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Rac1 melanoma

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
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...
October 3, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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
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
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 mitogen-activated protein kinase (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...
July 14, 2016: Molecular Cancer Research: MCR
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
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...
May 16, 2016: Oncogene
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
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
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
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
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
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
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
A Hunter Shain, Maria Garrido, Thomas Botton, Eric Talevich, Iwei Yeh, J Zachary Sanborn, Jongsuk Chung, Nicholas J Wang, Hojabr Kakavand, Graham J Mann, John F Thompson, Thomas Wiesner, Ritu Roy, Adam B Olshen, Alexander Gagnon, Joe W Gray, Nam Huh, Joe S Hur, Klaus J Busam, Richard A Scolyer, Raymond J Cho, Rajmohan Murali, Boris C Bastian
Desmoplastic melanoma is an uncommon variant of melanoma with sarcomatous histology, distinct clinical behavior and unknown pathogenesis. We performed low-coverage genome and high-coverage exome sequencing of 20 desmoplastic melanomas, followed by targeted sequencing of 293 genes in a validation cohort of 42 cases. A high mutation burden (median of 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers. Mutation patterns strongly implicate ultraviolet radiation as the dominant mutagen, indicating a superficially located cell of origin...
October 2015: Nature Genetics
Andreia F A Henriques, Patrícia Barros, Mary Pat Moyer, Paulo Matos, Peter Jordan
Mutations in the BRAF oncogene have been identified as a tumor-initiating genetic event in mainly melanoma, thyroid and colon cancer, resulting in an initial proliferative stimulus that is followed by a growth arrest period known as oncogene-induced senescence (OIS). It remains unknown what triggers subsequent escape from OIS to allow further tumor progression. A previous analysis revealed that around 80% of colorectal tumors carrying a mutation in BRAF also overexpress splice variant Rac1b. We used normal NCM460 colonocytes as a model to express oncogenic B-Raf-V600E in the presence or absence of co-transfected Rac1b and then analyzed the effect on expression of senescence markers...
December 28, 2015: Cancer Letters
Jean-Claude Beani
Skin cancer is the most common human malignancy, and sunlight exposure is known to play a role in its genesis. Ultraviolet B (UVB) (300-320 nm) has long been considered responsible for the skin damage underlying these cancers, whereas the toxicity of UVA (320-400 nm) has been largely overlooked The intimate mechanisms of photocarcinogenicity remain poorly understood, but UV-induced DNA damage appears to be a major initiating event. Cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) photoproducts (6-4PPs) are the main dimeric lesions induced by UVB, whereas the genotoxic effects of UVA have long been attributed to oxidative damage, the main lesion being the oxidized base 8-oxo-7,8dihydroguanine (8-oxoGua)...
February 2014: Bulletin de L'Académie Nationale de Médecine
Edgardo Salvatierra, Mariano J Alvarez, Claudia C Leishman, Elvia Rivas Baquero, Viviana P Lutzky, H Eduardo Chuluyan, Osvaldo L Podhajcer
Cell transition to a more aggressive mesenchymal-like phenotype is a hallmark of cancer progression that involves different steps and requires tightly regulated cell plasticity. SPARC (Secreted Protein Acidic and Rich in Cysteine) is a matricellular protein that promotes this transition in various malignant cell types, including melanoma cells. We found that suppression of SPARC expression in human melanoma cells compromised cell migration, adhesion, cytoskeleton structure, and cell size. These changes involved the Akt/mTOR pathway...
2015: PloS One
Linlu Tian, Lixian Li, Wenjing Xing, Rui Li, Chunying Pei, Xiao Dong, Yanran Fu, Changcong Gu, Xize Guo, Yulong Jia, Guangyou Wang, Jinghua Wang, Bo Li, Huan Ren, Hongwei Xu
Melanoma is one of the most aggressive skin cancers and is well known for its high metastatic rate. Studies have shown that epithelial mesenchymal transition (EMT) is essential for melanoma cell metastasis. However, the molecular mechanisms underlying EMT are still not fully understood. We have shown that IRGM1, a member of immunity-related GTPase family that regulates immune cell motility, is highly expressed by melanoma cells. The current study aimed to explore whether and how IRGM1 may regulate melanoma cell metastasis...
2015: Scientific Reports
Ha Linh Vu, Sheera Rosenbaum, Timothy J Purwin, Michael A Davies, Andrew E Aplin
Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants...
September 2015: Pigment Cell & Melanoma Research
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