The Journal of Pathology最新文献

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Comprehensive functional splicing analysis of non-canonical CNGB3 variants using in vitro minigene splice assays 利用体外小基因剪接法对非典型CNGB3变异进行综合功能剪接分析。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-30 DOI: 10.1002/path.6431
Katharina Rawnsley, Nicole Weisschuh, Susanne Kohl, Peggy Reuter
{"title":"Comprehensive functional splicing analysis of non-canonical CNGB3 variants using in vitro minigene splice assays","authors":"Katharina Rawnsley,&nbsp;Nicole Weisschuh,&nbsp;Susanne Kohl,&nbsp;Peggy Reuter","doi":"10.1002/path.6431","DOIUrl":"10.1002/path.6431","url":null,"abstract":"<p>Variants in the <i>CNGB3</i> gene, encoding the B3-subunit of the cone photoreceptor cyclic nucleotide gated channel, are a major cause of autosomal recessive achromatopsia, a rare inherited retinal disease. The mutation spectrum of achromatopsia-associated <i>CNGB3</i> variants comprises all types of mutations, including those that are straightforward to evaluate in molecular genetic diagnostics, such as frame-shifting, nonsense, and canonical splice site variants. Additionally, variants have been identified within splice regions outside the conserved ±1,2 splice site dinucleotides, making their potential impact on disease association challenging to interpret. This poses a major hurdle for clinical interpretation of causality between the patient's genotype and the proposed clinical diagnosis, but also for the inclusion of such patients into clinical trials for gene augmentation therapy, for which only patients with confirmed (likely) pathogenic <i>CNGB3</i> variants are eligible. We here performed comprehensive genetic functional analysis of 21 candidate spliceogenic <i>CNGB3</i> variants—15 reported and 6 novel variants—by means of <i>in vitro</i> minigene splice assays and cDNA analysis, and characterization of spliceogenic events by subcloning, Sanger-sequencing, and capillary fragment analysis. For 16 variants, an impact on splicing was confirmed, supporting the reclassification of 86% of variants of uncertain significance as likely pathogenic or pathogenic according to the ACMG/AMP guidelines. This reclassification enables the confirmation of patients’ genotypes, both retrospectively and prospectively. © 2025 The Author(s). <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":"266 3","pages":"322-336"},"PeriodicalIF":5.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6431","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956095","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}
引用次数: 0
Comparative transcriptomics of salivary basal cell adenoma and adenocarcinoma sustain linear neoplastic evolution and intertumor heterogeneity: classification and biological implications 唾液基底细胞腺瘤和腺癌的比较转录组学维持线性肿瘤进化和肿瘤间异质性:分类和生物学意义。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-24 DOI: 10.1002/path.6424
Yoshitsugu Mitani, Haneen Al-Maghrabi, Tatiana V Karpinets, Raissa T Relator, Lauren Hilder, Irene Y Chen, Ryan P Goepfert, Diana Bell, Jianhua Zhang, Renata Ferrarotto, Adel K El-Naggar
{"title":"Comparative transcriptomics of salivary basal cell adenoma and adenocarcinoma sustain linear neoplastic evolution and intertumor heterogeneity: classification and biological implications","authors":"Yoshitsugu Mitani,&nbsp;Haneen Al-Maghrabi,&nbsp;Tatiana V Karpinets,&nbsp;Raissa T Relator,&nbsp;Lauren Hilder,&nbsp;Irene Y Chen,&nbsp;Ryan P Goepfert,&nbsp;Diana Bell,&nbsp;Jianhua Zhang,&nbsp;Renata Ferrarotto,&nbsp;Adel K El-Naggar","doi":"10.1002/path.6424","DOIUrl":"10.1002/path.6424","url":null,"abstract":"<p>It remains uncertain whether basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland represent two distinct neoplasms or temporal stages of a single entity. The issue is central to reconciling their shared phenotypic resemblance and protracted behavior with current pathologic classification. We conducted a transcriptomic analysis on a cohort of both pathologic forms and correlated the findings with the clinicopathologic features using RNA extracted from fresh frozen samples of 25 salivary basal tumors (five BCAs and 20 BCACs) and eight instances of metastatic basal cell carcinomas (BCCs) to parotid glands. Unsupervised analysis revealed shared and intertumoral transcriptome differences within and between BCA and BCAC and distinct segregation from metastatic dermal BCC. Transcriptomic profiling delineated two intermixed subgroups of salivary basal cell neoplasms (SBNs); SBN-I group enriched with adverse pathologic features and SBN-II that lacked any of these features except for a single case. The category with the most instances of adverse pathologic features (SBN-I) manifested upregulations of transcriptional factors linked to cell proliferation pathways (<i>HOXB13</i>, <i>SOX21</i>, <i>MYB</i>, and <i>EN1</i> genes), while those lacking adverse pathologic features (SBN-II) demonstrated a high expression of the <i>TFAP2B</i> transcription- and differentiation-related pathways. Our transcriptomic findings support common neoplastic evolution and intertumoral heterogeneity of both pathologic forms of basal cell neoplasms and identify molecular pathways of potential biological and clinical significance. We therefore propose a nondeterministic designation of ‘basal cell salivary neoplasms, noninvasive (adenoma)/invasive (adenocarcinoma)’ as a platform that integrates conventional phenotypic classification and transcriptomic characteristics pending a classification consensus. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":"258-267"},"PeriodicalIF":5.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959776","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}
引用次数: 0
In-frame insertions of SOX10 are highly enriched and characterize a distinct transcriptomic profile in gastrointestinal schwannomas 在胃肠道神经鞘瘤中,框架内插入的SOX10高度富集,具有独特的转录组特征。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-24 DOI: 10.1002/path.6426
Pei-Hang Lee, Shih-Chiang Huang, Jen-Chieh Lee, Sung-Chou Li, Jen-Wei Tsai, Yi-Ming Chang, Yu-Chien Kao, Wen-Lang Fan, Ching-Di Chang, Hui-Chun Chen, Chih-Hao Li, Chia-Fa Hu, Ting-Ting Liu, Pao-Shu Wu, Mann-Hua Nam, Shih-Chen Yu, Jui-Chu Wang, Hsuan-Ying Huang
{"title":"In-frame insertions of SOX10 are highly enriched and characterize a distinct transcriptomic profile in gastrointestinal schwannomas","authors":"Pei-Hang Lee,&nbsp;Shih-Chiang Huang,&nbsp;Jen-Chieh Lee,&nbsp;Sung-Chou Li,&nbsp;Jen-Wei Tsai,&nbsp;Yi-Ming Chang,&nbsp;Yu-Chien Kao,&nbsp;Wen-Lang Fan,&nbsp;Ching-Di Chang,&nbsp;Hui-Chun Chen,&nbsp;Chih-Hao Li,&nbsp;Chia-Fa Hu,&nbsp;Ting-Ting Liu,&nbsp;Pao-Shu Wu,&nbsp;Mann-Hua Nam,&nbsp;Shih-Chen Yu,&nbsp;Jui-Chu Wang,&nbsp;Hsuan-Ying Huang","doi":"10.1002/path.6426","DOIUrl":"10.1002/path.6426","url":null,"abstract":"<p>Gastrointestinal schwannomas are molecularly and histologically distinct from their non-gastrointestinal counterparts, lacking <i>NF2</i> alterations, although the primary drivers of these tumors are barely understood. A recent study has identified <i>SOX10</i> in-frame insertions in schwannomas, particularly in intracranial non-vestibular lesions, whereas their role in gastrointestinal schwannomas remains unexplored. Whole exome sequencing of 15 gastrointestinal and two non-gastrointestinal schwannomas revealed recurrent <i>SOX10</i> in-frame insertions in 14 gastrointestinal cases (93%) without other nerve sheath tumor-related alterations, such as <i>NF2</i> mutations or <i>SH3PXD2A</i>::<i>HTRA1</i> fusions (~14% in non-gastrointestinal cases). The prevalence, mutation spectrum, and specificity of <i>SOX10</i> insertions were validated using Sanger sequencing in a large cohort comprising 61 gastrointestinal and 98 non-gastrointestinal schwannomas, as well as 110 non-schwannomatous mesenchymal and melanocytic neoplasms. <i>SOX10</i> insertions, occurring within or near the high mobility group box domain, were significantly enriched in gastrointestinal schwannomas (91.8%) compared with non-gastrointestinal cases (5.1%). The most common insertion, p.Y173_Q174insKY, was present in 86.9% of gastrointestinal schwannomas but absent in non-gastrointestinal cases. Another recurrent insertion, p.P175_R176insKYQP, was rare and exclusively found in non-gastrointestinal schwannomas (3/98), while all non-schwannomatous controls were <i>SOX10</i>-normal. <i>SOX10</i>-inserted schwannomas exhibited histologic features characteristic of gastrointestinal schwannomas, including a microtrabecular arrangement of Schwann cells, peripheral lymphoid cuffs, and a lack of encapsulation. Both <i>SOX10</i>-inserted and <i>SOX10</i>-normal schwannomas demonstrated diffuse SOX10 immunoreactivity. The <i>SOX10</i>-inserted group was significantly associated with gastrointestinal locations (<i>p</i> &lt; 0.001), older patients (<i>p</i> &lt; 0.001), fusion negativity (<i>p</i> &lt; 0.001), and larger tumor size (<i>p</i> = 0.013). Gene expression profiling of 44 cases revealed distinct transcriptomic profiles between primarily <i>SOX10</i>-inserted and <i>SOX10</i>-normal groups, with the latter group being classifiable into fusion-poor and fusion-enriched sub-clusters. This study highlights the genetic heterogeneity of schwannomas and suggests that <i>SOX10</i> insertions play a pivotal role in the tumorigenesis of gastrointestinal schwannomas, distinctly separating them from non-gastrointestinal counterparts and contributing to their unique molecular profile. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":"268-279"},"PeriodicalIF":5.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958073","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}
引用次数: 0
Nicotine-driven enhancement of tumor malignancy in triple-negative breast cancer via additive regulation of CHRNA9 and IGF1R 尼古丁通过加性调节CHRNA9和IGF1R在三阴性乳腺癌中增强肿瘤恶性
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-17 DOI: 10.1002/path.6423
Yung-Che Kuo, Chi-Long Chen, Kha-Liang Lee, Hsiao-Feng Wang, Victor James Drew, Pei-Chi Lan, Yuan-Soon Ho, Yen-Hua Huang
{"title":"Nicotine-driven enhancement of tumor malignancy in triple-negative breast cancer via additive regulation of CHRNA9 and IGF1R","authors":"Yung-Che Kuo,&nbsp;Chi-Long Chen,&nbsp;Kha-Liang Lee,&nbsp;Hsiao-Feng Wang,&nbsp;Victor James Drew,&nbsp;Pei-Chi Lan,&nbsp;Yuan-Soon Ho,&nbsp;Yen-Hua Huang","doi":"10.1002/path.6423","DOIUrl":"https://doi.org/10.1002/path.6423","url":null,"abstract":"<p>Cigarette smoking is a significant risk factor for cancer development with complex mechanisms. This study aims to investigate the impact of nicotine exposure on the regulation of stemness- and metastasis-related properties via cholinergic receptor nicotinic alpha 9 subunit (CHRNA9) and insulin-like growth factor-1 receptor (IGF1R) and to evaluate their therapeutic potential in triple-negative breast cancer (TNBC). We performed Kaplan–Meier survival analysis of public databases and revealed that high expression of CHRNA9, IGF1R signaling molecules, and stemness genes was significantly associated with poor recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in TNBC samples. Additionally, we examined two patient cohorts to determine the clinical associations between the expression levels of different genes (<i>n</i> = 67) and proteins (<i>n</i> = 42) and showed a strong positive correlation between the expression levels of CHRNA9, IGF1R signaling molecules, and stemness markers POU5F1/NANOG in tumor tissues. We carried out nicotine treatment and knockdown of CHRNA9 and IGF1R in TNBC cells to identify the effects on stemness-related properties <i>in vitro</i>. Furthermore, primary and secondary metastatic <i>in vivo</i> animal models were examined using micro-computed tomography (μCT) screening and <i>in situ</i> hybridization with a human Alu probe to detect tumor cells. Nicotine was found to upregulate the expression of CHRNA9, POU5F1, and IGF1R, influencing stemness- and metastasis-related properties. Knockdown of CHRNA9 expression attenuated nicotine-induced stemness-related properties in a TNBC cell model. Furthermore, knockdown of IGF1R expression significantly alleviated nicotine/CHRNA9-induced stemness features and cancer cell metastasis in cell cultures and lung metastatic mouse models. These results demonstrate that nicotine triggers IGF1R signaling, thereby enhancing stemness-related properties, cell migration, invasion, and tumor metastasis, resulting in a poorer prognosis for patients with TNBC. These findings highlight IGF1R as a promising therapeutic target for reducing stemness and metastasis in TNBC patients exposed to environmental nicotine. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 2","pages":"230-245"},"PeriodicalIF":5.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913991","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}
引用次数: 0
Nicotine-driven enhancement of tumor malignancy in triple-negative breast cancer via additive regulation of CHRNA9 and IGF1R 尼古丁通过加性调节CHRNA9和IGF1R在三阴性乳腺癌中增强肿瘤恶性
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-17 DOI: 10.1002/path.6423
Yung-Che Kuo, Chi-Long Chen, Kha-Liang Lee, Hsiao-Feng Wang, Victor James Drew, Pei-Chi Lan, Yuan-Soon Ho, Yen-Hua Huang
{"title":"Nicotine-driven enhancement of tumor malignancy in triple-negative breast cancer via additive regulation of CHRNA9 and IGF1R","authors":"Yung-Che Kuo,&nbsp;Chi-Long Chen,&nbsp;Kha-Liang Lee,&nbsp;Hsiao-Feng Wang,&nbsp;Victor James Drew,&nbsp;Pei-Chi Lan,&nbsp;Yuan-Soon Ho,&nbsp;Yen-Hua Huang","doi":"10.1002/path.6423","DOIUrl":"https://doi.org/10.1002/path.6423","url":null,"abstract":"<p>Cigarette smoking is a significant risk factor for cancer development with complex mechanisms. This study aims to investigate the impact of nicotine exposure on the regulation of stemness- and metastasis-related properties via cholinergic receptor nicotinic alpha 9 subunit (CHRNA9) and insulin-like growth factor-1 receptor (IGF1R) and to evaluate their therapeutic potential in triple-negative breast cancer (TNBC). We performed Kaplan–Meier survival analysis of public databases and revealed that high expression of CHRNA9, IGF1R signaling molecules, and stemness genes was significantly associated with poor recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in TNBC samples. Additionally, we examined two patient cohorts to determine the clinical associations between the expression levels of different genes (<i>n</i> = 67) and proteins (<i>n</i> = 42) and showed a strong positive correlation between the expression levels of CHRNA9, IGF1R signaling molecules, and stemness markers POU5F1/NANOG in tumor tissues. We carried out nicotine treatment and knockdown of CHRNA9 and IGF1R in TNBC cells to identify the effects on stemness-related properties <i>in vitro</i>. Furthermore, primary and secondary metastatic <i>in vivo</i> animal models were examined using micro-computed tomography (μCT) screening and <i>in situ</i> hybridization with a human Alu probe to detect tumor cells. Nicotine was found to upregulate the expression of CHRNA9, POU5F1, and IGF1R, influencing stemness- and metastasis-related properties. Knockdown of CHRNA9 expression attenuated nicotine-induced stemness-related properties in a TNBC cell model. Furthermore, knockdown of IGF1R expression significantly alleviated nicotine/CHRNA9-induced stemness features and cancer cell metastasis in cell cultures and lung metastatic mouse models. These results demonstrate that nicotine triggers IGF1R signaling, thereby enhancing stemness-related properties, cell migration, invasion, and tumor metastasis, resulting in a poorer prognosis for patients with TNBC. These findings highlight IGF1R as a promising therapeutic target for reducing stemness and metastasis in TNBC patients exposed to environmental nicotine. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 2","pages":"230-245"},"PeriodicalIF":5.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913990","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}
引用次数: 0
Activated immune infiltrates expand opportunities for targeted therapy in p53-abnormal endometrial carcinoma 激活的免疫浸润扩大了p53异常子宫内膜癌靶向治疗的机会。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-14 DOI: 10.1002/path.6429
Spencer D Martin, Shelby Thornton, Christine Chow, Katy Milne, Juliana Sobral de Barros, Kayleigh A Morris, Samuel Leung, Amy Jamieson, Brad H Nelson, Dawn R Cochrane, David G Huntsman, C Blake Gilks, Lien Hoang, Jessica N McAlpine, Allen W Zhang
{"title":"Activated immune infiltrates expand opportunities for targeted therapy in p53-abnormal endometrial carcinoma","authors":"Spencer D Martin,&nbsp;Shelby Thornton,&nbsp;Christine Chow,&nbsp;Katy Milne,&nbsp;Juliana Sobral de Barros,&nbsp;Kayleigh A Morris,&nbsp;Samuel Leung,&nbsp;Amy Jamieson,&nbsp;Brad H Nelson,&nbsp;Dawn R Cochrane,&nbsp;David G Huntsman,&nbsp;C Blake Gilks,&nbsp;Lien Hoang,&nbsp;Jessica N McAlpine,&nbsp;Allen W Zhang","doi":"10.1002/path.6429","DOIUrl":"10.1002/path.6429","url":null,"abstract":"<p>Tumor protein p53 mutated/abnormal (p53abn) endometrial carcinomas account for over 50% of deaths but comprise only 15% of all endometrial carcinomas. Most patients show limited response to standard-of-care chemotherapy with or without radiotherapy, and only a minority of cases are amenable to targeted therapies like poly-ADP ribose polymerase (PARP) inhibitors and HER2-directed therapies. Recent immunotherapy clinical trials have demonstrated remarkable efficacy, not only in mismatch repair deficient (MMRd) tumors but also in a subset of mismatch repair-proficient (MMRp) tumors. However, the immune microenvironment and its relationship to other therapeutic targets in MMRp endometrial carcinoma remains poorly understood. Here, we characterize the immune microenvironment of p53abn endometrial carcinoma, the most clinically aggressive subtype of MMRp endometrial carcinoma, and correlate antitumor immune signatures with other targetable alterations. We accrued 256 treatment-naïve p53abn endometrial carcinomas and systemically profiled T-cell, B-cell, myeloid, and tumor-cell populations with multiplex immunofluorescence to assess the tissue localization and functional status of immune cells. Shallow whole-genome sequencing was performed on a subset of 126 cases. Patterns of immune infiltration were compared to survival outcomes and mutational signatures. Mixture modeling divided p53abn endometrial carcinoma into tumor-infiltrating lymphocyte (TIL)-rich and TIL-poor subsets. Over 50% of tumors were TIL-rich. TIL-rich cases overexpressed targetable immune evasion molecules and were associated with longer overall and disease-specific survival in multivariate analysis. This effect was particularly pronounced in advanced stage disease and in patients who did not receive adjuvant chemotherapy. TIL did not associate with homologous recombination deficient mutational signatures or HER2 amplification. Our findings demonstrate a biological rationale for immunotherapy in a substantial subset of patients with p53abn endometrial cancer and may help inform combination therapies with immune checkpoint inhibition, PARP inhibitors, and anti-HER2 agents. © 2025 The Author(s). <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":"266 3","pages":"292-305"},"PeriodicalIF":5.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6429","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956472","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}
引用次数: 0
Histone deacetylase 6 inhibition attenuates pathological cardiac hypertrophy by promoting autophagy through MAP1LC3B ubiquitination 组蛋白去乙酰化酶6抑制通过MAP1LC3B泛素化促进自噬,减轻病理性心肌肥大
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-11 DOI: 10.1002/path.6419
Jiayu Yao, Xiaoou Sun, Yousheng Chen, Xuan Xu, Junxiao Feng, Mingming Zhang, Xiangdong Liu, Xingjuan Shi
{"title":"Histone deacetylase 6 inhibition attenuates pathological cardiac hypertrophy by promoting autophagy through MAP1LC3B ubiquitination","authors":"Jiayu Yao,&nbsp;Xiaoou Sun,&nbsp;Yousheng Chen,&nbsp;Xuan Xu,&nbsp;Junxiao Feng,&nbsp;Mingming Zhang,&nbsp;Xiangdong Liu,&nbsp;Xingjuan Shi","doi":"10.1002/path.6419","DOIUrl":"https://doi.org/10.1002/path.6419","url":null,"abstract":"<p>Cardiac hypertrophy is an adaptive response of the heart to pathological stimuli that may lead to cardiac dysfunction and heart failure. Histone deacetylase 6 (HDAC6) participates in the progression of multiple cardiovascular diseases, including chronic hypertension, ischemic stroke, and acute cardiac injury. A delicate balance of autophagy regulates heart homeostasis, whereas dysregulated autophagy is involved in myocardial hypertrophy. However, whether HDAC6 participates in pathological cardiac hypertrophy by regulating autophagy remains unclear. In this paper, we report for the first time that HDAC6 is involved in isoproterenol (ISO)-induced pathological cardiac hypertrophy by interacting with and ubiquitinating MAP1LC3B. First, the expression level of HDAC6 was found to be increased in cardiac hypertrophy models induced by ISO. <i>HDAC6</i> overexpression promoted the expression of hypertrophic genes and enhanced cell surface area. Conversely, HDAC6 inhibition attenuated ISO-induced hypertrophic responses. Mechanistically, HDAC6 promoted hypertrophic responses by negatively regulating autophagy. Furthermore, HDAC6 interacted with MAP1LC3B and mediated its monoubiquitination, thereby contributing to reduced MAP1LC3B levels and impaired autophagy. Inhibition of HDAC6 activity in mice abrogated the hypertrophic effects of ISO by restoring MAP1LC3B expression. In summary, our data demonstrate that HDAC6 participates in ISO-induced cardiac hypertrophy by limiting the availability of MAP1LC3B and suppressing autophagy. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 2","pages":"217-229"},"PeriodicalIF":5.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914471","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}
引用次数: 0
Aberrant TERT expression: linking chronic inflammation to hepatocellular carcinoma† TERT表达异常:慢性炎症与肝细胞癌之间的联系
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-11 DOI: 10.1002/path.6421
Rui Dong, Gregoire Najjar, Cagatay Günes, André Lechel
{"title":"Aberrant TERT expression: linking chronic inflammation to hepatocellular carcinoma†","authors":"Rui Dong,&nbsp;Gregoire Najjar,&nbsp;Cagatay Günes,&nbsp;André Lechel","doi":"10.1002/path.6421","DOIUrl":"https://doi.org/10.1002/path.6421","url":null,"abstract":"<p>Telomerase reverse transcriptase (TERT), the catalytic enzyme component of telomerase, plays multiple roles in cellular biology. Its canonical function is primarily associated with telomere maintenance and genomic stability. In addition, several studies revealed critical non-canonical extra-telomeric functions of TERT in various cellular processes, including cell proliferation and survival, DNA damage response, transcription, signal transduction, and metabolic regulation, both in normal and in cancer cells. Notably, TERT is aberrantly upregulated in more than 80% of hepatocellular carcinoma (HCC) cases, making it an important target in liver cancer research. However, due to the diversity and complexity of TERT's functions <i>in vivo</i>, the precise mechanisms by which TERT contributes to the initiation and progression of HCC remain unclear. A recent study published in <i>The Journal of Pathology</i> using the <i>Alb-Cre;Tert</i>Tg mouse model and clinical HCC samples addresses the role of TERT in hepatocarcinogenesis. The study demonstrates that TERT promotes cell cycle progression and hepatocarcinogenesis by enhancing NF-κB promoter activity and facilitating the ubiquitination of p21. Notably, absence of functional p53 accelerates liver tumor development in TERT transgenic mice. These findings further underscore the critical role of TERT in inflammation-driven hepatocarcinogenesis and provide new insights into its underlying mechanisms. © 2025 The Author(s). <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":"266 2","pages":"130-133"},"PeriodicalIF":5.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914484","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}
引用次数: 0
BMP signalling in colorectal cancer: losing the yin to WNTs yang 结直肠癌中BMP信号传导:WNTs阳失阴。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-11 DOI: 10.1002/path.6428
Eloise Clarkson, Annabelle Lewis
{"title":"BMP signalling in colorectal cancer: losing the yin to WNTs yang","authors":"Eloise Clarkson,&nbsp;Annabelle Lewis","doi":"10.1002/path.6428","DOIUrl":"10.1002/path.6428","url":null,"abstract":"<p>Colorectal cancer (CRC) is the third most common form of cancer globally, and arises from the hyperproliferation of epithelial cells in the intestine. The architecture and maintenance of these cells is governed by two major signalling pathways working in a counter-gradient: the stem cell WNT signalling pathway, and the prodifferentiation bone morphogenetic protein (BMP) pathway. It has long been known that this WNT-BMP balance is disrupted in CRC, with hyperactive WNT signalling leading to increased proliferation of epithelial cells and tumour progression. BMP signalling, and its prodifferentiation effects, have increasingly become a focus for CRC research. Loss of BMP signalling, and that of its receptors, has been shown to increase WNT signalling and cancer stem cells in CRC. BMP signalling is further modulated through secreted BMP antagonists localised to the intestinal crypts, which create a niche ensuring that sustained WNT signalling can maintain stem-cell self-renewal capacity. A number of studies combine to demonstrate the effects of overexpression of these BMP antagonists, showing that hyperactivity of the stem-cell-supporting WNT signalling pathway ensues, leading to deregulation of the intestinal epithelium. Cellular hyperproliferation, the emergence of ectopic crypts, and an increase in stem cell numbers and characteristics are common themes, contributing to disrupted epithelial homeostasis, an increase in CRC risk and progression, and resistance to therapy. This review aims to compile the current knowledge on BMP antagonists, their role in CRC development, and how we can utilise this information for biomarker research and novel therapeutics. © 2025 The Author(s). <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":"266 3","pages":"280-291"},"PeriodicalIF":5.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952521","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}
引用次数: 0
Aberrant TERT expression: linking chronic inflammation to hepatocellular carcinoma† TERT表达异常:慢性炎症与肝细胞癌之间的联系
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-04-11 DOI: 10.1002/path.6421
Rui Dong, Gregoire Najjar, Cagatay Günes, André Lechel
{"title":"Aberrant TERT expression: linking chronic inflammation to hepatocellular carcinoma†","authors":"Rui Dong,&nbsp;Gregoire Najjar,&nbsp;Cagatay Günes,&nbsp;André Lechel","doi":"10.1002/path.6421","DOIUrl":"https://doi.org/10.1002/path.6421","url":null,"abstract":"<p>Telomerase reverse transcriptase (TERT), the catalytic enzyme component of telomerase, plays multiple roles in cellular biology. Its canonical function is primarily associated with telomere maintenance and genomic stability. In addition, several studies revealed critical non-canonical extra-telomeric functions of TERT in various cellular processes, including cell proliferation and survival, DNA damage response, transcription, signal transduction, and metabolic regulation, both in normal and in cancer cells. Notably, TERT is aberrantly upregulated in more than 80% of hepatocellular carcinoma (HCC) cases, making it an important target in liver cancer research. However, due to the diversity and complexity of TERT's functions <i>in vivo</i>, the precise mechanisms by which TERT contributes to the initiation and progression of HCC remain unclear. A recent study published in <i>The Journal of Pathology</i> using the <i>Alb-Cre;Tert</i>Tg mouse model and clinical HCC samples addresses the role of TERT in hepatocarcinogenesis. The study demonstrates that TERT promotes cell cycle progression and hepatocarcinogenesis by enhancing NF-κB promoter activity and facilitating the ubiquitination of p21. Notably, absence of functional p53 accelerates liver tumor development in TERT transgenic mice. These findings further underscore the critical role of TERT in inflammation-driven hepatocarcinogenesis and provide new insights into its underlying mechanisms. © 2025 The Author(s). <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":"266 2","pages":"130-133"},"PeriodicalIF":5.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914469","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}
引用次数: 0
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