scholarly journals STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Paula Granado-Martínez ◽  
Sara Garcia-Ortega ◽  
Elena González-Sánchez ◽  
Kimberley McGrail ◽  
Rafael Selgas ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Somatic Mutations ◽  
Human Cancer ◽  
Tumor Biology ◽  
Missense Mutations ◽  
Expression Of Genes ◽  
Promote Tumor Growth ◽  
Genes Encoding ◽  
Differential Gene ◽  
Somatic Mutant

AbstractElucidating the contribution of somatic mutations to cancer is essential for personalized medicine. STK11 (LKB1) appears to be inactivated in human cancer. However, somatic missense mutations also occur, and the role/s of these alterations to this disease remain unknown. Here, we investigated the contribution of four missense LKB1 somatic mutations in tumor biology. Three out of the four mutants lost their tumor suppressor capabilities and showed deficient kinase activity. The remaining mutant retained the enzymatic activity of wild type LKB1, but induced increased cell motility. Mechanistically, LKB1 mutants resulted in differential gene expression of genes encoding vesicle trafficking regulating molecules, adhesion molecules and cytokines. The differentially regulated genes correlated with protein networks identified through comparative secretome analysis. Notably, three mutant isoforms promoted tumor growth, and one induced inflammation-like features together with dysregulated levels of cytokines. These findings uncover oncogenic roles of LKB1 somatic mutations, and will aid in further understanding their contributions to cancer development and progression.

scholarly journals Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw

2021 ◽  
Author(s):  
Christine Hirschberger ◽  
Victoria A Sleight ◽  
Katharine E Criswell ◽  
Stephen J Clark ◽  
J Andrew Gillis
Keyword(s):  
Evolutionary Biology ◽  
Gill Arch ◽  
Dorsoventral Patterning ◽  
Pharyngeal Arches ◽  
Mandibular Arch ◽  
Serial Homology ◽  
Expression Of Genes ◽  
Developmental Patterning ◽  
Genes Encoding ◽  
Differential Gene

Abstract The origin of the jaw is a long-standing problem in vertebrate evolutionary biology. Classical hypotheses of serial homology propose that the upper and lower jaw evolved through modifications of dorsal and ventral gill arch skeletal elements, respectively. If the jaw and gill arches are derived members of a primitive branchial series, we predict that they would share common developmental patterning mechanisms. Using candidate and RNAseq/differential gene expression analyses, we find broad conservation of dorsoventral patterning mechanisms within the developing mandibular, hyoid and gill arches of a cartilaginous fish, the skate (Leucoraja erinacea). Shared features include expression of genes encoding members of the ventralising BMP and endothelin signalling pathways and their effectors, the joint markers nkx3.2 and gdf5 and pro-chondrogenic transcription factor barx1, and the dorsal territory marker pou3f3. Additionally, we find that mesenchymal expression of eya1/six1 is an ancestral feature of the mandibular arch of jawed vertebrates, while differences in notch signalling distinguish the mandibular and gill arches in skate. Comparative transcriptomic analyses of mandibular and gill arch tissues reveal additional genes differentially expressed along the dorsoventral axis of the pharyngeal arches, including scamp5 as a novel marker of the dorsal mandibular arch, as well as distinct transcriptional features of mandibular and gill arch muscle progenitors and developing gill buds. Taken together, our findings reveal conserved patterning mechanisms in the pharyngeal arches of jawed vertebrates, consistent with serial homology of their skeletal derivatives, as well as unique transcriptional features that may underpin distinct jaw and gill arch morphologies.

scholarly journals RhoGDIα-dependent balance between RhoA and RhoC is a key regulator of cancer cell tumorigenesis

2011 ◽  
Vol 22 (17) ◽  
pp. 3263-3275 ◽  
Author(s):  
T. T. Giang Ho ◽  
Audrey Stultiens ◽  
Johanne Dubail ◽  
Charles M. Lapière ◽  
Betty V. Nusgens ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Progression ◽  
Dynamic Balance ◽  
Cellular Functions ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Interfering Rna

RhoGTPases are key signaling molecules regulating main cellular functions such as migration, proliferation, survival, and gene expression through interactions with various effectors. Within the RhoA-related subclass, RhoA and RhoC contribute to several steps of tumor growth, and the regulation of their expression affects cancer progression. Our aim is to investigate their respective contributions to the acquisition of an invasive phenotype by using models of reduced or forced expression. The silencing of RhoC, but not of RhoA, increased the expression of genes encoding tumor suppressors, such as nonsteroidal anti-inflammatory drug–activated gene 1 (NAG-1), and decreased migration and the anchorage-independent growth in vitro. In vivo, RhoC small interfering RNA (siRhoC) impaired tumor growth. Of interest, the simultaneous knockdown of RhoC and NAG-1 repressed most of the siRhoC-related effects, demonstrating the central role of NAG-1. In addition of being induced by RhoC silencing, NAG-1 was also largely up-regulated in cells overexpressing RhoA. The silencing of RhoGDP dissociation inhibitor α (RhoGDIα) and the overexpression of a RhoA mutant unable to bind RhoGDIα suggested that the effect of RhoC silencing is indirect and results from the up-regulation of the RhoA level through competition for RhoGDIα. This study demonstrates the dynamic balance inside the RhoGTPase network and illustrates its biological relevance in cancer progression.

scholarly journals Effect of hypoxia on the expression of genes encoding insulin-like growth factors and some related proteins in U87 glioma cells without IRE1 function

2016 ◽  
Vol 50 (2) ◽  
pp. 43-54 ◽  
Author(s):  
Dmytro O. Minchenko ◽  
A. P. Kharkova ◽  
O. V. Halkin ◽  
L. L. Karbovskyi ◽  
O. H. Minchenko
Keyword(s):  
Growth Factors ◽  
Tumor Growth ◽  
Metabolic Diseases ◽  
Glioma Cells ◽  
Hypoxic Condition ◽  
Enzyme Function ◽  
Igf2 Gene ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Insulin Like Growth Factors

AbstractObjective. The aim of the present study was to investigate the effect of hypoxia on the expression of genes encoding insulin-like growth factors (IGF1 and IGF2), their receptor (IGF1R), binding protein-4 (IGFBP4), and stanniocalcin 2 (STC2) in U87 glioma cells in relation to inhibition of endoplasmic reticulum stress signaling mediated by IRE1 (inositol requiring enzyme 1) for evaluation of their possible significance in the control of tumor growth. Methods. The expression of IGF1, IGF2, IGF1R, IGFBP4, and STC2 genes in U87 glioma cells transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia was studied by qPCR. Results. The expression of IGF1 and IGF2 genes is down-regulated in glioma cells without IRE1 signaling enzyme function in comparison with the control cells. At the same time, the expression of IGF1R, IGFBP4, and STC2 genes was up-regulated in glioma cells upon inhibition of IRE1, with more significant changes for IGFBP4 and STC2 genes. We also showed that hypoxia does not change significantly the expression of IGF1, IGF2, and IGF1R genes but up-regulated IGFBP4 and STC2 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in glioma cells does not change significantly the effect of hypoxia on the expression of IGF1, IGF1R, and IGFBP4 genes but introduces sensitivity of IGF2 gene to hypoxic condition. Thus, the expression of IGF2 gene is resistant to hypoxia only in control glioma cells and significantly down-regulated in cells without functional activity of IRE1 signaling enzyme, which is central mediator of the unfolded protein response and an important component of the tumor growth as well as metabolic diseases. Conclusions. Results of this study demonstrate that the expression of IGF1 and IGF1R genes is resistant to hypoxic condition both in control U87 glioma cells and cells without IRE1 signaling enzyme function. However, hypoxia significantly up-regulates the expression of IGFBP4 gene independently on the inhibition of IRE1 enzyme. These data show that proteins encoded by these genes are resistant to hypoxia except IGFBP4 and participate in the regulation of metabolic and proliferative processes through IRE1 signaling.

scholarly journals Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw

2021 ◽  
Author(s):  
Christine Hirschberger ◽  
Victoria A. Sleight ◽  
Katharine E. Criswell ◽  
Stephen J. Clark ◽  
J. Andrew Gillis
Keyword(s):  
Evolutionary Biology ◽  
Gill Arch ◽  
Dorsoventral Patterning ◽  
Pharyngeal Arches ◽  
Mandibular Arch ◽  
Serial Homology ◽  
Expression Of Genes ◽  
Developmental Patterning ◽  
Genes Encoding ◽  
Differential Gene

AbstractThe origin of the jaw is a long-standing problem in vertebrate evolutionary biology. Classical hypotheses of serial homology propose that the upper and lower jaw evolved through modifications of dorsal and ventral gill arch skeletal elements, respectively. If the jaw and gill arches are derived members of a primitive branchial series, we predict that they would share common developmental patterning mechanisms. Using candidate and RNAseq/differential gene expression analyses, we find broad conservation of dorsoventral patterning mechanisms within the developing mandibular, hyoid and gill arches of a cartilaginous fish, the skate (Leucoraja erinacea). Shared features include expression of genes encoding members of the ventralising BMP and endothelin signalling pathways and their effectors, the joint markers bapx1 and gdf5 and pro-chondrogenic transcription factors barx1 and gsc, and the dorsalising transcription factor pou3f3. Additionally, we find that mesenchymal expression of eya1/six1 is an ancestral feature of the mandibular arch of jawed vertebrates, while differences in notch signalling distinguish the mandibular and gill arches in skate. Comparative transcriptomic analyses of mandibular and gill arch tissues reveal additional genes differentially expressed along the dorsoventral axis of the pharyngeal arches, including scamp5 as a novel marker of the dorsal mandibular arch, as well as distinct transcriptional features of mandibular and gill arch muscle progenitors and developing gill buds. Taken together, our findings reveal conserved patterning mechanisms in the pharyngeal arches of jawed vertebrates, consistent with serial homology of their skeletal derivatives, as well as unique transcriptional features that may underpin distinct jaw and gill arch morphologies.

scholarly journals Downregulated pseudogene CTNNAP1 promote tumor growth in human cancer by downregulating its cognate gene CTNNA1 expression

Oncotarget ◽  
2016 ◽  
Vol 7 (34) ◽  
pp. 55518-55528 ◽  
Author(s):  
Xiangjian Chen ◽  
Hua Zhu ◽  
Xiaoli Wu ◽  
Xuemeng Xie ◽  
Guanli Huang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Human Cancer ◽  
Promote Tumor Growth ◽  
Cognate Gene

scholarly journals 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations

2019 ◽  
Vol 3 (s1) ◽  
pp. 103-103 ◽  
Author(s):  
Divya R Nair ◽  
Elizabeth Bhoj
Keyword(s):  
Somatic Mutations ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Germline Mutations ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Repair Gene ◽  
Histone 3 ◽  
Expression Of Genes ◽  
Dna Repair Gene

OBJECTIVES/SPECIFIC AIMS: Histones are nuclear proteins that associate with DNA to facilitate packaging into condensed chromatin. Histones are dynamically decorated with post-translational modifications (PTMs), which regulate such processes as DNA repair, gene expression, mitosis, and meiosis. Histone 3 Family 3 (H3F3) histones (H3.3), encoded by H3F3A and H3F3B, mark active genes, maintain epigenetic memory, and maintain heterochromatin and telomeric integrity. Specific somatic mutations in H3F3A and H3F3B have been strongly associated with pediatric glia and other tumors, but no germline mutations have been reported. The goal of our study was to further understand the functional effects of germline mutations of H3F3A and H3F3B. METHODS/STUDY POPULATION: We analyzed 32 patients bearing de novo germline missense mutations in H3F3A or H3F3B with core phenotypes of progressive neurologic dysfunction and congenital anomalies, but no malignancies. Patient histones were analyzed by quantitative mass spectrometry (qMS). RESULTS/ANTICIPATED RESULTS: qMS results revealed that the mutant histone proteins are present at a concentration similar to that of wild-type H3.3. qMS analysis showed strikingly aberrant PTM patterns that suggested local dysregulation. These patterns are distinct from the dominant negative somatic mutations, which cause more global PTM dysregulation. Patient cells also demonstrated upregulation of the expression of genes related to mitosis and cell division, and had a greater proliferative capacity. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggests that the pathogenic mechanism of germline histone mutations is distinct from that of the published cancer-associated somatic histone mutations, but may converge on control of cell proliferation. Further clarification of the pathophysiology in these patients can elucidate the roles of histones and histone PTMs in human development and non-syndromic neurodegeneration. In addition, it provides a framework for targeted therapy development for this and related progressive neurologic disorders.

scholarly journals Stimulation of MC38 tumor growth by insulin analog X10 involves the serine synthesis pathway

2012 ◽  
Vol 19 (4) ◽  
pp. 557-574 ◽  
Author(s):  
Henning Hvid ◽  
Sarah-Maria Fendt ◽  
Marie-José Blouin ◽  
Elena Birman ◽  
Gregory Voisin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Insulin Analog ◽  
Insulin Analogs ◽  
Isotopic Tracers ◽  
Expression Of Genes ◽  
Increased Risk ◽  
Genes Encoding ◽  
Growth Promoting

Recent evidence suggests that type II diabetes is associated with increased risk and/or aggressive behavior of several cancers, including those arising from the colon. Concerns have been raised that endogenous hyperinsulinemia and/or exogenous insulin and insulin analogs might stimulate proliferation of neoplastic cells. However, the mechanisms underlying possible growth-promoting effects of insulin and insulin analogs in cancer cellsin vivo, such as changes in gene expression, are incompletely described. We observed that administration of the insulin analog X10 significantly increased tumor growth and proliferation in a murine colon cancer model (MC38 cell allografts). Insulin and X10 altered gene expression in MC38 tumors in a similar fashion, but X10 was more potent in terms of the number of genes influenced and the magnitude of changes in gene expression. Many of the affected genes were annotated to metabolism, nutrient uptake, and protein synthesis. Strikingly, expression of genes encoding enzymes in the serine synthesis pathway, recently shown to be critical for neoplastic proliferation, was increased following treatment with insulin and X10. Using stable isotopic tracers and mass spectrometry, we confirmed that insulin and X10 increased glucose contribution to serine synthesis in MC38 cells. The data demonstrate that the tumor growth-promoting effects of insulin and X10 are associated with changes in expression of genes involved in cellular energy metabolism and reveal previously unrecognized effects of insulin and X10 on serine synthesis.

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