Hypoxia-induced alternative splicing in human diseases: the pledge, the turn, and the prestige

Natua, Subhashis; Ashok, Cheemala; Shukla, Sanjeev

doi:10.1007/s00018-020-03727-0

Cited by 15 publications

(20 citation statements)

References 162 publications

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“… 69 Accumulating evidence indicates that pre-mRNA splicing plays an essential role in the adaptation to hypoxic stress. 70 − 72 Hypoxia-induced alternative splicing of, for example, VEGF, Bcl-x, BNIP3, and CAIX, changes gene expression patterns to enhance proliferation and survival. 71 This may explain the ischemia-induced changes in phosphorylation of splicing-related proteins in our model.…”

Section: Discussionmentioning

confidence: 99%

Combined Quantitative (Phospho)proteomics and Mass Spectrometry Imaging Reveal Temporal and Spatial Protein Changes in Human Intestinal Ischemia–Reperfusion

et al. 2021

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Intestinal ischemia–reperfusion (IR) injury is a severe clinical condition, and unraveling its pathophysiology is crucial to improve therapeutic strategies and reduce the high morbidity and mortality rates. Here, we studied the dynamic proteome and phosphoproteome in the human intestine during ischemia and reperfusion, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to gain quantitative information of thousands of proteins and phosphorylation sites, as well as mass spectrometry imaging (MSI) to obtain spatial information. We identified a significant decrease in abundance of proteins related to intestinal absorption, microvillus, and cell junction, whereas proteins involved in innate immunity, in particular the complement cascade, and extracellular matrix organization increased in abundance after IR. Differentially phosphorylated proteins were involved in RNA splicing events and cytoskeletal and cell junction organization. In addition, our analysis points to mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase (CDK) families to be active kinases during IR. Finally, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MSI presented peptide alterations in abundance and distribution, which resulted, in combination with Fourier-transform ion cyclotron resonance (FTICR) MSI and LC-MS/MS, in the annotation of proteins related to RNA splicing, the complement cascade, and extracellular matrix organization. This study expanded our understanding of the molecular changes that occur during IR in the human intestine and highlights the value of the complementary use of different MS-based methodologies.

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Section: Discussionmentioning

confidence: 99%

Combined Quantitative (Phospho)proteomics and Mass Spectrometry Imaging Reveal Temporal and Spatial Protein Changes in Human Intestinal Ischemia–Reperfusion

et al. 2021

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“…It is unclear whether these results are due to the off-target effects of LW1497 or caused by the inhibition of malate dehydrogenase and subsequent inhibition of HIF-1α expression. However, since it is well known that RNA-processing mechanisms generally adapt to hypoxia, this phenomenon may also be due to the conversion from hypoxia to normoxia by LW1497 [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

LW1497, an Inhibitor of Malate Dehydrogenase, Suppresses TGF-β1-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells by Downregulating Slug

et al. 2021

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LW1497 suppresses the expression of the hypoxia-inducing factor (HIF)-1α inhibiting malate dehydrogenase. Although hypoxia and HIF-1α are known to be important in cancer, LW1497 has not been therapeutically applied to cancer yet. Thus, we investigated the effect of LW1497 on the epithelial-mesenchymal transition (EMT) of lung cancer cells. A549 and H1299 lung cancer cells were induced to undergo via TGF-β1 treatment, resulting in the downregulation of E-cadherin and upregulation of N-cadherin and Vimentin concurrently with increases in the migration and invasion capacities of the cells. These effects of TGF-β1 were suppressed upon co-treatment of the cells with LW1497. An RNA-seq analysis revealed that LW1497 induced differential expression of genes related to hypoxia, RNA splicing, angiogenesis, cell migration, and metastasis in the A549 lung cancer cell lines. We confirmed the differential expression of Slug, an EMT-related transcription factor. Results from Western blotting and RT-PCR confirmed that LW1497 inhibited the expression of EMT markers and Slug. After orthotopically transplanting A549 cancer cells into mice, LW1497 was administered to examine whether the lung cancer progression was inhibited. We observed that LW1497 reduced the area of cancer. In addition, the results from immunohistochemical analyses showed that LW1497 downregulated EMT markers and Slug. In conclusion, LW1497 suppresses cancer progression through the inhibition of EMT by downregulating Slug.

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“…As opposed to the traditional approaches, targeting hypoxia‐elicited RNA metabolism serves as an outstanding therapeutic strategy. Major therapeutic strategies against hypoxic RNA metabolism could be targeting HIFs (Semenza, 2019), inferring spliceosomal proteins and their kinases (Natua et al, 2021), targeting the factors involved in miRNA biogenesis (S. Lin & Gregory, 2015; G. Shen et al, 2013), and so on.…”

Section: Therapeutic Manipulation Of Tumor Microenvironment To Interv...mentioning

confidence: 99%

Interplay within tumor microenvironment orchestrates neoplastic RNA metabolism and transcriptome diversity

et al. 2021

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The heterogeneous population of cancer cells within a tumor mass interacts intricately with the multifaceted aspects of the surrounding microenvironment. The reciprocal crosstalk between cancer cells and the tumor microenvironment (TME) shapes the cancer pathophysiome in a way that renders it uniquely suited for immune tolerance, angiogenesis, metastasis, and therapy resistance. This dynamic interaction involves a dramatic reconstruction of the transcriptomic landscape of tumors by altering the synthesis, modifications, stability, and processing of gene readouts. In this review, we categorically evaluate the influence of TME components, encompassing a myriad of resident and infiltrating cells, signaling molecules, extracellular vesicles, extracellular matrix, and blood vessels, in orchestrating the cancer-specific metabolism and diversity of both mRNA and noncoding RNA, including micro RNA, long noncoding RNA, circular RNA among others. We also highlight the transcriptomic adaptations in response to the physicochemical idiosyncrasies of TME, which include tumor hypoxia, extracellular acidosis, and osmotic stress. Finally, we provide a nuanced analysis of existing and prospective therapeutics targeting TME to ameliorate cancer-associated RNA metabolism, consequently thwarting the cancer progression.

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Hypoxia-induced alternative splicing in human diseases: the pledge, the turn, and the prestige

Cited by 15 publications

References 162 publications

Combined Quantitative (Phospho)proteomics and Mass Spectrometry Imaging Reveal Temporal and Spatial Protein Changes in Human Intestinal Ischemia–Reperfusion

Combined Quantitative (Phospho)proteomics and Mass Spectrometry Imaging Reveal Temporal and Spatial Protein Changes in Human Intestinal Ischemia–Reperfusion

LW1497, an Inhibitor of Malate Dehydrogenase, Suppresses TGF-β1-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells by Downregulating Slug

Interplay within tumor microenvironment orchestrates neoplastic RNA metabolism and transcriptome diversity

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