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Rac1 melanoma

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https://www.readbyqxmd.com/read/28277539/epidermal-rac1-regulates-the-dna-damage-response-and-protects-from-uv-light-induced-keratinocyte-apoptosis-and-skin-carcinogenesis
#1
Jayesh Deshmukh, Ruth Pofahl, Ingo Haase
Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far...
March 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28210865/the-impact-of-melanoma-genetics-on-treatment-response-and-resistance-in-clinical-and-experimental-studies
#2
M Kunz, M Hölzel
Recent attempts to characterize the melanoma mutational landscape using high-throughput sequencing technologies have identified new genes and pathways involved in the molecular pathogenesis of melanoma. Apart from mutated BRAF, NRAS, and KIT, a series of new recurrently mutated candidate genes with impact on signaling pathways have been identified such as NF1, PTEN, IDH1, RAC1, ARID2, and TP53. Under targeted treatment using BRAF and MEK1/2 inhibitors either alone or in combination, a majority of patients experience recurrences, which are due to different genetic mechanisms such as gene amplifications of BRAF or NRAS, MEK1/2 and PI3K mutations...
February 16, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28052407/p21-activated-kinase-1-regulates-resistance-to-braf-inhibition-in-human-cancer-cells
#3
Mahamat Babagana, Sydney Johnson, Hannah Slabodkin, Wiam Bshara, Carl Morrison, Eugene S Kandel
BRAF is a commonly mutated oncogene in various human malignancies and a target of a new class of anti-cancer agents, BRAF-inhibitors (BRAFi). The initial enthusiasm for these agents, based on the early successes in the management of metastatic melanoma, is now challenged by the mounting evidence of intrinsic BRAFi-insensitivity in many BRAF-mutated tumors, by the scarcity of complete responses, and by the inevitable emergence of drug resistance in initially responsive cases. These setbacks put an emphasis on discovering the means to increase the efficacy of BRAFi and to prevent or overcome BRAFi-resistance...
January 4, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/27908735/unr-csde1-drives-a-post-transcriptional-program-to-promote-melanoma-invasion-and-metastasis
#4
Laurence Wurth, Panagiotis Papasaikas, David Olmeda, Nadine Bley, Guadalupe T Calvo, Santiago Guerrero, Daniela Cerezo-Wallis, Javier Martinez-Useros, María García-Fernández, Stefan Hüttelmaier, Maria S Soengas, Fátima Gebauer
RNA binding proteins (RBPs) modulate cancer progression through poorly understood mechanisms. Here we show that the RBP UNR/CSDE1 is overexpressed in melanoma tumors and promotes invasion and metastasis. iCLIP sequencing, RNA sequencing, and ribosome profiling combined with in silico studies unveiled sets of pro-metastatic factors coordinately regulated by UNR as part of RNA regulons. In addition to RNA steady-state levels, UNR was found to control many of its targets at the level of translation elongation/termination...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27890785/genomic-characterization-of-dysplastic-nevi-unveils-implications-for-diagnosis-of%C3%A2-melanoma
#5
Rachel D Melamed, Iraz T Aydin, Geena Susan Rajan, Robert Phelps, David N Silvers, Kevin J Emmett, Georg Brunner, Raul Rabadan, Julide Tok Celebi
A well-defined risk factor and precursor for cutaneous melanoma is the dysplastic nevus. These benign tumors represent clonal hyperproliferation of melanocytes that are in a senescent-like state, but with occasional malignant transformation events. To portray the mutational repertoire of dysplastic nevi in patients with the dysplastic nevus syndrome and to determine the discriminatory profiles of melanocytic nevi (including dysplastic nevi) from melanoma, we sequenced exomes of melanocytic nevi including dysplastic nevi (n = 19), followed by a targeted gene panel (785 genes) characterization of melanocytic nevi (n = 46) and primary melanomas (n = 42)...
November 24, 2016: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27846383/unrelenting-translation-unrestrains-melanoma-migration
#6
Ashani T Weeraratna, Myriam Gorospe
The cytoplasmic RNA-binding protein UNR influences key developmental processes by controlling mRNA turnover and translation initiation. In this issue of Cancer Cell, Wurth et al. report that UNR is highly expressed in melanoma and enhances invasion and metastasis at least partly by inducing translation elongation of VIM and RAC1 mRNAs.
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27715393/expression-of-kindlin-3-in-melanoma-cells-impedes-cell-migration-and-metastasis
#7
Chen Feng, Wei-Kiat Wee, Huizhi Chen, Li-Teng Ong, Jing Qu, Hui-Foon Tan, Suet-Mien Tan
Kindlins are a small family of 4.1-ezrin-radixin-moesin (FERM)-containing cytoplasmic proteins. Kindlin-3 is expressed in platelets, hematopoietic cells, and endothelial cells. Kindlin-3 promotes integrin activation, clustering and outside-in signaling. Aberrant expression of kindlin-3 was reported in melanoma and breast cancer. Intriguingly, kindlin-3 has been reported to either positively or negatively regulate cancer cell metastasis. In this study, we sought to clarify the expression of kindlin-3 in melanoma cells and its role in melanoma metastasis...
October 7, 2016: Cell Adhesion & Migration
https://www.readbyqxmd.com/read/27699663/impact-of-point-mutation-p29s-in-rac1-on-tumorigenesis
#8
Vidya Rajendran, Chandrasekhar Gopalakrishnan, Rituraj Purohit
A point mutation (P29S) in the RAS-related C3 botulinum toxin substrate 1 (RAC1) was considered to be a trigger for melanoma, a form of skin cancer with highest mortality rate. In this study, we have investigated the pathogenic role of P29S based on the conformational behavior of RAC1 protein toward guanosine triphosphate (GTP). Molecular interaction, molecular dynamics trajectory analysis (RMSD, RMSF, Rg, SASA, DSSP, and PCA), and shape analysis of binding pocket were performed to analyze the interaction energy and the dynamic behavior of native and mutant RAC1 at the atomic level...
November 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27575453/the-ig-vh-complementarity-determining-region-3-containing-rb9-peptide-inhibits-melanoma-cells-migration-and-invasion-by-interactions-with-hsp90-and-an-adhesion-g-protein-coupled-receptor
#9
Natalia Girola, Alisson L Matsuo, Carlos R Figueiredo, Mariana H Massaoka, Camyla F Farias, Denise C Arruda, Ricardo A Azevedo, Hugo P Monteiro, Pedro T Resende-Lara, Rodrigo L O R Cunha, Luciano Polonelli, Luiz R Travassos
The present work aims at investigating the mechanism of action of the Rb9 peptide, which contains the VHCDR 3 sequence of anti-sodium-dependent phosphate transport protein 2B (NaPi2B) monoclonal antibody RebMab200 and displayed antitumor properties. Short peptides corresponding to the hypervariable complementarity-determining regions (CDRs) of immunoglobulins have been associated with antimicrobial, antiviral, immunomodulatory and antitumor activities regardless of the specificity of the antibody. We have shown that the CDR derived peptide Rb9 induced substrate hyperadherence, inhibition of cell migration and matrix invasion in melanoma and other tumor cell lines...
August 26, 2016: Peptides
https://www.readbyqxmd.com/read/27487150/the-inhibitory-effect-of-7-7-dimethoxyagastisflavone-on-the-metastasis-of-melanoma-cells-via-the-suppression-of-f-actin-polymerization
#10
Ching-Min Lin, Yu-Ling Lin, Shu-Yi Ho, Pin-Rong Chen, Yi-Hsuan Tsai, Chen-Han Chung, Chia-Hsiang Hwang, Nu-Man Tsai, Shey-Cherng Tzou, Chun-Yen Ke, Jung Chang, Yi-Lin Chan, Yu-Shan Wang, Kwan-Hwa Chi, Kuang-Wen Liao
7,7"-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from Taxus x media cv. Hicksii, induces apoptotic and autophagic cell death. However, whether DMGF suppresses tumor metastasis is unclear. The aim of this study was to investigate the anti-metastatic activities of DMGF on the metastatic processes of melanoma cells in vivo and in vitro. A transwell assay showed that DMGF could effectively attenuate the motility of B16F10 cells, and the results of real-time PCR revealed that DMGF also suppressed the expressions of matrix metalloproteinase-2 (MMP-2)...
July 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27418645/erk-mapk-signaling-drives-overexpression-of-the-rac-gef-prex1-in-braf-and-nras-mutant-melanoma
#11
Meagan B Ryan, Alexander J Finn, Katherine H Pedone, Nancy E Thomas, Channing J Der, Adrienne D Cox
Recently, we identified that PREX1 overexpression is critical for metastatic but not tumorigenic growth in a mouse model of NRAS-driven melanoma. In addition, a PREX1 gene signature correlated with and was dependent on ERK MAPK activation in human melanoma cell lines. In the current study, the underlying mechanism of PREX1 overexpression in human melanoma was assessed. PREX1 protein levels were increased in melanoma tumor tissues and cell lines compared with benign nevi and normal melanocytes, respectively...
October 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27314100/mechanistic-insights-into-the-role-of-truncating-prex2-mutations-in-melanoma
#12
Yonathan Lissanu Deribe
PREX2 is a PTEN binding protein that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. We recently reported the molecular mechanism of tumorigenesis associated with PREX2 mutations: truncating PREX2 mutations activate its RAC1 guanine nucleotide exchanger activity leading to increased PI3K/AKT signaling and enhanced cell proliferation.
May 2016: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/27181209/microphthalmia-associated-transcription-factor-suppresses-invasion-by-reducing-intracellular-gtp-pools
#13
A Bianchi-Smiraglia, A Bagati, E E Fink, S Moparthy, J A Wawrzyniak, E K Marvin, S Battaglia, P Jowdy, M Kolesnikova, C E Foley, A E Berman, N I Kozlova, B C Lipchick, L M Paul-Rosner, W Bshara, J J Ackroyd, D S Shewach, M A Nikiforov
Melanoma progression is associated with increased invasion and, often, decreased levels of microphthalmia-associated transcription factor (MITF). Accordingly, downregulation of MITF induces invasion in melanoma cells; however, little is known about the underlying mechanisms. Here, we report for the first time that depletion of MITF results in elevation of intracellular GTP levels and increased amounts of active (GTP-bound) RAC1, RHO-A and RHO-C. Concomitantly, MITF-depleted cells display larger number of invadopodia and increased invasion...
January 5, 2017: Oncogene
https://www.readbyqxmd.com/read/27121131/hypoxia-promotes-rab5-activation-leading-to-tumor-cell-migration-invasion-and-metastasis
#14
Patricio Silva, Pablo Mendoza, Solange Rivas, Jorge Díaz, Carolina Moraga, Andrew F G Quest, Vicente A Torres
Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion...
May 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27111337/interplay-between-prex2-mutations-and-the-pi3k-pathway-and-its-effect-on-epigenetic-regulation-of-gene-expression-in-nras-mutant-melanoma
#15
Yonathan Lissanu Deribe
PREX2 is a PTEN interacting protein that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. Recently, we reported the mechanistic basis of melanomagenesis by PREX2 mutations. Truncating PREX2 mutations activate its guanine nucleotide exchange factor activity for its substrate RAC1. This leads to increased PI3K/AKT signaling associated with reduced DNA methylation and increased cell proliferation in NRAS-mutant melanoma. Here, we provide additional data that indicates a reciprocal regulation of PREX2 by PTEN whereby loss of PTEN results in a dramatic increase in expression of PREX2 at the protein level...
July 2, 2016: Small GTPases
https://www.readbyqxmd.com/read/26884185/truncating-prex2-mutations-activate-its-gef-activity-and-alter-gene-expression-regulation-in-nras-mutant-melanoma
#16
Yonathan Lissanu Deribe, Yanxia Shi, Kunal Rai, Luigi Nezi, Samir B Amin, Chia-Chin Wu, Kadir C Akdemir, Mozhdeh Mahdavi, Qian Peng, Qing Edward Chang, Kirsti Hornigold, Stefan T Arold, Heidi C E Welch, Levi A Garraway, Lynda Chin
PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2(E824)*) in vivo in the context of mutant NRAS...
March 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26873115/the-involvement-of-mutant-rac1-in-the-formation-of-invadopodia-in-cultured-melanoma-cells
#17
REVIEW
Or-Yam Revach, Sabina E Winograd-Katz, Yardena Samuels, Benjamin Geiger
In this article, we discuss the complex involvement of a Rho-family GTPase, Rac1, in cell migration and in invadopodia-mediated matrix degradation. We discuss the involvement of invadopodia in invasive cell migration, and their capacity to promote cancer metastasis. Considering the regulation of invadopodia formation, we describe studies that demonstrate the role of Rac1 in the metastatic process, and the suggestion that this effect is attributable to the capacity of Rac1 to promote invadopodia formation. This notion is demonstrated here by showing that knockdown of Rac1 in melanoma cells expressing a wild-type form of this GTPase, reduces invadopodia-dependent matrix degradation...
April 10, 2016: Experimental Cell Research
https://www.readbyqxmd.com/read/26782071/rhoa-mediates-the-expression-of-acidic-extracellular-ph-induced-matrix-metalloproteinase-9-mrna-through-phospholipase-d1-in-mouse-metastatic-b16-bl6-melanoma-cells
#18
Toyonobu Maeda, Satoshi Yuzawa, Atsuko Suzuki, Yuh Baba, Yukio Nishimura, Yasumasa Kato
Solid tumors are characterized by acidic extracellular pH (pHe). The present study examined the contribution of small GTP-binding proteins to phospholipase D (PLD) activation of acidic pHe-induced matrix metalloproteinase-9 (MMP-9) production. Acidic pHe-induced MMP-9 production was reduced by C3 exoenzyme, which inhibits the Rho family of GTPases; cytochalasin D, which inhibits actin reorganization; and simvastatin, which inhibits geranylgeranylation of Rho. Small interfering RNA (siRNA) against RhoA, but not against Rac1 or Cdc42, significantly inhibited acidic pHe induction of MMP-9...
March 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/26744134/targeted-next-generation-sequencing-reveals-unique-mutation-profile-of-primary-melanocytic-tumors-of-the-central-nervous-system
#19
Johannes van de Nes, Marco Gessi, Antje Sucker, Inga Möller, Mathias Stiller, Susanne Horn, Simone L Scholz, Carina Pischler, Nadine Stadtler, Bastian Schilling, Lisa Zimmer, Uwe Hillen, Richard A Scolyer, Michael E Buckland, Libero Lauriola, Torsten Pietsch, Andreas Waha, Dirk Schadendorf, Rajmohan Murali, Klaus G Griewank
Melanocytic tumors originating in the central nervous system (MT-CNS) are rare tumors that generally have a favorable prognosis, however malignant tumors do occur. Pathogenetically MT-CNS are not well characterized. Similar to uveal melanoma and blue nevi, they frequently harbor activating GNAQ or GNA11 mutations. Rare NRAS mutations have also been reported. Other mutations have not yet been described. We analyzed 19 MT-CNS, 7 uveal melanomas and 19 cutaneous melanomas using a targeted next generation sequencing approach analyzing 29 genes known to be frequently mutated in other melanocytic tumors (in particular uveal and cutaneous melanomas)...
May 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/26392417/mt1-mmp-dependent-repression-of-the-tumor-suppressor-spry4-contributes-to-mt1-mmp-driven-melanoma-cell-motility
#20
Khvaramze Shaverdashvili, Keman Zhang, Iman Osman, Kord Honda, Rauli Jobava, Barbara Bedogni
Metastatic melanoma is the deadliest of all skin cancers. Despite progress in diagnostics and treatment of melanoma, the prognosis for metastatic patients remains poor. We previously showed that Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) is one of the drivers of melanoma metastasis. Classically, MT1-MMP regulates a verity of cellular functions including cell-to-cell interaction and cell-to-matrix communication. Recently, MT1-MMP has been found to also modulate gene expression. To specifically assess MT1-MMP dependent gene regulation in melanoma, microarray gene expression analysis was performed in a melanoma cell line whose metastatic properties depend on the activity of MT1-MMP...
October 20, 2015: Oncotarget
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