent or -independent pathways aiming mainly at restraining abnormal cell growth and at maintaining genomic stability. As such, ARF is a critical component of tumor surveillance, and its expression is decreased in human tumors. In this review, we present the current knowledge on ARF regulation and major functions. The ARF status in human tumors is also briefly summarized.
MicroRNA-125b suppresses the development of bladder cancer by targeting E2F3
by Li Huang, Junhua Luo, Qingqing Cai, Qiuhui Pan, Hong Zeng, Zhenghui Guo, Wen Dong, Jian Huang, Tianxin Lin
14 Jun 2010 at 8:42am
Increasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to tumorigenesis. microRNA-125b (miR-125b) was implicated to have close relationship with cell proliferation and differentiation, and downregulation of miR-125b was observed in various types of cancers. However, the biological function of miR-125b in bladder tumorigenesis is still unknown. In our study, we showed that the expression of miR-125b was significantly decreased in bladder cancer tissues and four bladder cancer cell lines. Moreover, miR-125b could suppress bladder cancer cells to form colonies in vitro and to develop tumors in nude mice. E2F3, which was critical for G1/S transition and was overexpressed in most of poor-differentiated bladder cancers, was identified as a target of miR-125b by luciferase assay. The E2F3 mRNA and protein expression levels were detected in bladder cancer tissues and cell lines, and interestingly, inverse correlations between miR-125b and E2F3 protein level were found in bladder cancer tissues and four E2F3 nonamplified cell lines. Introduction of miR-125b could reduce the expression of E2F3 protein but not the E2F3 mRNA. In addition, we observed that transfection of miR-125b could inhibit the expression of Cyclin A2, one of the E2Fs-responsive genes involved in G1/S transition. These results suggest that miR-125b may regulate G1/S transition through the E2F3-Cyclin A2 signaling pathway. Taken together, miR-125b may act as a tumor suppressor in bladder urothelium, and downregulation of miR-125b may contribute to the tumorigenesis of bladder cancer.
HB-EGF orchestrates the complex signals involved in triple-negative and trast...
by Fusanori Yotsumoto, Eiji Oki, Eriko Tokunaga, Yoshihiko Maehara, Masahide Kuroki, Shingo Miyamoto
24 May 2010 at 5:08am
A number of therapeutic strategies targeting epidermal growth factor receptor (EGFR) have not always led to success in the present state of breast cancer therapy. Notably, there is currently no way to treat trastuzumab-resistant and triple-negative breast cancer (TNBC). Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGFR ligands, was predominantly expressed in breast cancer and that treatment with crossreacting material 197 (CRM197), a specific inhibitor of HB-EGF, blocked ERK as well as AKT activation via complexes of EGFR and unknown growth factor receptors in TNBC or through complexes of EGFR and human epidermal growth factor receptor-2 in trastuzumab-resistant breast cancer, caused significant cell apoptosis and inhibited tumor growth. Accordingly, we can provide a novel concept that a certain EGFR ligand is recognized as a rational target against breast cancer. In addition, it is plausible that CRM197 could be an effective anticancer agent for molecularly targeted therapies.
CHI3L1 (YKL-40) is expressed in human gliomas and regulates the invasion, gro...
by Bo Mi Ku, Yeon Kyung Lee, Jinhyun Ryu, Joo Yeon Jeong, Jungil Choi, Keyoung Mi Eun, Hye Young Shin, Dong Gyu Kim, Eun Mi Hwang, Jae cheal Yoo, Jae-Yong Park, Gu Seob Roh, Hyun Joon Kim, Gyeong Jae Cho, Wan Sung Choi, Sun Ha Paek, Sang Soo Kang
20 May 2010 at 4:29am
Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that has pleiotropic activity in aggressive cancers. In our study, we examined the expression and function of CHI3L1 in glioma cells. CHI3L1 was highly expressed in human glioma tissue, whereas its expression in normal brain tissue was very low. CHI3L1 suppression by shRNA reduced glioma cell invasion, anchorage-independent growth and increased cell death triggered by several anticancer drugs, including cisplatin, etoposide and doxorubicin, whereas CHI3L1 overexpression had the opposite effect in glioma cells. Because the invasive nature of glioma cells plays a critical role in the high morbidity of glioma, we have further defined the role of CHI3L1 in the process of glioma invasion. Downregulation of CHI3L1 results in decreased cell-matrix adhesion and causes a marked increase in stress fiber formation and cell size with fewer cellular processes. Furthermore, the expression and activity of matrix metalloproteinase-2 was also decreased in glioma cells in which CHI3L1 was knocked down. Taken together, these results suggest that CHI3L1 plays an important role in the regulation of malignant transformation and local invasiveness in gliomas. Thus, targeting the CHI3L1 molecule may be a potential therapeutic molecular target for gliomas.
Tumour-associated glycan modifications of antigen enhance MGL2 dependent upta...
by Satwinder Kaur Singh, Ingeborg Streng-Ouwehand, Manja Litjens, Hakan Kalay, Eirikur Saeland, Yvette van Kooyk
13 May 2010 at 5:18am
We recently showed that MGL2 specifically binds tumour-associated glycan N-acetylgalactosamine (GalNAc). We here demonstrate that modification of an antigen with tumour-associated glycan GalNAc, targets antigen specifically to the MGL2 on bone marrow derived (BM)-DCs and splenic DCs. Glycan-modification of antigen with GalNAc that mimics tumour-associated glycosylation, promoted antigen internalisation in DCs and presentation to CD4 T cells, as well as differentiation of IFN-[gamma] producing CD4 T cells. Furthermore, GalNAc modified antigen enhanced cross-presentation of both BM-DCs and primary splenic DCs resulting in enhanced antigen specific CD8 T cell responses. Using MyD88-TRIFF-/- BM-DCs we demonstrate that the enhanced cross-presentation of the GalNAc modified antigen is TLR independent. Our data strongly suggest that tumour-associated GalNAc modification of antigen targets MGL on DCs and greatly enhances both MHC class II and class I presentation in a TLR independent manner.
Oral benzo[a]pyrene-induced cancer: Two distinct types in different target or...
by Zhanquan Shi, Nadine Dragin, Marian L. Miller, Keith F. Stringer, Elisabet Johansson, Jing Chen, Shigeyuki Uno, Frank J. Gonzalez, Carlos A. Rubio, Daniel W. Nebert
2 Feb 2010 at 1:38am
Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1 and CYP1B1) can both detoxify PAHs and activate them to cancer-causing reactive intermediates. Following high dosage of oral BaP (125 mg/kg/day), ablation of the mouse Cyp1a1 gene causes immunosuppression and death within [sim]28 days, whereas Cyp1(+/+) wild-type mice remain healthy for >12 months on this regimen. In this study, male Cyp1(+/+) wild-type, Cyp1a1(-/-) and Cyp1b1(-/-) single-knockout and Cyp1a1/1b1(-/-) double-knockout mice received a lower dose (12.5 mg/kg/day) of oral BaP. Tissues from 16 different organs - including proximal small intestine (PSI), liver and preputial gland duct (PGD) - were evaluated; microarray cDNA expression and >30 mRNA levels were measured. Cyp1a1(-/-) mice revealed markedly increased CYP1B1 mRNA levels in the PSI, and between 8 and 12 weeks developed unique PSI adenomas and adenocarcinomas. Cyp1a1/1b1(-/-) mice showed no PSI tumors but instead developed squamous cell carcinoma of the PGD. Cyp1(+/+) and Cyp1b1(-/-) mice remained healthy with no remarkable abnormalities in any tissue examined. PSI adenocarcinomas exhibited striking upregulation of the Xist gene, suggesting epigenetic silencing of specific genes on the Y-chromosome; the Rab30 oncogene was upregulated; the Nr0b2 tumor suppressor gene was downregulated; paradoxical overexpression of numerous immunoglobulin kappa- and heavy-chain variable genes was found - although the adenocarcinoma showed no immunohistochemical evidence of being lymphatic in origin. This oral BaP mouse paradigm represents an example of "gene-environment interactions" in which the same exposure of carcinogen results in altered target organ and tumor type, as a function of just 1 or 2 globally absent genes.
Menopausal hormone therapy and risk of colorectal cancer in the European Pros...
by Konstantinos K. Tsilidis, Naomi E. Allen, Timothy J. Key, Miguel A. SanJoaquin, Kjersti Bakken, Franco Berrino, Agnès Fournier, Eiliv Lund, Kim Overvad, Anja Olsen, Anne Tjønneland, Graham Byrnes, Veronique Chajes, Sabina Rinaldi, Marie-Christine Boutron-Ruault, Francoise Clavel-Chapelon, Jenny Chang-Claude, Rudolf Kaaks, Manuela Bergmann, Heiner Boeing, Yvoni Koumantaki, Domenico Palli, Valeria Pala, Salvatore Panico, Rosario Tumino, Paolo Vineis, H. Bas Bueno-de-Mesquita, Fränzel J.B. van Duijnhoven, Carla H. van Gils, Petra H.M. Peeters, Laudina Rodríguez, Carlos A. González, María-José Sánchez, Maria-Dolores Chirlaque, Aurelio Barricarte, Miren Dorronsoro, Kay-Tee Khaw, Sheila A. Rodwell, Teresa Norat, Dora Romaguera, Elio Riboli
9 Jun 2010 at 5:57am
Menopausal hormone therapy (HT) may influence colorectal cancer risk. A total of 136,275 postmenopausal women from the European Prospective Investigation into Cancer and Nutrition were followed for an average of 9 years, during which time 1,186 colorectal cancers were diagnosed. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models stratified by center and age, and adjusted for body mass index, smoking, diabetes, physical activity and alcohol consumption. Compared to never use of HT at study enrolment, current use of estrogen-only (HR, 1.02; 95% CI, 0.79-1.31) or estrogen plus progestin (HR, 0.94; 95% CI, 0.77-1.14) was not significantly associated with the risk of colorectal cancer, and these associations did not vary by recency, duration, route of administration, regimen or specific constituent of HT. Our results show no significant association of estrogen-only or estrogen plus progestin therapy with colorectal cancer risk.
Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant me...
by Richard P. Gallagher, Amy C. MacArthur, Tim K. Lee, Jean-Philippe Weber, Alain Leblanc, J. Mark Elwood, Marilyn Borugian, Zenaida Abanto, John J. Spinelli
9 Jun 2010 at 5:57am
A number of epidemiologic studies have suggested that exposure to polychlorinated biphenyls (PCB) and other organochlorine compounds (OCC) increase risk of cutaneous malignant melanoma (CMM). However, these studies have generally had no biologic measure of OCC exposure, and have been unable to control for sun exposure, the major known environmental risk factor for this disease. This preliminary study examined the relationship between OCC residues in plasma and risk of CMM adjusting for sun sensitivity and sun exposure. A case-control study of 80 CMM patients and 310 control subjects was conducted. Lifetime sun exposure information, along with data on pigmentation variables and sun sensitivity data was collected, along with a blood sample. Cases and controls were assayed for plasma levels of 14 PCB congeners and 11 organochlorine pesticide residues using gas chromatography. Strong associations were seen between risk of CMM and plasma levels of non-dioxin-like PCBs (Adjusted OR = 7.02; 95% CI: 2.30-21.43 for highest quartile) and several PCB congeners, organochlorine pesticides or metabolites. These associations persisted after control for sun sensitivity and sun exposure. Results from this investigation require independent confirmation in larger studies. However, they suggest that environmental factors other than UV radiation may play a role in genesis of CMM, and indicate that it may be productive to search for further agents which might increase risk.
Overexpression of carbonic anhydrase XII in tissues from resectable non-small...
by Marius I. Ilie, Véronique Hofman, Cécile Ortholan, Reda El Ammadi, Christelle Bonnetaud, Katia Havet, Nicolas Venissac, Jerôme Mouroux, Nathalie M. Mazure, Jacques Pouysségur, Paul Hofman
2 Jun 2010 at 2:31am
The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase XII (CAXII) is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation and enhanced expression is often present in several types of tumors. The aim of our study was to assess the prognostic significance of CAXII tumor tissues expression in patients with NSCLC. Five hundred fifty-five tumors were immunostained for CAXII on tissue microarrays (TMA) and the results were correlated with clinicopathological parameters and outcome of patients. CAXII overexpression was present in 105/555 (19%) cases and was associated with tumors of lower grade (p = 0.015) and histological type (p < 0.001), being significantly higher in squamous cell carcinoma. High CAXII expression correlated with better overall and disease-specific survival of patients with resectable NSCLC in univariate (p < 0.001) and multivariate survival analyses (p < 0.001). In conclusion, this is the first study demonstrating that a high CAXII tumor tissue expression evaluated on TMAs is related to a better outcome in a large series of patients with resectable NSCLC.
Antioxidant intake and risk of endometrial cancer: Results from the Nurses' H...
by Xiaohui Cui, Bernard Rosner, Walter C. Willett, Susan E. Hankinson
27 Apr 2010 at 2:42am
To investigate the associations between antioxidant intake and risk of endometrial cancer, the authors analyzed data from the prospective Nurses' Health Study. From 1980 to 2006, 669 invasive adenocarcinoma cases were identified over 1.3 million person-years of follow-up. Information on dietary intake was collected in 1980 and updated every 2-4 years. Cox proportional hazard models were used to calculate the multivariate relative risks (RR), controlling for total energy and potential risk factors for endometrial cancer. Overall, the authors found no association between intakes of vitamins A, C, E or carotenoids from foods or supplements and cancer risk. The RR and 95% confidence intervals (CI) for the highest vs. lowest quintiles of vitamins A, C, E and total carotenoids were 1.09 (95% CI: 0.85-1.39), 0.98 (95% CI: 0.76-1.25), 1.07 (95% CI: 0.83-1.38) and 1.12 (95% CI: 0.86-1.45), respectively. Similarly, the use of multivitamins or specific vitamins A, C or E supplements was unassociated with risk. In subgroup analyses, several associations seemed to vary by postmenopausal hormone use. Our results suggest that there is no overall association between dietary antioxidant intake or use of antioxidant supplements with risk of endometrial cancer.
Imatinib response in two GIST patients carrying two hitherto functionally unc...
by Palma Dileo, Sabrina Pricl, Elena Tamborini, Tiziana Negri, Silvia Stacchiotti, Alessandro Gronchi, Paola Posocco, Erik Laurini, Paola Coco, Elena Fumagalli, Paolo G. Casali, Silvana Pilotti
27 Apr 2010 at 2:43am
Beside the well known "in vivo" and "in vitro" Imatinib resistant D842V mutation in PDGFRA receptor, very few are the information concerning the "in vivo" Imatinib activity with respect to the other PDGFRA mutations for which only "in vitro" data are available. Two patients carrying PDGFRA mutations in exons 18 (involving residues DIMH842-845) and 12 (V561D), respectively, were treated with Imatinib at a dose of 400 mg/day. According to Response Evaluation Criteria in Solid Tumors criteria, after a median treatment of 7 months both patients showed clinical partial response, and underwent surgery of the minimal residual disease. Tumor response was confirmed pathologically. In both patients, analyses of PDGFRA performed on pre- and/or post-treatment material were compared to affinity data of the mutated receptor towards the inhibitor. Molecular modeling evidence was found to be consistent with sensitivity of mutated PDGFRA receptors to Imatinib. Thus, the "in vivo" evidence that these two mutations of PDGFRA are sensitive to Imatinib was confirmed by a multidimensional approach comprising "in silico" experiments that, in association to molecular and biochemical analyses, constitutes a powerful tool to predict Imatinib sensitivity, clinically beneficial in the treatment of these tumors with molecularly targeted therapies.
Autoregulation of phospholipase D activity is coupled to selective induction ...
by Dong Woo Kang, Mi Hee Park, Young Jun Lee, Hyung Sik Kim, Craig W. Lindsley, H. Alex Brown, Do Sik Min
19 Apr 2010 at 4:30am
Phospholipase D (PLD) is an important signaling enzyme implicated in the control of many biological processes, including cell proliferation and survival. Despite the importance of the duration and amplitude of PLD signaling in carcinogenesis, mechanisms that regulate PLD expression remain poorly understood. In our study, we define the regulatory components of the machinery that specifies selective PLD1 induction via signals propagated through PLD activity. We demonstrate for the first time that establishment of a positive feedback loop that is dependent on enzymatic activity originating from both PLD1 and PLD2 isozymes enhances selective expression of PLD1, but not PLD2. Phosphatidic acid, the product of PLD activity, leads to an increase in the Ras-ERK/PI3K-NF[kappa]B signaling cascade and enhances binding of NF[kappa]B to the PLD1 promoter, consequently inducing selective PLD1 expression in SK-BR3 breast cancer cells. Moreover, selective PLD inhibitor suppressed epidermal growth factor-induced matrix metalloproteinase upregulation and invasion by inhibiting PLD1 expression. In conclusion, we propose that autoregulation of PLD activity might be coupled to induction of PLD1 expression, and thereby play a role in carcinogenesis.
Coordinated epigenetic repression of the miR-200 family and miR-205 in invasi...
by Erik D. Wiklund, Jesper B. Bramsen, Toby Hulf, Lars Dyrskjøt, Ramshanker Ramanathan, Thomas B. Hansen, Sune B. Villadsen, Shan Gao, Marie S. Ostenfeld, Michael Borre, Marcus E. Peter, Torben F. Ørntoft, Jørgen Kjems, Susan J
13 May 2010 at 5:18am
MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.

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