Dysregulation of the Splicing Machinery Is Associated to the Development of Nonalcoholic Fatty Liver Disease

Río-Moreno, Mercedes del; Alors‐Perez, Emilia; González-Rubio, Sandra; Ferrín, Gustavo; Reyes, Óscar; Rodríguez‐Perálvarez, Manuel; Sánchez-Frías, Marina; Sánchez‐Sánchez, Rafael; Ventura, Sebastián; López‐Miranda, José; Kineman, Rhonda D.; Mata, Manuel de la; Castaño, Justo P.; Gahete, Manuel D.; Luque, Raúl M.

doi:10.1210/jc.2019-00021

Cited by 55 publications

(46 citation statements)

References 56 publications

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“…Specific primers for human transcripts including components of the major spliceosome (n = 10), minor spliceosome (n = 4), associated SFs (n = 25) and three housekeeping genes (ACTB, GAPDH and HPRT) were specifically designed with the Primer3 software and StepOne TM Real-Time PCR System software v2.3 (Applied Biosystems, Foster City, CA, USA) (Supplemental Table 1). Preamplification, exonuclease treatment and qPCR dynamic array based on microfluidic technology were implemented as recently reported [11,12], following manufacturer's instructions using the Biomark System and the Real-Time PCR Analysis Software (Fluidigm). To control for variations in the efficiency of the retro-transcription reaction, mRNA copy numbers of the different transcripts analysed were adjusted by normalization factor, calculated with the expression levels of ACTB and GAPDH using GeNorm 3.3 [13].…”

Section: Qpcr Dynamic Array Based On Microfluidic Technologymentioning

confidence: 99%

“…Significant relation between categorized mRNA expression and biochemical PCa recurrence was studied using the long-rank-p-value method. Predictive models were constructed by Random Forest algorithm (with R language) as classifier as previously reported [11,12]. The rest of the statistical analyses were assessed using GraphPad Prism 7 (GraphPad Software, La Jolla, CA) or SPSS version 17.0.…”

Section: Statistical and Bioinformatic Analysesmentioning

confidence: 99%

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Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

et al. 2020

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Background: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored. Methods: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinicallylocalized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). Findings: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, T-Stage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/ DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK). Interpretation: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC.

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Section: Qpcr Dynamic Array Based On Microfluidic Technologymentioning

confidence: 99%

Section: Statistical and Bioinformatic Analysesmentioning

confidence: 99%

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

et al. 2020

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“…Such a model is well-established for other aggregation-prone RBPs in disease, including TDP-43 and FUS [21,63,64]. RBM45 regulates mRNA splicing and processing [3,65] and perturbing these functions may, therefore, have broad effects on gene expression and cellular physiology. Studies of RBM45's role in several biological processes support this prediction, showing that RBM45 regulates mitochondrial function [5], lipid metabolism [65], and the immune response [66].…”

Section: Discussionmentioning

confidence: 99%

“…RBM45 regulates mRNA splicing and processing [3,65] and perturbing these functions may, therefore, have broad effects on gene expression and cellular physiology. Studies of RBM45's role in several biological processes support this prediction, showing that RBM45 regulates mitochondrial function [5], lipid metabolism [65], and the immune response [66]. However, further studies into the RNA targets of RBM45 are needed to more precisely predict how loss of the protein's normal functions influences gene expression and other cellular and organismal phenotypes.…”

Section: Discussionmentioning

confidence: 99%

RBM45 associates with nuclear stress bodies and forms nuclear inclusions during chronic cellular stress and in neurodegenerative diseases

Collins

Bowser

2020

acta neuropathol commun

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The RNA binding protein (RBP) RBM45 forms nuclear and cytoplasmic inclusions in neurons and glia in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), and Alzheimer's disease (AD). The normal functions of RBM45 are poorly understood, as are the mechanisms by which it forms inclusions in disease. To better understand the normal and pathological functions of RBM45, we evaluated whether the protein functions via association with several membraneless organelles and whether such an association could promote the formation of nuclear RBM45 inclusions. Under basal conditions, RBM45 is diffusely distributed throughout the nucleus and does not localize to membraneless organelles, including nuclear speckles, Cajal bodies, or nuclear gems. During cellular stress, however, nuclear RBM45 undergoes a reversible, RNA-binding dependent incorporation into nuclear stress bodies (NSBs). Chronic stress leads to the persistent association of RBM45 with NSBs and the irreversible accumulation of nuclear RBM45 inclusions. We also quantified the cell type-and diseasespecific patterns of RBM45 pathology in ALS, FTLD-TDP, and AD. RBM45 nuclear and cytoplasmic inclusions are found in both neurons and glia in ALS, FTLD-TDP, and AD but are absent in non-neurologic disease controls. Across neurodegenerative diseases, RBM45 nuclear inclusion pathology occurs more frequently than cytoplasmic RBM45 inclusion pathology and exhibits cell type-specific variation. Collectively, our results define new stress-associated functions of RBM45, a mechanism for nuclear RBM45 inclusion formation, a role for NSBs in the pathogenesis of ALS, FTLD-TDP, and AD, and further underscore the importance of protein self-association to both the normal and pathological functions of RBPs in these diseases.

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“…Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease characterized by the accumulation of fat in the liver, which can be associated with obesity, and can progress to brosis, cirrhosis, and even liver cancer [1].NAFLD is considered as an important feature of metabolic syndrome and an important factor causing cardiovascular diseases. More studies have suggested that NAFLD is related to male sexual dysfunction and reproductive dysfunction [2].NAFLD has also been shown to be associated with poor metabolism and oxidative stress [3].Other studies have linked NAFLD to sedentary behavior and poor eating habits [4].NAFLD is one of the most common chronic liver diseases in developed countries [5].…”

Section: Introductionmentioning

confidence: 99%

Study on the Independent Effect of Thyroid Hormone Based on Uric Acid Level on NAFLD

Chao

Chen

2020

Preprint

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Objective:This study aims to further explain the correlation among NAFLD, hyperuricemia and thyroid function and to find independent risk factors for each other.Methods:Datas were obtained from subjects who underwent health examination in the Health promotion centre of Sir Run Run Shaw hospital of Zhejiang University from January 2017 to February 2019.The diagnosis of NAFLD was according to the clinical diagnosis of the Guidelines.Serum uric acid (SUA) >360 mol/L (female) and SUA>420 mol/L (male) were enrolled in the hyperuricemia group.R software was used for statistical analysis.Results:55,449 subjects were included in the analysis.Gender ratio, age, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, HbA1c, triglyceride, high-density lipoprotein, glutamate transaminase, glutamate transaminase, urea nitrogen, creatinine, FT3, FT4 and TSH were significantly different between the two groups.age, BMI, waist circumference, diastolic blood pressure, rapid blood glucose, HbA1c, total cholesterol, low-density lipoprotein, AST, and uric acid were all independent risk factors for NAFLD.In the normal uric acid group, variables other than systolic blood pressure and TSH were independent factors of NAFLD.In the hyperuricemia group, all variables except systolic blood pressure, FT4 and TSH were independent factors of NAFLD.Conclusion:The level of uric acid is related to the occurrence of NAFLD. Hyperuricemia is one of the independent risk factors of NAFLD.TSH level is not related to the occurrence of NAFLD, while FT3 and FT4 may be related to NAFLD.

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Dysregulation of the Splicing Machinery Is Associated to the Development of Nonalcoholic Fatty Liver Disease

Cited by 55 publications

References 56 publications

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

RBM45 associates with nuclear stress bodies and forms nuclear inclusions during chronic cellular stress and in neurodegenerative diseases

Study on the Independent Effect of Thyroid Hormone Based on Uric Acid Level on NAFLD

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