Cet article passe en revue les travaux récents sur le rôle joué par des protéines de liaison à l'élément cytoplasmique de polyadénylation (CEPB) dans la régulation du cycle cellulaire, la tumorigenèse et le processus métastatique

Translational control of cell growth and malignancy by the CPEBs

D'Ambrogio, Andrea ; Nagaoka, Kentaro ; Richter, Joel D.

The cytoplasmic polyadenylation element binding proteins (CPEBs) associate with specific sequences in mRNA 3′ untranslated regions to promote translation. They do so by inducing cytoplasmic polyadenylation, which requires specialized poly(A) polymerases. Aberrant expression of these proteins correlates with certain types of cancer, indicating that cytoplasmic RNA 3′ end processing is important in the control of growth. Several CPEB-regulated mRNAs govern cell cycle progression, regulate [...]

Cet article passe en revue les travaux récents sur le rôle d'un mécanisme métabolique, l'oxydation des acides gras, dans le fonctionnement des cellules cancéreuses

Cancer metabolism: fatty acid oxidation in the limelight

Carracedo, Arkaitz ; Cantley, Lewis C. ; Pandolfi, Pier Paolo

Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the 'metabolic switch' in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a [...]

Menée à l'aide d'une méhode bioinformatique sur 88 cultures cellulaires de mélanome, cette étude met en évidence un mécanisme anti-apoptotique par lequel la voie de signalisation MITF-BCL2A1 favorise la croissance tumorale et la résistance des cellules cancéreuses à un traitement par inhibiteur de BRAF

BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition

Haq, Rizwan ; Yokoyama, Satoru ; Hawryluk, Elena B. ; Jönsson, Göran B. ; Frederick, Dennie Tompers ; McHenry, Kevin ; Porter, Dale ; Tran, Thanh-Nga ; Love, Kevin T. ; Langer, Robert ; Anderson, Daniel G. ; Garraway, Levi A. ; Duncan, Lyn McDivitt ; Morton, Donald L. ; Hoon, Dave S. B. ; Wargo, Jennifer A. ; Song, Jun S. ; Fisher, David E.

Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, “driver” oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par la voie de signalisation PI3K/PDK1 dans les adénocarcinomes canalaires du pancréas induits par une activation du gène Kras

Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer

Eser, Stefan ; Reiff, Nina ; Messer, Marlena ; Seidler, Barbara ; Gottschalk, Kathleen ; Dobler, Melanie ; Hieber, Maren ; Arbeiter, Andreas ; Klein, Sabine ; Kong, Bo ; Michalski, Christoph W ; Schlitter, Anna Melissa ; Esposito, Irene ; Kind, Alexander J ; Rad, Lena ; Schnieke, Angelika E ; Baccarini, Manuela ; Alessi, Dario R ; Rad, Roland ; Schmid, Roland M ; Schneider, Günter ; Saur, Dieter

Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where [...]

Menée à l'aide d'un modèle murin et de bases de données d'expression de gènes, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de BRCA1, le gène TNRC9 favorise une forme agressive de cancer du sein

TNRC9 downregulates BRCA1 expression and promotes breast cancer aggressiveness

Shan, Jingxuan ; DSousza, Shoba P. ; Bakhru, Sasha ; Al-Azwani, Eman K. ; Ascierto, Maria L. ; Sastry, Konduru S. ; Bedri, Shahinaz ; Kizhakayil, Dhanya ; Aigha, Idil I. ; Malek, Joel ; Al-Bozom, Issam ; Gehani, Salah ; Furtado, Stacia ; Mathiew, Edith ; Wang, Ena ; Marincola, Francesco M. ; Chouchane, Lotfi

Although the linkage between germ-line mutations of BRCA1 and hereditary breast/ovarian cancers is well established, recent evidence suggests that altered expression of wild type BRCA1 might contribute to the sporadic forms of breast cancer. The breast cancer gene TNRC9 (TOX3) has been associated with disease susceptibility but its function is undetermined. Here we report that TNRC9 is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer. Gene amplification [...]

Menée sur des échantillons tumoraux prélevés sur 53 patients atteints d'un carcinome hépatocellulaire et à l'aide de modèles murins, cette étude met en évidence le rôle joué par la protéine SSX2IP dans le processus métastatique et la résistance thérapeutique

SSX2IP promotes metastasis and chemotherapeutic resistance of hepatocellular carcinoma

Li, Pu ; Lin, Ying ; Zhang, Yu ; Zhu, Zhenggang ; Huo, Keke

BACKGROUND:Synovial sarcoma, X breakpoint 2 interacting protein (SSX2IP), which has been identified as an acute myeloid leukemia associated antigen, is a potential target for leukemia immunotherapy. In rodents, its homologous gene, ADIP, plays an important role in the regulation of cell adhesion and migration, underlying its potential role in promoting metastasis of other cancers. METHODS:To investigate the correlation between the expression level of SSX2IP and the clinicopathologic factors of [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par une protéine se liant au récepteur HER2, PELO, dans la progression tumorale et le processus invasif

PELO negatively regulates HER receptor signalling and metastasis

Pedersen, K. ; Canals, F. ; Prat, A. ; Tabernero, J. ; Arribas, J.

The HER family is composed of four receptor tyrosine kinases, which are frequently deregulated in several types of cancer. Activated HER receptors initiate intracellular signalling pathways by attracting to the plasma membrane a plethora of adaptor and signalling molecules. Although there are more than a dozen HER-interacting proteins that regulate signal transduction and have been extensively studied, recent proteomic studies have shown the existence of many novel but largely uncharacterized [...]

Menée in vitro et sur des bases de données d'expression de gènes, cette étude met en évidence le rôle joué par le facteur de transcription HOXA1 dans le processus métastatique d'un mélanome

HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome

Wardwell-Ozgo, J. ; Dogruluk, T. ; Gifford, A. ; Zhang, Y. ; Heffernan, T. P. ; van Doorn, R. ; Creighton, C. J. ; Chin, L. ; Scott, K. L.

Melanoma is a highly lethal malignancy notorious for its aggressive clinical course and eventual resistance to existing therapies. Currently, we possess a limited understanding of the genetic events driving melanoma progression, and much effort is focused on identifying pro-metastatic aberrations or perturbed signaling networks that constitute new therapeutic targets. In this study, we validate and assess the mechanism by which homeobox transcription factor A1 (HOXA1), a pro-invasion oncogene [...]

Menée sur 40 échantillons prélevés à l'autopsie sur des patients atteints d'un adénocarcinome du pancréas, sur 14 échantillons prélevés lors d'une opération chirurgicale et sur 8 témoins, cette étude met en évidence des différences dans l'expression de mucines au cours de la progression du cancer

Aberrant expression of mucin core proteins and O-linked glycans associated with progression of pancreatic cancer

Remmers, Neeley ; Anderson, Judy M. ; Linde, Erin ; DiMaio, Dominick J ; Lazenby, Audrey ; Hans, Wandall ; Mandell, Ulla ; Clausen, Henrik ; Yu, Fang ; Hollingsworth, Michael A.

Purpose: Mucin expression is a common feature of most adenocarcinomas and features prominently in current attempts to improve diagnosis and therapy of pancreatic cancer and other adenocarcinomas. We investigated the expression of a number of mucin core proteins and associated O-linked glycans expressed in pancreatic adenocarcinoma (PA) - sialyl Tn (STn), Tn, T antigen, sialyl Lewis A (CA19-9), sialyl Lewis C (SLeC), Lewis X (LeX) and sialyl Lewis X (SLeX) - during the progression of pancreatic [...]

A partir de bases de données recueillies au cours d'autopsies, cette étude de modélisation mathématique identifie deux types de processus métastatique d'un cancer du poumon

Spreaders and sponges define metastasis in lung cancer: A Markov chain mathematical model

Newton, Paul K. ; Mason, Jeremy ; Bethel, Kelly ; Bazhenova, Lyudmila ; Nieva, Jorge ; Norton, Larry ; Kuhn, Peter

The classic view of metastatic cancer progression is that it is a unidirectional process initiated at the primary tumor site, progressing to variably distant metastatic sites in a fairly predictable, though not perfectly understood, fashion. A Markov chain Monte Carlo mathematical approach can determine a pathway diagram that classifies metastatic tumors as 'spreaders' or 'sponges' and orders the timescales of progression from site to site. In light of recent experimental evidence highlighting [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel le facteur de croissance des fibroblastes FGF19 favorise la progression d'un cancer de la prostate

The endocrine fibroblast growth factor FGF19 promotes prostate cancer progression

Feng, Shu ; Dakhova, Olga ; Creighton, Chad J. ; Ittmann, Michael M.

Prostate cancer (PCa) is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that FGF receptors are important in PCa initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21 and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require alpha-Klotho (KL) and/or beta-Klotho (KLB), two [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du gène YAP1, le micro-ARN 200a favorise le processus métastatique d'un cancer du sein

MicroRNA-200a Promotes Anoikis Resistance and Metastasis by Targeting YAP1 in Human Breast Cancer

Yu, San-Jian ; Hu, Jing-Ying ; Kuang, Xia-Ying ; Luo, Jian-Min ; Hou, Yi-Feng ; Di, Gen-Hong ; Wu, Jiong ; Shen, Zhen-Zhou ; Song, Hou-Yan ; Shao, Zhi-Ming

Purpose: The process of metastases involves the dissociation of cells from the primary tumor, penetration into the basement membrane, invasion, and exiting from the vasculature to seed and colonize distant tissues. miR-200a is involved in this multistep metastatic cascade. This study aimed to test the hypothesis that miR-200a promotes metastasis through increased anoikis resistance in breast cancer. Experimental Design: Breast cancer cells transfected with mimic or inhibitor for miR-200a were [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en interagissant avec le gène Arid4b, le micro-ARN 290 réprime le processus métastatique d'un cancer du sein

Inherited variation in miR-290 expression suppresses breast cancer progression by targeting the metastasis susceptibility gene Arid4b

Hunter, Kent W. ; Goldberger, Natalie ; Walker, Renard C. ; Kim, Chang Hee ; Winter, Scott

The metastatic cascade is a complex and extremely inefficient process with many barriers. Understanding this process is of critical importance since most cancer mortality is associated with metastatic disease. Recently, it has become evident that certain microRNAs (miRNAs) control metastasis, yet few studies have examined how germline variations that dysregulate these miRNAs may affect metastatic potential. To explore this possibility, highly metastatic MMTV-PyMT mice were crossed with AKXD [...]

Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur 295 patientes atteintes d'un cancer du sein sans envahissement ganglionnaire, cette étude met en évidence des mécanismes par lesquels la perte du gène FBP1 favorise une transition épithélio-mésenchymateuse dans les cancers du sein de type "basal-like"

Loss of FBP1 by Snail-Mediated Repression Provides Metabolic Advantages in Basal-like Breast Cancer

Dong, Chenfang ; Yuan, Tingting ; Wu, Yadi ; Wang, Yifan ; Fan, Teresa W M. ; Miriyala, Sumitra ; Lin, Yiwei ; Yao, Jun ; Shi, Jian ; Kang, Tiebang ; Lorkiewicz, Pawel ; St Clair, Daret ; Hung, Mien-Chie ; Evers, B.  Mark ; Zhou, Binhua P

The epithelial-mesenchymal transition (EMT) enhances cancer invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We show that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecule biosynthesis, formation of tetrameric PKM2, and [...]