scholarly journals K-RAS4A: Lead or Supporting Role in Cancer Biology?

2021 ◽  
Vol 8 ◽  
Author(s):  
Veronica Aran
Keyword(s):  
Cancer Biology ◽  
Splice Variants ◽  
Human Cancer ◽  
Human Tissues ◽  
Gene Products ◽  
Ras Oncogene ◽  
Relevant Evidence ◽  
Leading Role ◽  
Oncogenic Mutations ◽  
Different Levels

The RAS oncogene is one of the most frequently mutated genes in human cancer, with K-RAS having a leading role in tumorigenesis. K-RAS undergoes alternative splicing, and as a result its transcript generates two gene products K-RAS4A and K-RAS4B, which are affected by the same oncogenic mutations, are highly homologous, and are expressed in a variety of human tissues at different levels. In addition, both isoforms localise to the plasma membrane by distinct targeting motifs. While some evidence suggests nonredundant functions for both splice variants, most work to date has focused on K-RAS4B, or even just K-RAS (i.e., without differentiating between the splice variants). This review aims to address the most relevant evidence published regarding K-RAS4A and to discuss if this “minor” isoform could also play a leading role in cancer, concluding that a significant body of evidence supports a leading role rather than a supporting (or secondary) role for K-RAS4A in cancer biology.

scholarly journals Oncogenic KRAS Drives Metabolic Vulnerabilities by Directly Regulating Metabolic Enzymes in Cancer

2020 ◽  
Vol 07 (01) ◽  
pp. 001-002
Author(s):  
Liyi Zhang
Keyword(s):  
Cancer Cells ◽  
Splice Variants ◽  
Human Cancer ◽  
Aerobic Glycolysis ◽  
Metabolic Enzymes ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Functional Differences ◽  
Oncogenic Mutations ◽  
Novel Therapeutic Strategies

AbstractMetabolic reprogramming, such as enhanced aerobic glycolysis, allows cancer cells to maintain viability and promote proliferation. It is one of the major consequences of oncogenic mutations. KRAS is the most frequently mutated oncogene in human cancer. It is thought to be closely related to metabolic reprogramming. However, it is not clear whether it can participate in metabolic reprogramming by directly regulating metabolic enzymes. Additionally, the functional differences among the splice variants of KRAS have not been determined. In a study, recently published in Nature, Amendola et al reported a unique interaction between one of the KRAS splice variants (KRAS4A) and the major glycolytic enzyme (hexokinase 1) in cancer cells. Their findings indicated that a better understanding on the regulation of hexokinase 1 by KRAS may reveal novel therapeutic strategies.

scholarly journals Finite mixture clustering of human tissues with different levels of IGF-1 splice variants mRNA transcripts

2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Michele Pelosi ◽  
Marco Alfò ◽  
Francesca Martella ◽  
Elisa Pappalardo ◽  
Antonio Musarò
Keyword(s):  
Splice Variants ◽  
Finite Mixture ◽  
Human Tissues ◽  
Mrna Transcripts ◽  
Different Levels

scholarly journals Expression of AR-V7 (Androgen Receptor Variant 7) Protein in Granular Cytoplasmic Structures Is an Independent Prognostic Factor in Prostate Cancer Patients

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2639
Author(s):  
Paul König ◽  
Markus Eckstein ◽  
Rudolf Jung ◽  
Amer Abdulrahman ◽  
Juan Guzman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Regression Analysis ◽  
Androgen Receptor ◽  
Prognostic Factor ◽  
Cancer Biology ◽  
Splice Variants ◽  
Independent Prognostic Factor ◽  
Cytoplasmic Granules ◽  
Cox's Regression ◽  
Cytoplasmic Structures

Prostate cancer (PCa) is the second most common cancer, causing morbidity and mortality among men world-wide. The expression of the androgen receptor (AR) and its splice variants is a crucial factor of prostate cancer biology that has not been comprehensively studied in PCa tumors. The aim of this study was to characterize the protein expression of the AR and its splice variant, AR-V7, and their subcellular distributions in PCa by immunohistochemistry and to correlate the results to the clinicopathological data and prognosis. Immunohistochemical staining for AR and AR-V7 was performed on a tissue microarray (TMA) with specimens from 410 PCa patients using an immunoreactive score (IRS) or only the percentage of AR-V7 staining in cytoplasmic granules. Nuclear or cytoplasmic AR staining was not associated with prognosis. AR-V7 staining was only occasionally observed in the nucleus. However, AR-V7 staining in the cytoplasm or in cytoplasmic granules was associated with relapse-free survival (RFS). AR-V7 staining of the cytoplasm was associated with a shorter RFS, whereas AR-V7 staining of cytoplasmic granules was associated with a longer RFS. In a multivariate Cox’s regression analysis, only negative (<5%) AR-V7 staining of cytoplasmic granules remained an independent prognostic factor for RFS (HR = 5.3; p = 0.006). In a further subgroup analysis by multivariate Cox’s regression analysis, AR-V7 was an independent prognostic factor in the following groups: age ≤ 65 (HR = 9.7; p = 0.029), negative CK20 staining (HR = 7.0; p = 0.008), and positive perineural invasion (HR = 3.7; p = 0.034). Altogether, AR-V7 protein in granular cytoplasmic structures is an independent prognostic factor for RFS in PCa patients.

scholarly journals HUMANIZED MICE: CREATION, MODELS AND USE IN EXPERIMENTAL ONCOLOGY (REVIEW)

Biomeditsina ◽  
2019 ◽  
pp. 67-81
Author(s):  
O. I. Kit ◽  
A. Yu. Maksimov ◽  
T. P. Protasova ◽  
A. S. Goncharova ◽  
D. S. Kutilin ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Human Cancer ◽  
Transgenic Animals ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Antitumour Agents ◽  
Human Genes ◽  
Oncology Review ◽  
Wide Range ◽  
Humanized Mouse Models

Research laboratories in various countries are constantly endeavouring to improve the existing and to create new biological objects to simulate various human diseases. Immunodefi cient mice with transplanted human functional cells and tissues, as well as transgenic animals with the relevant human genes integrated in their genome — i. e. humanized mice — are increasingly used as test systems in biomedical studies. Humanized mouse models are constantly being improved to fi nd application in studies investigating human biological reactions and identifying the pathogenetic mechanisms behind a wide range of diseases, or as preclinical tools for medicine testing. In particular, such animals play an increasingly important role both in studies of human-specifi c infectious agents, cancer biology research and in the development of new antitumour agents. In addition, humanized mice are increasingly used as translational models in many areas of clinical research, including transplantology, immunology and oncology. Ultimately, the use of humanized animals can lead to the introduction of a truly personalized medicine into clinical practice. In this review, we discuss modern advances in the creation and use of humanized mice, emphasizing their usefulness for the pathogenesis study, as well as the development of new methods for human cancer treatment.

scholarly journals SAM68: Signal Transduction and RNA Metabolism in Human Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Paola Frisone ◽  
Davide Pradella ◽  
Anna Di Matteo ◽  
Elisa Belloni ◽  
Claudia Ghigna ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Nuclear Export ◽  
Cell Biology ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Human Cancer ◽  
Rna Metabolism ◽  
Regulatory Sequences

Alterations in expression and/or activity of splicing factors as well as mutations incis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer.

Molecular profiling in cancer research and personalized medicine

2019 ◽  
pp. 347-362
Author(s):  
Pieter-Jan van Dam ◽  
Steven Van Laere
Keyword(s):  
Personalized Medicine ◽  
High Throughput ◽  
Cancer Biology ◽  
Complex Disease ◽  
Human Cancer ◽  
Molecular Profiling ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Molecular Heterogeneity ◽  
Profiling Techniques

Recent efforts by worldwide consortia such as The Cancer Genome Atlas and the International Cancer Genome Consortium have greatly accelerated our knowledge of human cancer biology. Nowadays, complete sets of human tumours that have been characterized at the genomic, epigenomic, transcriptomic, or proteomic level are available to the research community. The generation of these data was made possible thanks to the application of high-throughput molecular profiling techniques such as microarrays and next-generation sequencing. The primary conclusion from current profiling experiments is that human cancer is a complex disease characterized by extreme molecular heterogeneity, both between and within the classical, tissue-defined cancer types. This molecular variety necessitates a paradigm shift in patient management, away from generalized therapy schemes and towards more personalized treatments. This chapter provides an overview of how molecular cancer profiling can assist in facilitating this transition. First, the state-of-the-art of molecular breast cancer profiling is reviewed to provide a general background. Then, the most pertinent high-throughput molecular profiling techniques along with various data mining techniques (i.e. unsupervised clustering, statistical learning) are discussed. Finally, the challenges and perspectives with respect to molecular cancer profiling, also from the perspective of personalized medicine, are summarized.

Novel splice variants of the amyotrophic lateral sclerosis-associated gene VAPB expressed in human tissues

2010 ◽  
Vol 394 (3) ◽  
pp. 703-708 ◽  
Author(s):  
T. Nachreiner ◽  
M. Esser ◽  
V. Tenten ◽  
D. Troost ◽  
J. Weis ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Splice Variants ◽  
Human Tissues ◽  
Lateral Sclerosis

Blocking the mTOR pathway: a drug discovery perspective

2011 ◽  
Vol 39 (2) ◽  
pp. 451-455 ◽  
Author(s):  
Carlos Garcia-Echeverria
Keyword(s):  
Drug Discovery ◽  
Cancer Patients ◽  
Cancer Biology ◽  
Human Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mechanisms Of Action ◽  
Mtor Pathway ◽  
Lipid Kinase ◽  
Phosphoinositide 3 Kinase

Substantial drug discovery efforts have been devoted, over the last few years, to identifying and developing mTOR (mammalian target of rapamycin) kinase modulators. This has resulted in a number of mTOR inhibitors with different mechanisms of action and/or distinct protein and lipid kinase selectivity profiles. As briefly reviewed in the present paper, these compounds have provided us with a better understanding of the roles of mTOR and other phosphoinositide 3-kinase/mTOR pathway components in human cancer biology, and a few of them have already demonstrated clinical benefit in cancer patients.

Molecular Insights into Regulation of L-Type Ca Channel Function

Physiology ◽  
1991 ◽  
Vol 6 (6) ◽  
pp. 277-281 ◽  
Author(s):  
P Lory ◽  
G Varadi ◽  
A Schwartz
Keyword(s):  
Structure Function ◽  
Splice Variants ◽  
Ca Channel ◽  
Gene Products ◽  
Ca Channels ◽  
Channel Activity ◽  
Excitable Cells ◽  
Multiple Gene ◽  
Channel Function ◽  
Voltage Dependent

The diversity of voltage-dependent Ca channels is well documented. How excitable cells produce their specific Ca channel activity is being approached by structure-function studies. The implications of multiple gene products, splice variants, and subunit assembly in Ca channel function are updated in this review.

scholarly journals Biosystem Analysis of the Hypoxia Inducible Domain Family Member 2A: Implications in Cancer Biology

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 206 ◽  
Author(s):  
Celia Salazar ◽  
Osvaldo Yañez ◽  
Alvaro A. Elorza ◽  
Natalie Cortes ◽  
Olimpo García-Beltrán ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bone Marrow ◽  
Cancer Biology ◽  
Chromosomal Abnormalities ◽  
Human Cancer ◽  
Expression Profiles ◽  
Homology Modelling ◽  
B Cell Lymphoma ◽  
Qrt Pcr

The expression of HIGD2A is dependent on oxygen levels, glucose concentration, and cell cycle progression. This gene encodes for protein HIG2A, found in mitochondria and the nucleus, promoting cell survival in hypoxic conditions. The genomic location of HIGD2A is in chromosome 5q35.2, where several chromosomal abnormalities are related to numerous cancers. The analysis of high definition expression profiles of HIGD2A suggests a role for HIG2A in cancer biology. Accordingly, the research objective was to perform a molecular biosystem analysis of HIGD2A aiming to discover HIG2A implications in cancer biology. For this purpose, public databases such as SWISS-MODEL protein structure homology-modelling server, Catalogue of Somatic Mutations in Cancer (COSMIC), Gene Expression Omnibus (GEO), MethHC: a database of DNA methylation and gene expression in human cancer, and microRNA-target interactions database (miRTarBase) were accessed. We also evaluated, by using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), the expression of Higd2a gene in healthy bone marrow-liver-spleen tissues of mice after quercetin (50 mg/kg) treatment. Thus, among the structural features of HIG2A protein that may participate in HIG2A translocation to the nucleus are an importin α-dependent nuclear localization signal (NLS), a motif of DNA binding residues and a probable SUMOylating residue. HIGD2A gene is not implicated in cancer via mutation. In addition, DNA methylation and mRNA expression of HIGD2A gene present significant alterations in several cancers; HIGD2A gene showed significant higher expression in Diffuse Large B-cell Lymphoma (DLBCL). Hypoxic tissues characterize the “bone marrow-liver-spleen” DLBCL type. The relative quantification, by using qRT-PCR, showed that Higd2a expression is higher in bone marrow than in the liver or spleen. In addition, it was observed that quercetin modulated the expression of Higd2a gene in mice. As an assembly factor of mitochondrial respirasomes, HIG2A might be unexpectedly involved in the change of cellular energetics happening in cancer. As a result, it is worth continuing to explore the role of HIGD2A in cancer biology.

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