Menée sur un modèle murin de carcinome hépatocellulaire, cette étude évalue la pertinence d'un modèle alternatif à l'hypothèse du double événement pour rendre compte de l'inactivation des gènes suppresseurs de tumeurs

A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions

Xue, Wen ; Kitzing, Thomas ; Roessler, Stephanie ; Zuber, Johannes ; Krasnitz, Alexander ; Schultz, Nikolaus ; Revill, Kate ; Weissmueller, Susann ; Rappaport, Amy R. ; Simon, Janelle ; Zhang, Jack ; Luo, Weijun ; Hicks, James ; Zender, Lars ; Wang, Xin Wei ; Powers, Scott ; Wigler, Michael ; Lowe, Scott W.

The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a “two-hit” mechanism in the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which [...]

A partir d'une analyse du nombre de copies de gènes dans 125 échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire et du séquençage des exons sur 24 de ces échantillons, cette étude française identifie des gènes et des voies de signalisation associés au développement de ce cancer

Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma

Guichard, Cecile ; Amaddeo, Giuliana ; Imbeaud, Sandrine ; Ladeiro, Yannick ; Pelletier, Laura ; Maad, Ichrafe Ben ; Calderaro, Julien ; Bioulac-Sage, Paulette ; Letexier, Melanie ; Degos, Francoise ; Clement, Bruno ; Balabaud, Charles ; Chevet, Eric ; Laurent, Alexis ; Couchy, Gabrielle ; Letouzé, Eric ; Calvo, Fabien ; Zucman-Rossi, Jessica

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, [...]

Cette étude évaue la pertinence d'un modèle "continu" pour rendre compte de la façon dont des mutations somatiques induisent le développement d'une tumeur

The continuum model of selection in human tumours: general paradigm or niche product?

Leedham, Simon ; Tomlinson, Ian

Berger et al recently proposed a "continuum" model of how somatic mutations cause tumours to grow, thus supplementing the established binary models such as oncogene activation and "two hits" at tumour suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the "fail-safe" model envisaged an optimum level of gene derangement for tumour growth, but that the cell [...]

A partir d'échantillons tumoraux prélevés sur 69 patientes chinoises atteintes d'un cancer de l'ovaire, cette étude identifie 4 tumeurs dans lesquelles la kinase ALK est surexprimée

Identification of Anaplastic Lymphoma Kinase as a Potential Therapeutic Target in Ovarian Cancer

Ren, Hong ; Tan, Zhi-Ping ; Zhu, Xin ; Crosby, Katherine ; Haack, Herbert ; Ren , Jian-Min ; Beausoleil, Sean ; Moritz, Albrecht ; Innocenti, Gregory ; Rush , John ; Zhang, Yi ; Zhou, Xin-Min ; Gu, Ting-Lei ; Yang, Yi-Feng ; Comb, Michael J

Ovarian cancer is the leading cause of death from gynecological cancer. Improvement in the clinical outcome of patients is likely to be achieved by the identification of molecular events that underlie the oncogenesis of ovarian cancer. Here we show that the anaplastic lymphoma kinase (ALK) is aberrantly activated in ovarian cancer. Using an unbiased and global phospho-proteomic approach, we profiled 69 Chinese primary ovarian tumor tissues and found ALK to be aberrantly expressed and [...]

Menée sur des échantillons de tumeurs et de tissus sains prélevés sur 8 patients atteints d'un cholangiosarcome associé au parasite Opisthorchis viverrini, cette étude de séquençage des exons identifie des gènes dont les mutations sont associées au développement de cette forme de cancer

Exome sequencing of liver fluke-associated cholangiocarcinoma

Ong, Choon Kiat ; Subimerb, Chutima ; Pairojkul, Chawalit ; Wongkham, Sopit ; Cutcutache, Ioana ; Yu, Willie ; McPherson, John R. ; Allen, George E. ; Ng, Cedric Chuan Young ; Wong, Bernice Huimin ; Myint, Swe Swe ; Rajasegaran, Vikneswari ; Heng, Hong Lee ; Gan, Anna ; Zang, Zhi Jiang ; Wu, Yingting ; Wu, Jeanie ; Lee, Ming Hui ; Huang, DaChuan ; Ong, Pauline ; Chan-on, Waraporn ; Cao, Yun ; Qian, Chao-Nan ; Lim, Kiat Hon ; Ooi, Aikseng ; Dykema, Karl ; Furge, Kyle ; Kukongviriyapan, Veerapol ; Sripa, Banchob ; Wongkham, Chaisiri ; Yongvanit, Puangrat ; Futreal, P. Andrew ; Bhudhisawasdi, Vajarabhongsa ; Rozen, Steve ; Tan, Patrick ; Teh, Bin Tean

Opisthorchis viverrini–related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini–related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 [...]

Menée sur des modèles murins, cette étude suggère que le gène Ncoa2/Src-2 joue un rôle de suppresseur de tumeurs dans les cancers du foie

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

O’Donnell, Kathryn A. ; Keng, Vincent W. ; York, Brian ; Reineke, Erin L. ; Seo, Daekwan ; Fan, Danhua ; Silverstein, Kevin A. T. ; Schrum, Christina T. ; Xie, Wei Rose ; Mularoni, Loris ; Wheelan, Sarah J. ; Torbenson, Michael S. ; O’Malley, Bert W. ; Largaespada, David A. ; Boeke, Jef D.

The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that [...]

Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire, cette étude suggère que la protéine SCYL1BP1 joue un rôle de suppresseur de tumeurs

SCYL1 binding protein 1 promotes the ubiquitin-dependent degradation of Pirh2 and has tumor suppressive function in the development of hepatocellular carcinoma

Hu, Liang ; Liu, Ming ; Chen, Leilei ; Chan, Tim Hon Man ; Wang, Jian ; Huo, Ke-Ke ; Zheng, Bo-Jian ; Xie, Dan ; Guan, Xin-Yuan

Pirh2 is a Ring-H2 domain containing E3 ubiquitin ligase which target several important tumor suppressor genes for proteasomal degradation. Overexpression of Pirh2 is frequently detected in many clinical tumor tissues including hepatocellular carcinoma (HCC). However, the molecular mechanism of Pirh2 activation in tumorigenesis still remains poorly understood. In the present study, we find a Pirh2 binding protein SCYL1 binding protein 1 (SCYL1BP1) can promote the ubiquitin-dependent degradation [...]

Menée à l'aide d'un modèle murin et de 261 échantillons tumoraux prélevés sur des patients atteints de cancer, cette étude évalue le rôle d'une surexpression du gène TRIM27 dans le développement d'un cancer

Role of the Tripartite Motif Protein 27 in Cancer Development

Zoumpoulidou, Georgia ; Broceño, Cristina ; Li, He ; Bird, Demelza ; Thomas, George ; Mittnacht, Sibylle

Background The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that interacts with, and attenuates senescence induction by, the retinoblastoma-associated protein (RB1). High expression of TRIM27 was noted in several human cancer types including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Here, we investigated the role of TRIM27 expression in cancer development.Methods We assessed TRIM27 expression in human cancer using [...]

Cet article passe en revue le rôle des facteurs de transcription "pionniers" dans le développement des cancers hormono-dépendants

Pioneer factors in hormone-dependent cancers

Jozwik, Kamila M. ; Carroll, Jason S.

Pioneer factors are a special class of transcription factor that can associate with compacted chromatin to facilitate the binding of additional transcription factors. The function of pioneer factors was originally described during development; more recently, they have been implicated in hormone-dependent cancers, such as oestrogen receptor-positive breast cancer and androgen receptor-positive prostate cancer. We discuss the importance of pioneer factors in these specific cancers, the discovery [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine nucléaire TRADD joue un rôle suppresseur de tumeur

TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation

Christine Chio, Iok In ; Sasaki, Masato ; Ghazarian, Danny ; Moreno, Juan ; Done, Susan ; Ueda, Takeshi ; Inoue, Satoshi ; Chang, Yu-Ling ; Chen, Nien Jung ; Mak, Tak Wah

Tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) protein is a central adaptor in the TNFR1 signalling complex that mediates both cell death and inflammatory signals. Here, we report that Tradd deficiency in mice accelerated tumour formation in a chemical-induced carcinogenesis model independently of TNFR1 signalling. In vitro, primary cells lacking TRADD were less susceptible to HRas-induced senescence and showed a reduced level of accumulation of the p19Arf tumour [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la sirtuine SIRT7 dans la régulation de la chromatine, les programmes de transformation cellulaire et la formation d'une tumeur

SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

Barber, Matthew F. ; Michishita-Kioi, Eriko ; Xi, Yuanxin ; Tasselli, Luisa ; Kioi, Mitomu ; Moqtaderi, Zarmik ; Tennen, Ruth I. ; Paredes, Silvana ; Young, Nicolas L. ; Chen, Kaifu ; Struhl, Kevin ; Garcia, Benjamin A. ; Gozani, Or ; Li, Wei ; Chua, Katrin F.

Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it [...]

Menée à l'aide d'un modèle murin et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel la protéine nucléaire Nupr1 favorise la tumorigenèse

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

Hamidi, Tewfik ; Algül, Hana ; Cano, Carla Eliana ; Sandi, Maria José ; Molejon, Maria Inés ; Riemann, Marc ; Calvo, Ezequiel Luis ; Lomberk, Gwen ; Dagorn, Jean-Charles ; Weih, Falk ; Urrutia, Raul ; Schmid, Roland Michael ; Iovanna, Juan Lucio

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic KrasG12D, we found that loss of Nupr1 protected from the development of pancreatic [...]

Cette étude suggère qu'une enzyme du métabolisme de la choline, EDI3, joue un rôle dans le processus métastatique des cancers de l'ovaire et de l'endomètre

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Stewart, Joanna D. ; Marchan, Rosemarie ; Lesjak, Michaela S. ; Lambert, Joerg ; Hergenroeder, Roland ; Ellis, James K. ; Lau, Chung-Ho ; Keun, Hector C. ; Schmitz, Gerd ; Schiller, Juergen ; Eibisch, Mandy ; Hedberg, Christian ; Waldmann, Herbert ; Lausch, Ekkehart ; Tanner, Berno ; Sehouli, Jalid ; Sagemueller, Jens ; Staude, Hagen ; Steiner, Eric ; Hengstler, Jan G.

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit [...]

Menée in vitro, à l'aide de xénogreffes et sur des échantillons tumoraux, cette étude met en évidence un mécanisme par lequel le micro-ARN 708, en régulant l'expression de CD44 dans les cellules souches cancéreuses, joue un rôle dans le développement et la progression d'un cancer de la prostate

miRNA-708 control of CD44+ prostate cancer initiating cells

Saini, Sharanjot ; Majid, Shahana ; Shahryari, Varahram ; Arora, Sumit ; Yamamura, Soichiro ; Chang, Inik ; Zaman, Mohd. Saif ; Deng, Guoren ; Tanaka, Yuichiro ; Dahiya, Rajvir

Tumor recurrence in prostate cancer (PCa) has been attributed to the presence of CD44 expressing tumor-initiating cells (TIC). In this study, we report that miR-708 is a key negative regulator of this CD44+ subpopulation of PCa cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44+ cells from PCa xenografts. Reconstitution of miR-708 in PCa cell lines or CD44+ PCa cells led to decreased tumorigenicity in vitro. Intratumoral delivery [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel la surexpression de la protéine HMGB1 favorise la prolifération des cellules de mésothéliome malin

Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma

Jube, Sandro ; Rivera, Zeyana ; Bianchi, Marco E ; Powers, Amy ; Wang, Ena ; Pagano, Ian S ; Pass, Harvey I ; Gaudino, Giovanni ; Carbone, Michele ; Yang, Haining

Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer that is believed to be caused by chronic exposure to asbestos and erionite. Prognosis for this cancer is generally poor due to late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern (DAMP) protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in MM cells that influences their [...]

Menée sur un modèle murin de cancer mammaire, cette étude met en évidence un mécanisme vasculaire par lequel la perte du gène HIF-1α dans les fibroblastes associés aux tumeurs accélère la croissance tumorale

Loss of fibroblast HIF-1α accelerates tumorigenesis

Kim, Jung-whan ; Evans, Colin ; Weidemann, Alexander ; Takeda, Norihiko ; Lee, Yun Sok ; Stockmann, Christian ; Branco-Price, Cristina ; Brandberg, Filip ; Leone, Gustavo ; Ostrowski, Michael C ; Johnson, Randall S.

Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, [...]

Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints de neuroblastome, cette étude met en évidence un mécanisme par lequel le micro-ARN 9, en régulant l'expression de la métalloprotéase matricielle MMP-14, inhibe les processus invasif et métastatique

microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis and angiogenesis of neuroblastoma cells

Zhang, Huanyu ; Qi, Meng ; Li, Shiwang ; Qi, Teng ; Mei, Hong ; Huang, Kai ; Zheng, Liduan ; Tong, Qiangsong

Matrix metalloproteinase 14 (MMP-14) is the only membrane anchored MMP that plays a critical role in tumor metastasis and angiogenesis. However, the mechanisms underlying MMP-14 expression in tumors still remain largely unknown. In this study, MMP-14 immunostaining was identified in 29/42 neuroblastoma (NB) tissues, which was correlated with clinicopathological features and shorter patients' survival. In subtotal twenty NB cases, microRNA 9 (miR-9) was down-regulated and inversely correlated [...]

Menée à l'aide de xénogreffes et d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude suggère que la protéine FRMD4A joue un rôle clé dans le processus métastatique

FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis

Goldie, Stephen J. ; Mulder, Klaas W. ; Tan, David Wei-Min ; Lyons, Scott K. ; Sims, Andrew H. ; Watt, Fiona M.

New therapeutic strategies are needed to improve treatment for head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here we report that FRMD4A upregulation occurs in primary human HNSCC where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in [...]