The Journal of Pathology最新文献

{"title":"CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer","authors":"Haiwei Mou,&nbsp;Onur Eskiocak,&nbsp;Kadir A. Özler,&nbsp;Megan Gorman,&nbsp;Junjiayu Yue,&nbsp;Ying Jin,&nbsp;Zhikai Wang,&nbsp;Ya Gao,&nbsp;Tobias Janowitz,&nbsp;Hannah V. Meyer,&nbsp;Tianxiong Yu,&nbsp;John E Wilkinson,&nbsp;Alper Kucukural,&nbsp;Deniz M. Ozata,&nbsp;Semir Beyaz","doi":"10.1002/path.6054","DOIUrl":"10.1002/path.6054","url":null,"abstract":"<p>CRISPR/Cas9-driven cancer modeling studies are based on the disruption of tumor suppressor genes by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of <i>Ctnnb1</i> (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms <i>in vivo</i>. CRISPR/Cas9-mediated exon skipping of <i>Ctnnb1</i> induces liver tumor formation in synergy with YAP^S127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAP^S127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar <i>CTNNB1</i> exon-skipping events in patients with hepatocellular carcinoma. Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, <i>in vivo</i>, to study gain-of-function mutations of oncogenes in cancer. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 4","pages":"415-427"},"PeriodicalIF":7.3,"publicationDate":"2023-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5700557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-CD40L therapy prevents the formation of precursor lesions to gastric B-cell MALT lymphoma in a mouse model","authors":"Le Ying,&nbsp;Phoebe Liu,&nbsp;Zhoujie Ding,&nbsp;Georgie Wray-McCann,&nbsp;Jack Emery,&nbsp;Nina Colon,&nbsp;Lena HM Le,&nbsp;Le Son Tran,&nbsp;Ping Xu,&nbsp;Liang Yu,&nbsp;Dana J Philpott,&nbsp;Yugang Tu,&nbsp;Daryl MZ Cheah,&nbsp;Chee L Cheng,&nbsp;Soon T Lim,&nbsp;Choon K Ong,&nbsp;Richard L Ferrero","doi":"10.1002/path.6053","DOIUrl":"10.1002/path.6053","url":null,"abstract":"<p>Mucosa-associated lymphoid tissue (MALT) lymphoma is a B-cell tumour that develops over many decades in the stomachs of individuals with chronic <i>Helicobacter pylori</i> infection. We developed a new mouse model of human gastric MALT lymphoma in which mice with a myeloid-specific deletion of the innate immune molecule, Nlrc5, develop precursor B-cell lesions to MALT lymphoma at only 3 months post-<i>Helicobacter</i> infection versus 9–24 months in existing models. The gastric B-cell lesions in the <i>Nlrc5</i> knockout mice had the histopathological features of the human disease, notably lymphoepithelial-like lesions, centrocyte-like cells, and were infiltrated by dendritic cells (DCs), macrophages, and T-cells (CD4⁺, CD8⁺ and Foxp3⁺). Mouse and human gastric tissues contained immune cells expressing immune checkpoint receptor programmed death 1 (PD-1) and its ligand PD-L1, indicating an immunosuppressive tissue microenvironment. We next determined whether CD40L, overexpressed in a range of B-cell malignancies, may be a potential drug target for the treatment of gastric MALT lymphoma. Importantly, we showed that the administration of anti-CD40L antibody either coincident with or after establishment of <i>Helicobacter</i> infection prevented gastric B-cell lesions in mice, when compared with the control antibody treatment. Mice administered the CD40L antibody also had significantly reduced numbers of gastric DCs, CD8⁺ and Foxp3⁺ T-cells, as well as decreased gastric expression of B-cell lymphoma genes. These findings validate the potential of CD40L as a therapeutic target in the treatment of human gastric B-cell MALT lymphoma. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 4","pages":"402-414"},"PeriodicalIF":7.3,"publicationDate":"2023-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5847099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycolysis and de novo fatty acid synthesis cooperatively regulate pathological vascular smooth muscle cell phenotypic switching and neointimal hyperplasia","authors":"Kaixiang Cao,&nbsp;Tiejun Zhang,&nbsp;Zou Li,&nbsp;Mingchuan Song,&nbsp;Anqi Li,&nbsp;Jingwei Yan,&nbsp;Shuai Guo,&nbsp;Litao Wang,&nbsp;Shuqi Huang,&nbsp;Ziling Li,&nbsp;Wenzhong Hou,&nbsp;Xiaoyan Dai,&nbsp;Yong Wang,&nbsp;Du Feng,&nbsp;Jun He,&nbsp;Xiaodong Fu,&nbsp;Yiming Xu","doi":"10.1002/path.6052","DOIUrl":"10.1002/path.6052","url":null,"abstract":"<p>Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid metabolism is recognized as a hallmark of tumors but has not thoroughly been elucidated in neointima formation. Here, we investigated the cooperative role of glycolysis and fatty acid synthesis in vascular injury-induced VSMC dedifferentiation and neointima formation. We found that the expression of hypoxia-inducible factor-1α (HIF-1α) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a critical glycolytic enzyme, were induced in the neointimal VSMCs of human stenotic carotid arteries and wire-injured mouse carotid arteries. HIF-1α overexpression led to elevated glycolysis and resulted in a decreased contractile phenotype while promoting VSMC proliferation and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Conversely, silencing <i>Pfkfb3</i> had the opposite effects. Mechanistic studies demonstrated that glycolysis generates acetyl coenzyme A to fuel <i>de novo</i> fatty acid synthesis and mTORC1 activation. Whole-transcriptome sequencing analysis confirmed the increased expression of PFKFB3 and fatty acid synthetase (FASN) in dedifferentiated VSMCs. More importantly, FASN upregulation was observed in neointimal VSMCs of human stenotic carotid arteries. Finally, interfering with PFKFB3 or FASN suppressed vascular injury-induced mTORC1 activation, VSMC dedifferentiation, and neointima formation. Together, this study demonstrated that PFKFB3-mediated glycolytic reprogramming and FASN-mediated lipid metabolic reprogramming are distinctive features of VSMC phenotypic switching and could be potential therapeutic targets for treating vascular diseases with neointima formation. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 4","pages":"388-401"},"PeriodicalIF":7.3,"publicationDate":"2023-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5852488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Jeremy Jass Prize for Research Excellence in Pathology 2021","authors":"","doi":"10.1002/path.6051","DOIUrl":"10.1002/path.6051","url":null,"abstract":"<p>Every year the Editorial team of <i>The Journal of Pathology</i> awards the Jeremy Jass Prize for Research Excellence to the paper published in the prior calendar year that they perceive to be of the highest scientific calibre. Selection is always difficult because the standard of papers published in the Journal is so high.</p><p>The paper selected for the Jass Prize for the calendar year 2021 is:</p><p>\u0000 <span>Kana Hasegawa</span>, <span>Shinsuke Fujii*</span>, <span>Shinji Matsumoto</span>, <span>Yudai Tajiri</span>, <span>Akira Kikuchi</span>, <span>Tamotsu Kiyoshima</span>. YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation. <i>J Pathol</i> <span>2021</span>; <span>253:</span> <span>80</span>–<span>93</span>. DOI: 10.1002/path.5553.</p><p>*<i>Corresponding author</i>.</p><p>We offer our congratulations to the authors, who are shown in Figure 1. The paper is available Free to Read at https://onlinelibrary.wiley.com/doi/full/10.1002/path.5553</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 3","pages":"357"},"PeriodicalIF":7.3,"publicationDate":"2023-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5657669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma","authors":"Ken Kumagai,&nbsp;Takahiro Shimizu,&nbsp;Mitsuhiro Nikaido,&nbsp;Tomonori Hirano,&nbsp;Nobuyuki Kakiuchi,&nbsp;Yasuhide Takeuchi,&nbsp;Sachiko Minamiguchi,&nbsp;Takaki Sakurai,&nbsp;Mari Teramura,&nbsp;Takahiro Utsumi,&nbsp;Yukiko Hiramatsu,&nbsp;Yuki Nakanishi,&nbsp;Atsushi Takai,&nbsp;Shin'ichi Miyamoto,&nbsp;Seishi Ogawa,&nbsp;Hiroshi Seno","doi":"10.1002/path.6050","DOIUrl":"10.1002/path.6050","url":null,"abstract":"<p>Most gastric cancers develop in inflamed gastric mucosa due to <i>Helicobacter pylori</i> infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide-expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71-year-old woman without <i>H. pylori</i> infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6-positive mucous cells, referred to as SPEM, expanded between them. Whole-exome sequencing analysis revealed a truncating <i>KRAS</i>(G12D) mutation in IGC, OGA, and SPEM. In addition, <i>TP53</i> and <i>CDKN2A</i> mutations and a loss of chromosome 17p were found in the IGC, whereas a <i>GNAS</i> mutation was observed in the OGA. These results indicated that IGC and OGA originated from the <i>KRAS</i>-mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 4","pages":"362-368"},"PeriodicalIF":7.3,"publicationDate":"2023-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6187277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrence risk assessment for stage III colorectal cancer based on five methylation biomarkers in plasma cell-free DNA","authors":"Wei Wang,&nbsp;Xiaohui Zhu,&nbsp;Xuecong Zhang,&nbsp;Chengyong Lei,&nbsp;Zhicheng Zeng,&nbsp;Xiaoliang Lan,&nbsp;Wenzhi Cui,&nbsp;Feifei Wang,&nbsp;Shaowan Xu,&nbsp;Juan Zhou,&nbsp;Xuehui Wu,&nbsp;Haijun Deng,&nbsp;Xia Li,&nbsp;Jianbing Fan,&nbsp;Yanqing Ding,&nbsp;Zhongxi Huang,&nbsp;Li Liang","doi":"10.1002/path.6047","DOIUrl":"10.1002/path.6047","url":null,"abstract":"<p>For stage III colorectal cancer (CRC) patients with a high risk of recurrence, intensified adjuvant chemotherapy can improve overall survival. We aimed to develop a circulating tumor DNA (ctDNA) methylation marker model for predicting the relapse risk of stage III CRC patients. Differentially methylated markers identified between 53 normal mucosa samples and 165 CRC tissue samples, as well as between plasma samples from 75 stage I/II (early-stage) CRC patients and 55 stage IV (late-stage) CRC patients, were analyzed using Student's <i>t</i>-tests. The overlapping methylation markers shared by plasma and tissue samples were used to establish a methylation marker model to evaluate the tumor burden in the peripheral blood of CRC patients using the random forest method. This model was verified in the validation cohort (<i>n</i> = 44) and then applied to predict recurrence risk in 50 stage III CRC patients and monitor the clinical disease course in serial samples from four CRC patients. We built a five-marker-based ctDNA methylation model that had high sensitivity (84.21%) and specificity (84%) in identifying late-stage CRC in a validation cohort containing 24 stage I/II CRC patients and 20 stage IV CRC patients. The model achieved high sensitivity (87.5%) and specificity (94.12%) in predicting tumor relapse in an independent cohort of 50 stage III CRC patients and could be an independent recurrence risk factor for stage III patients [Hazard ratio (HR), 60.4; 95% confidence interval (CI): 7.68–397; <i>p</i> = 9.73e−5]. Analysis of serial blood samples of CRC showed that the model could monitor disease relapse earlier than imaging examination and serum carcinoembryonic antigen (CEA) and so may provide an opportunity for the early adjustment of therapeutic strategies. Moreover, the model could potentially monitor the clinical course and treatment response dynamically. © 2022 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 4","pages":"376-387"},"PeriodicalIF":7.3,"publicationDate":"2022-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6066077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma","authors":"Nandini Karthik,&nbsp;Jane Jia Hui Lee,&nbsp;Joshua Ling Jun Soon,&nbsp;Hsin Yao Chiu,&nbsp;Amos Hong Pheng Loh,&nbsp;Derrick Sek Tong Ong,&nbsp;Wai Leong Tam,&nbsp;Reshma Taneja","doi":"10.1002/path.6048","DOIUrl":"10.1002/path.6048","url":null,"abstract":"<p>The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar RMS (ARMS), an aggressive subtype of RMS. Functionally, knockdown of <i>H3F3A</i>, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent <i>in vivo</i>. Using RNA-sequencing and ChIP-sequencing analyses, we identified melanoma cell adhesion molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks and an increase in the occupancy of H1 at the <i>MCAM</i> promoter. Cell migration and invasion were rescued in <i>H3F3A</i>-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by <i>EHMT2</i>, as an upstream regulator of <i>H3F3A</i>. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients. © 2022 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 3","pages":"342-356"},"PeriodicalIF":7.3,"publicationDate":"2022-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5845435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDT1 drives replication overlicensing and enhances tumorigenesis in the gut†","authors":"Giovanni Monteleone,&nbsp;Carmine Stolfi","doi":"10.1002/path.6045","DOIUrl":"10.1002/path.6045","url":null,"abstract":"<p>Colorectal carcinoma (CRC) is one of the most common forms of malignancy in the Western world. Recent decades have witnessed enormous progress in our understanding of the mechanisms that sustain CRC, even though the factors implicated in the initiation and progression of this neoplasia are not fully understood. A recent study published in <i>The Journal of Pathology</i> looked at the consequences of hyperactivity of chromatin licensing and DNA replication factor 1 (CDT1), a regulator of DNA replication that is produced in excess in CRC, on the course of intestinal tumorigenesis. Mice engineered to selectively overexpress CDT1 and/or lack Geminin, an inhibitor of CDT1, in the intestinal epithelium were more susceptible to experimental intestinal tumorigenesis compared to wild-type mice. This work supports the pro-tumorigenic role of CDT1 and suggests the potential prognostic value of this protein in CRC. © 2022 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 3","pages":"233-235"},"PeriodicalIF":7.3,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5647134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing gastric cancer precision medicine with novel genomic screens†","authors":"Nicole B Halmai,&nbsp;Luis G Carvajal-Carmona","doi":"10.1002/path.6046","DOIUrl":"10.1002/path.6046","url":null,"abstract":"A recent study published in The Journal of Pathology used an shRNA library targeting all known human genes involved in metabolism to identify genes important for gastric cancer. The screen identified aspartyl‐tRNA synthetase (DARS) as a potential drug target, and patients whose tumors had high DARS levels had a worse prognosis, particularly among diffuse‐type gastric cancer. These findings identify a potential therapeutic target for precision medicine of gastric cancer patients, and may be useful for further investigations to discover additional interacting targets. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 4","pages":"359-361"},"PeriodicalIF":7.3,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5961684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myocd regulates airway smooth muscle cell remodeling in response to chronic asthmatic injury","authors":"Qin Yang,&nbsp;Qing Miao,&nbsp;Hui Chen,&nbsp;Duo Li,&nbsp;Yongfeng Luo,&nbsp;Joanne Chiu,&nbsp;Hong-Jun Wang,&nbsp;Michael Chuvanjyan,&nbsp;Michael S Parmacek,&nbsp;Wei Shi","doi":"10.1002/path.6044","DOIUrl":"10.1002/path.6044","url":null,"abstract":"<p>Abnormal growth of airway smooth muscle cells is one of the key features in asthmatic airway remodeling, which is associated with asthma severity. The mechanisms underlying inappropriate airway smooth muscle cell growth in asthma remain largely unknown. Myocd has been reported to act as a key transcriptional coactivator in promoting airway-specific smooth muscle development in fetal lungs. Whether Myocd controls airway smooth muscle remodeling in asthma has not been investigated. Mice with lung mesenchyme-specific deletion of <i>Myocd</i> after lung development were generated, and a chronic asthma model was established by sensitizing and challenging the mice with ovalbumin for a prolonged period. Comparison of the asthmatic pathology between the <i>Myocd</i> knockout mice and the wild-type controls revealed that abrogation of Myocd mitigated airway smooth muscle cell hypertrophy and hyperplasia, accompanied by reduced peri-airway inflammation, decreased fibrillar collagen deposition on airway walls, and attenuation of abnormal mucin production in airway epithelial cells. Our study indicates that Myocd is a key transcriptional coactivator involved in asthma airway remodeling. Inhibition of Myocd in asthmatic airways may be an effective approach to breaking the vicious cycle of asthmatic progression, providing a novel strategy in treating severe and persistent asthma. © 2022 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"259 3","pages":"331-341"},"PeriodicalIF":7.3,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6201569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}