Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

AbstractThe functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3′ splice junctions. The presence of S34F caused a shift in cross-linking at 3′ splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.

Download Full-text

Hypoxia-induced TGF-β–RBFOX2–ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer

NAR Cancer ◽

10.1093/narcan/zcaa021 ◽

2020 ◽

Vol 2 (3) ◽

Cited By ~ 2

Author(s):

Neha Ahuja ◽

Cheemala Ashok ◽

Subhashis Natua ◽

Deepak Pant ◽

Anna Cherian ◽

...

Keyword(s):

Breast Cancer ◽

Alternative Splicing ◽

Transcriptional Repression ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Global Changes ◽

Invasion And Metastasis ◽

New Paradigm ◽

Mesenchymal Transition ◽

Splicing Regulator

Abstract Hypoxic microenvironment heralds epithelial–mesenchymal transition (EMT), invasion and metastasis in solid tumors. Deregulation of alternative splicing (AS) of several cancer-associated genes has been instrumental in hypoxia-induced EMT. Our study in breast cancer unveils a previously unreported mechanism underlying hypoxia-mediated AS of hMENA, a crucial cytoskeleton remodeler during EMT. We report that the hypoxia-driven depletion of splicing regulator ESRP1 leads to skipping of hMENA exon 11a producing a pro-metastatic isoform, hMENAΔ11a. The transcriptional repression of ESRP1 is mediated by SLUG, which gets stimulated via hypoxia-driven TGF-β signaling. Interestingly, RBFOX2, an otherwise RNA-binding protein, is also found to transcriptionally repress ESRP1 while interacting with SLUG. Similar to SLUG, RBFOX2 gets upregulated under hypoxia via TGF-β signaling. Notably, we found that the exosomal delivery of TGF-β contributes to the elevation of TGF-β signaling under hypoxia. Moreover, our results show that in addition to hMENA, hypoxia-induced TGF-β signaling contributes to global changes in AS of genes associated with EMT. Overall, our findings reveal a new paradigm of hypoxia-driven AS regulation of hMENA and insinuate important implications in therapeutics targeting EMT.

Download Full-text

LncRNA LINC01006 facilitates cell proliferation, migration and EMT in lung adenocarcinoma via targeting miR-129-2-3p/CTNNB1 axis and activating Wnt/β-catenin signaling pathway

Molecular and Cellular Biology ◽

10.1128/mcb.00380-20 ◽

2021 ◽

Author(s):

Yu Zhang ◽

Hailin Liu ◽

Qiang Zhang ◽

Zhenfa Zhang

Keyword(s):

Lung Adenocarcinoma ◽

Signaling Pathway ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Animal Experiments ◽

Luciferase Reporter ◽

Mesenchymal Transition

Lung adenocarcinoma (LUAD) is a common type of malignancy of lung cancers. Long intergenic non-coding RNAs (lincRNAs) have emerged as crucial regulators of various cancers, including LUAD. LINC01006 is a newly discovered lncRNA whose function in LUAD remains to be explored. This study is to explore the role of LINC01006 in LUAD. Quantitative real-time PCR (RT-qPCR) analysis and western blot were used to determine the expressions and protein levels respectively. Functional assays and animal experiments investigated the role of LINC01006 both in vivo and in vitro. Moreover, TOP/FOP assay was performed to detect the activation of Wnt/β-catenin signaling pathway. The interaction between LINC01006 and miR-129-2-3p/catenin beta 1 (CTNNB1) was explored by RNA binding protein immunoprecipitation (RIP), RNA pull down, luciferase reporter assays and rescue experiments. According to the results, LINC01006 was highly expressed in LUAD tissues and cell lines. LINC01006 knockdown significantly suppressed cell proliferative, migratory, epithelial-mesenchymal transition (EMT) capacities and the tumor development. Moreover, LINC01006 enhanced CTNNB1 via sequestering miR-129-2-3p and activated Wnt/β-catenin pathway in LUAD. Overall, LINC01006 promotes LUAD development via activating Wnt/β-catenin pathway, implying that LINC01006 might be a promising biomarker for LUAD treatment.

Download Full-text

Pathomorphology of the carcinomas

Medycyna Weterynaryjna ◽

10.21521/mw.5838 ◽

2018 ◽

Vol 74 (1) ◽

pp. 5-15

Author(s):

JANUSZ A. MADEJ

Keyword(s):

Cell Line ◽

Epithelial Mesenchymal Transition ◽

Functional Differentiation ◽

Mesenchymal Transition ◽

Expression Of Genes ◽

Cancer Types ◽

Specific Antigens

The paper describes the morphological and functional differentiation of cancer cells and mentions basic markers combined with that phenomenon. Table 1 presents cariotypic and immunophenotypic changes, neoplastic biomarkers and biological products present within the cells in selected cancer types. The authors also present changes in the cell cycle that leads to cancerogenesis with an emphasis put on the role of so-called genome guardians, i.e. TP53 and RB1 genes, and describe the main epigenetic factors, including the DNA methylation process in CDH1 (cadherin1) gene. The article also shows the morphologic types of proliferative changes: pre-cancer lesions (laesio praecancerosus), pre-cancer states (status praecancerosus) and pre-invasive carcinoma (carcinoma praeinvasivum, carcinoma in situ). A new classification of carcinomas is presented, including tumours originating from: a – a luminal epithelial-like cell line (with typical epithelial markers – E-cadherin, desmoplakin 1), b – a weakly luminal epithelial-like cell line (with a visibly weakened expression of epithelial antigenes) and c – a mesenchymal-like cell line (with the presence of proteins typical for mesenchymal cells – vimentin, N-cadherin, and lack of epithelial-specific antigens). Moreover, the authors extensively describe the so-called epithelial mesenchymal transition (EMT) that can be observed both in in vitro and in vivo conditions. The role of cancer-associated fibroblasts (CAFs) in that process is shown. The cells exhibit an increase in the expression of genes involved in adhesion and angiogenesis and an increased expression of neurotransmitter receptors (adrenaline, noradrenaline)....

Download Full-text

Magnesium Chloride is an Effective Therapeutic Agent for Prostate Cancer

Functional Foods in Health and Disease ◽

10.31989/ffhd.v8i1.368 ◽

2018 ◽

Vol 8 (1) ◽

pp. 62 ◽

Cited By ~ 2

Author(s):

Julianna Maria Santos ◽

Fazle Hussain

Keyword(s):

Prostate Cancer ◽

Magnesium Chloride ◽

Epithelial Mesenchymal Transition ◽

Chromatin Condensation ◽

Myosin Ii ◽

In Vivo Studies ◽

Migration Speed ◽

Mesenchymal Transition

Background: Reduced levels of magnesium can cause several diseases and increase cancer risk. Motivated by magnesium chloride’s (MgCl2) non-toxicity, physiological importance, and beneficial clinical applications, we studied its action mechanism and possible mechanical, molecular, and physiological effects in prostate cancer with different metastatic potentials.Methods: We examined the effects of MgCl2, after 24 and 48 hours, on apoptosis, cell migration, expression of epithelial mesenchymal transition (EMT) markers, and V-H+-ATPase, myosin II (NMII) and the transcription factor NF Kappa B (NFkB) expressions.Results: MgCl2 induces apoptosis, and significantly decreases migration speed in cancer cells with different metastatic potentials. MgCl2 reduces the expression of V-H+-ATPase and myosin II that facilitates invasion and metastasis, suppresses the expression of vimentin and increases expression of E-cadherin, suggesting a role of MgCl2 in reversing the EMT. MgCl2 also significantly increases the chromatin condensation and decreases NFkB expression.Conclusions: These results suggest a promising preventive and therapeutic role of MgCl2 for prostate cancer. Further studies should explore extending MgCl2 therapy to in vivo studies and other cancer types.Keywords: Magnesium chloride, prostate cancer, migration speed, V-H+-ATPase, and EMT.

Download Full-text

The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor Development

10.21236/ada612714 ◽

2014 ◽

Author(s):

Xin-Hai Pei

Keyword(s):

Mammary Gland ◽

Epithelial Mesenchymal Transition ◽

Tumor Development ◽

Mesenchymal Transition

Download Full-text

Effect of Annexins Translocated in Extracellular Vesicles on Tumorigenesis

Current Molecular Medicine ◽

10.2174/1566524020666200825163512 ◽

2020 ◽

Vol 20 ◽

Author(s):

Qionghui Wu ◽

Haidong Wei ◽

Wenbo Meng ◽

Xiaodong Xie ◽

Zhenchang Zhang ◽

...

Keyword(s):

Tumor Cells ◽

Extracellular Vesicles ◽

Immune Cell ◽

Epithelial Mesenchymal Transition ◽

Main Role ◽

Tumor Cell Adhesion ◽

Mesenchymal Transition ◽

Calcium Dependent ◽

Tumor Neovascularization

: Annexin, a calcium-dependent phospholipid binding protein, can affect tumor cell adhesion, proliferation, apoptosis, invasion and metastasis, as well as tumor neovascularization in different ways. Recent studies have shown that annexin exists not only as an intracellular protein in tumor cells, but also in different ways to be secret outside the cell as a “crosstalk” tool for tumor cells and tumor microenvironment, thus playing an important role in the development of tumors, such as participating in epithelial-mesenchymal transition, regulating immune cell behavior, promoting neovascularization and so on. The mechanism of annexin secretion in the form of extracellular vesicles and its specific role is still unclear. This paper summarizes the main role of annexin secreted into the extracellular space in the form of extracellular vesicles in tumorigenesis and drug resistance and analyzes its possible mechanism.

Download Full-text