Human molecular genetics最新文献_第3页

Study on the metastatic mechanism of LINC00115 in adenocarcinoma of the Esophagogastric junction. LINC00115在食管胃交界处腺癌中的转移机制研究

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-07 DOI: 10.1093/hmg/ddae193

Xia Zhao, Haifeng Zhang, Yangyang Liu, Li Li, Haitao Wei

{"title":"Study on the metastatic mechanism of LINC00115 in adenocarcinoma of the Esophagogastric junction.","authors":"Xia Zhao, Haifeng Zhang, Yangyang Liu, Li Li, Haitao Wei","doi":"10.1093/hmg/ddae193","DOIUrl":"10.1093/hmg/ddae193","url":null,"abstract":"Adenocarcinoma of the esophagogastric junction (AEG) is a common and deadly cancer, and an in-depth investigation of its molecular mechanisms of metastasis is crucial for discovering new therapeutic targets. This study explores the role of the long non-coding RNA (lncRNA) LINC00115 in AEG metastasis and its underlying mechanisms. Through the analysis of 108 pairs of AEG cancer tissues and matched adjacent tissues, we found a significant upregulation of LINC00115 in AEG tissues, closely associated with TNM staging and lymph node metastasis. Utilizing cell counting kit-8 (CCK-8) assays, colony formation experiments, wound healing assays, flow cytometry for apoptosis and cell cycle analysis, and Transwell assays, we have confirmed that LINC00115 significantly promotes proliferation, migration, and invasion of AEG cells in vitro. Animal experiments further validate the role of LINC00115 in promoting tumor growth and metastasis in vivo. Additionally, our nuclear-cytoplasmic fractionation experiments and RNA fluorescence in situ hybridization (FISH) reveal that LINC00115, along with its interacting protein KH-Type splicing regulatory protein (KHSRP), predominantly localizes to the cell nucleus. By conducting RNA pull-down assays and mass spectrometry (MS) analysis, we have identified a direct interaction between LINC00115 and KHSRP protein and further determined their binding sites through catRAPID and ENCORI databases. This study provides evidence of LINC00115 as a novel biomarker and potential therapeutic target for AEG and offers a fresh perspective on understanding the molecular mechanisms of AEG metastasis.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"492-511"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA. 在SMA小鼠模型中，心功能的改变与脂肪酸代谢的中断相关。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-07 DOI: 10.1093/hmg/ddaf006

Nithya N Nair, Rachel A Kline, Imogen Boyd, Meenakshi Anikumar, Adrian Thomson, Douglas J Lamont, Gillian A Gray, Thomas M Wishart, Lyndsay M Murray

{"title":"Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA.","authors":"Nithya N Nair, Rachel A Kline, Imogen Boyd, Meenakshi Anikumar, Adrian Thomson, Douglas J Lamont, Gillian A Gray, Thomas M Wishart, Lyndsay M Murray","doi":"10.1093/hmg/ddaf006","DOIUrl":"10.1093/hmg/ddaf006","url":null,"abstract":"Spinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/- mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/- mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/- mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/-, Smn-/-;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"547-562"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways. 肥胖相关的 MRAP2 变体会损害 MC4R 介导的多种信号通路。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-07 DOI: 10.1093/hmg/ddaf005

Rachael A Wyatt, Aqfan Jamaluddin, Vinesh Mistry, Caitlin Quinn, Caroline M Gorvin

{"title":"Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways.","authors":"Rachael A Wyatt, Aqfan Jamaluddin, Vinesh Mistry, Caitlin Quinn, Caroline M Gorvin","doi":"10.1093/hmg/ddaf005","DOIUrl":"10.1093/hmg/ddaf005","url":null,"abstract":"The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed at hypothalamic neurons that has an important role in appetite suppression and food intake. Mutations in MC4R are the most common cause of monogenic obesity and can affect multiple signaling pathways including Gs-cAMP, Gq, ERK1/2, β-arrestin recruitment, internalization and cell surface expression. The melanocortin-2 receptor accessory protein 2 (MRAP2), is a single-pass transmembrane protein that interacts with and regulates signaling by MC4R. Variants in MRAP2 have also been identified in overweight and obese individuals. However, functional studies that have only measured the effect of MRAP2 variants on MC4R-mediated cAMP signaling have produced inconsistent findings and most do not reduce MC4R function. Here we investigated the effect of twelve of these previously reported MRAP2 variants and showed that all variants that have been identified in overweight or obese individuals impair MC4R function. When expressed at equal concentrations, seven MRAP2 variants impaired MC4R-mediated cAMP signaling, while nine variants impaired IP3 signaling. Four mutations in the MRAP2 C-terminus affected internalization. MRAP2 variants had no effect on total or cell surface expression of either the MRAP2 or MC4R proteins. Structural models predicted that MRAP2 interacts with MC4R transmembrane helices 5 and 6, and mutations in two MRAP2 residues in putative contact sites impaired the ability of MRAP2 to facilitate MC4R signaling. In summary, our studies demonstrate that human MRAP2 variants associated with obesity impair multiple MC4R signaling pathways and that both Gs-cAMP and Gq-IP3 pathways should be assessed to determine variant pathogenicity.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"533-546"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insights into the molecular underpinning of type 2 diabetes complications. 洞察 2 型糖尿病并发症的分子基础。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-07 DOI: 10.1093/hmg/ddae203

Archit Singh, Ozvan Bocher, Eleftheria Zeggini

引用次数: 0

Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-05 DOI: 10.1093/hmg/ddaf032

Michelle L Brinkmeier, Leonard Y M Cheung, Sean P O'Connell, Diana K Gutierrez, Eve C Rhoads, Sally A Camper, Shannon W Davis

引用次数: 0

Mate-pair sequencing assisted prenatal counseling for a rare complex chromosomal rearrangement carrier.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-05 DOI: 10.1093/hmg/ddaf012

Lu Wan, Zeng Baitao, Tan Yuxin, Chen Zhongfa, Zhou Jihui, Huang Ning, Yang Bicheng, Huang Shuhui, Liu Yanqiu, Yuan Huizhen

引用次数: 0

A novel recurrent ARL3 variant c.209G > A p.(Gly70Glu) causes variable non-syndromic dominant retinal dystrophy with defective lipidated protein transport in human retinal stem cell models.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-03 DOI: 10.1093/hmg/ddaf029

Julio C Corral-Serrano, Veronika Vaclavik, Stijn Van de Sompele, Karolina Kaminska, Katarina Jovanovic, Pascal Escher, Filip Van den Broeck, Francesca Cancellieri, Vasileios Toulis, Bart P Leroy, Julie de Zaeytijd, Zhixuan You, Daniele Ottaviani, Mathieu Quinodoz, Gabriela Bordeanu, Alison J Hardcastle, Frauke Coppieters, Viet H Tran, Michael E Cheetham, Carlo Rivolta, Elfride De Baere

{"title":"A novel recurrent ARL3 variant c.209G > A p.(Gly70Glu) causes variable non-syndromic dominant retinal dystrophy with defective lipidated protein transport in human retinal stem cell models.","authors":"Julio C Corral-Serrano, Veronika Vaclavik, Stijn Van de Sompele, Karolina Kaminska, Katarina Jovanovic, Pascal Escher, Filip Van den Broeck, Francesca Cancellieri, Vasileios Toulis, Bart P Leroy, Julie de Zaeytijd, Zhixuan You, Daniele Ottaviani, Mathieu Quinodoz, Gabriela Bordeanu, Alison J Hardcastle, Frauke Coppieters, Viet H Tran, Michael E Cheetham, Carlo Rivolta, Elfride De Baere","doi":"10.1093/hmg/ddaf029","DOIUrl":"https://doi.org/10.1093/hmg/ddaf029","url":null,"abstract":"Inherited retinal dystrophies (IRDs) are characterized by their high clinical and genetic heterogeneity. Despite significant advances in the identification of genes associated with IRDs, many individuals and families still have not received a definite molecular diagnosis. Here, we performed clinical examinations and conducted genetic testing in five families with IRD. Whole exome sequencing in the five index cases revealed a heterozygous missense variant, c.209G > A, p.(Gly70Glu) in the ARL3 gene (NM_004311.4). A de novo occurrence was demonstrated in one affected individual and autosomal dominant inheritance in nine affected individuals from four families. Their phenotypes displayed variable expressivity, and ranged from rod-cone to cone-rod dystrophy with photophobia. Human induced pluripotent stem cells (hiPSCs) were generated from dermal fibroblasts from the individual with the de novo ARL3 variant and were differentiated to retinal pigment epithelium cells (RPE) and retinal organoids. Immunofluorescence analyses in these models showed decreased INPP5E localization within the cilia of RPE and connecting cilia of retinal organoids, as well as reduced PDE6⍺ in the organoid outer segments, suggesting that the p.(Gly70Glu) variant causes IRD by defective lipidated protein transport in photoreceptors and/or RPE. This is the first study of ARL3 dysfunction in human retinal cells, highlighting its importance for retinal homeostasis, as well as a variability in the clinical presentation of ARL3-associated IRD.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to: Expression variation of long noncoding RNAs in dopaminergic cells-derived from stem cells and their MPP+ induced PD models.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-03 DOI: 10.1093/hmg/ddaf034

引用次数: 0

New selective androgen receptor modulator TEI-SARM2 improves muscle function in a Duchenne muscular dystrophy rat model.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-28 DOI: 10.1093/hmg/ddaf028

Katsuyuki Nakamura, Masanobu Kanou, Wataru Fujii, Karina Kouzaki, Toshie Jimbo, Keitaro Yamanouchi, Koichi Nakazato, Hiroshi Ueda, Jun Hirata, Kei Yamana

{"title":"New selective androgen receptor modulator TEI-SARM2 improves muscle function in a Duchenne muscular dystrophy rat model.","authors":"Katsuyuki Nakamura, Masanobu Kanou, Wataru Fujii, Karina Kouzaki, Toshie Jimbo, Keitaro Yamanouchi, Koichi Nakazato, Hiroshi Ueda, Jun Hirata, Kei Yamana","doi":"10.1093/hmg/ddaf028","DOIUrl":"https://doi.org/10.1093/hmg/ddaf028","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by a genetic mutation in the Dmd gene. Dystrophin mutant mice (mdx) have traditionally been used for DMD research as a disease model in the preclinical stage; however, mdx mice exhibit only very mild phenotypes to partially mimic muscle degeneration and regeneration. To overcome this limitation in preclinical studies, DMD mutant rats (DMD rats) generated by CRISPR/Cas were used as a DMD model to exhibit age-dependent progressive muscle degeneration and pathophysiological features similar to DMD patients and more severe than those displayed by mdx mice. TEI-SARM2 is a non-steroidal, orally available selective androgen receptor modulator (SARM) developed as a pharmaceutical candidate for the treatment of muscle wasting diseases based on its potent anabolic activity on skeletal muscle mass. In this study, long-term treatment of daily oral administration of TEI-SARM2 to DMD rats significantly improved muscle function (endurance and strength) assessed by grip and tetanic force measurements. TEI-SARM2 did not increase the muscle weight of hindlimbs in male DMD rats; moreover, long-term, weekly oral administration for 24 weeks improved muscle function with reduced side effects on the prostate and testes weight. Histological analysis showed that TEI-SARM2 significantly reduced adipose tissue infiltration in DMD muscle. In female DMD rats, both daily and weekly TEI-SARM2 treatment showed anabolic effects and enhanced muscle strength and endurance. Taken together, these results indicate that TEI-SARM2 has non-anabolic and anabolic effects that improve dystrophic muscle dysfunction and can be a supportive therapeutic option for DMD.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-24 DOI: 10.1093/hmg/ddaf024

Yong Zhao, Guohong Shi, Xiang Huang, Zhongyuan Zhang, Kaijun Liao, Hao Xiong, Zhiqiang Feng, Shihui Mao, Xu Zhang

{"title":"LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop.","authors":"Yong Zhao, Guohong Shi, Xiang Huang, Zhongyuan Zhang, Kaijun Liao, Hao Xiong, Zhiqiang Feng, Shihui Mao, Xu Zhang","doi":"10.1093/hmg/ddaf024","DOIUrl":"https://doi.org/10.1093/hmg/ddaf024","url":null,"abstract":"Background: Advanced bladder cancer (bc) patients often have poor prognoses due to issues such as recurrence and drug resistance. The discovery of ferroptosis has opened new avenues for bc treatment; however, the specific regulatory mechanisms remain to be explored. This study aimed to investigate the mechanisms influencing ferroptosis in bc cells, with a particular focus on the role of low-density lipoprotein receptor-related protein 8 (LRP8).Methods: We utilized reverse transcription-quantitative polymerase chain reaction and western blot to assess the expression of LRP8 in bc cells, activation of the Wnt/β-catenin signaling pathway, and the expression of genes related to fatty acid synthesis. We measured changes in ferroptosis levels by evaluating mitochondrial membrane potential, Fe2+, malondialdehyde, and reactive oxygen species levels. A xenograft mouse model was employed to validate the impact of LRP8 on bc progression.Results: Cell experiments demonstrated a significant upregulation of LRP8 expression in bc cells. Knockdown of LRP8 induced ferroptosis in bc cells, a process directly triggered by the inhibition of the Wnt/β-catenin signaling pathway. Activation of the Wnt/β-catenin signaling pathway mediated by LRP8 upregulated the expression of stearoyl-CoA desaturase 1 (SCD1), subsequently leading to the suppression of ferroptosis. In vivo experiments indicated that LRP8 knockdown significantly impaired bc growth, accompanied by inhibition of the Wnt/β-catenin-SCD1 axis.Conclusion: LRP8 mediates the synthesis of monounsaturated fatty acids through the Wnt/β-catenin-SCD1 positive feedback loop, thereby inhibiting ferroptosis in bc cells. These findings provide a promising target for the regulation of ferroptosis in bc cells.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0