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Development and Validation of Potential Molecular Subtypes and Signatures of Thyroid Carcinoma Based on Aging-related Gene Analysis. 基于老化相关基因分析的甲状腺癌潜在分子亚型和特征的开发与验证
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-01-01 DOI: 10.21873/cgp.20433
Zhi Li, L I Jia, Huang-Ren Zhou, L U Zhang, Meng Zhang, Juan Lv, Zhi-Yong Deng, Chao Liu

Background/aim: Thyroid carcinoma (THCA) is a cancer of the endocrine system that most commonly affects women. Aging-associated genes play a critical role in various cancers. Therefore, we aimed to gain insight into the molecular subtypes of thyroid cancer and whether senescence-related genes can predict the overall prognosis of THCA patients.

Materials and methods: Thyroid carcinoma (THCA) transcriptome-related expression profiles were obtained from The Cancer Genome Atlas (TCGA) database. These profiles were randomly divided into training and validation subsets at a ratio of 1:1. Unsupervised clustering algorithms were used to compare differences between the two subtypes; prognosis-related senescence genes were used to further construct our prognostic models by univariate and multivariate Cox analyses and construct a nomogram to predict the 1-, 3-, and 5-year overall survival probability of THCA patients. In addition, we performed gene set enrichment analysis (GSEA) to predict the immune microenvironment and somatic mutations between the different risk groups. Finally, real-time PCR was used to verify the expression levels of key model genes.

Results: The 'ConsensusClusterPlus' R package was used to cluster thyroid cancer into two categories (Cluster1 and Cluster2) on the basis of 46 differentially expressed aging-related genes (DE-ARGs); patients in Cluster1 demonstrated a better prognosis than those in Cluster2. Cox analysis was used to screen six prognosis-related DE-ARGs. Finally, our real-time PCR results confirmed our hypothesis.

Conclusion: Differences exist between the two subtypes of thyroid cancer that help guide treatment decisions. The six DE-ARG genes have a high predictive value for risk stratifying THCA patients.

背景/目的:甲状腺癌(THCA)是一种内分泌系统癌症,最常见于女性。衰老相关基因在各种癌症中起着至关重要的作用。因此,我们旨在深入了解甲状腺癌的分子亚型,以及衰老相关基因能否预测甲状腺癌患者的总体预后:甲状腺癌(THCA)转录组相关表达谱来自癌症基因组图谱(TCGA)数据库。这些图谱按 1:1 的比例随机分为训练子集和验证子集。我们使用无监督聚类算法比较了两种亚型之间的差异;通过单变量和多变量 Cox 分析,我们使用预后相关的衰老基因进一步构建了预后模型,并构建了预测 THCA 患者 1 年、3 年和 5 年总生存概率的提名图。此外,我们还进行了基因组富集分析(GSEA),以预测不同风险组间的免疫微环境和体细胞突变。最后,我们使用实时 PCR 验证了关键模型基因的表达水平:使用 "ConsensusClusterPlus "R软件包根据46个差异表达的衰老相关基因(DE-ARGs)将甲状腺癌分为两类(Cluster1和Cluster2);Cluster1中的患者比Cluster2中的患者预后更好。Cox分析筛选出了6个与预后相关的DE-ARGs。最后,我们的实时 PCR 结果证实了我们的假设:结论:甲状腺癌的两种亚型之间存在差异,这有助于指导治疗决策。六个 DE-ARG 基因对甲状腺癌患者的风险分层具有很高的预测价值。
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引用次数: 0
Impact of Mutations in Subunit Genes of the Mammalian SWI/SNF Complex on Immunological Tumor Microenvironment. 哺乳动物 SWI/SNF 复合物亚基基因突变对免疫肿瘤微环境的影响
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-01-01 DOI: 10.21873/cgp.20432
Chikako Hozumi, Akira Iizuka, Tomoatsu Ikeya, Haruo Miyata, Chie Maeda, Tadashi Ashizawa, Takeshi Nagashima, Kenichi Urakami, Yuji Shimoda, Keiichi Ohshima, Koji Muramatsu, Takashi Sugino, Akio Shiomi, Yasuhisa Ohde, Etsuro Bando, Kenichiro Furukawa, Teiichi Sugiura, Takashi Mukaigawa, Seiichiro Nishimura, Yasuyuki Hirashima, Koichi Mitsuya, Shusuke Yoshikawa, Yasuhiro Tsubosa, Hirohisa Katagiri, Masashi Niwakawa, Ken Yamaguchi, Hirotsugu Kenmotsu, Yasuto Akiyama

Background/aim: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers.

Patients and methods: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis.

Results: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers.

Conclusion: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.

背景/目的:最近,有报道称癌症中的SWI/SNF染色质重塑基因发生了失活的体细胞突变。然而,有关染色质重塑复合基因突变肿瘤微环境(TME)免疫学分析的研究却很少。在本研究中,我们确定了携带各种哺乳动物SWI/SNF复合体突变的癌症患者,并调查了这些突变癌症的免疫学特征:筛选出携带任何一种染色质重塑复合体基因突变的癌症患者,并比较染色质重塑复合体基因表达量低和表达量高两组患者的临床病理特征。具体而言,采用火山图分析法比较了SMARCA4表达量低和表达量高两组之间免疫反应相关基因和癌症相关基因的表达水平:结果:在携带PBRM1、SAMRACA4和ARID2基因突变的癌症中,T细胞标记基因和成熟B细胞标记基因在肿瘤中上调。具体来说,T细胞效应基因(CD8B、CD40LG)、中央记忆标记基因(CD27、CCR7)和成熟B细胞标记基因(CD20、CD38、CD79和IRF4)在SMARCA4表达低的组中上调,而包括MYB、MYC和AURKB基因在内的癌症相关基因则下调。值得注意的是,基因表达和免疫组化(IHC)数据的热图显示,在SMARCA4基因突变的胃癌中,成熟B细胞的三级淋巴结构(TLS)基因特征被上调:这些结果表明,以TLS基因特征为特征的成熟B细胞募集和癌症信号下调介导的免疫激活等免疫肿瘤微环境状态可能有助于将SMARCA4基因突变的肿瘤划分为免疫检查点阻断疗法敏感的靶肿瘤。
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引用次数: 0
Depletion of DNTTIP2 Induces Cell Cycle Arrest in Pancreatic Cancer Cells. 消耗 DNTTIP2 可诱导胰腺癌细胞的细胞周期停滞。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-01-01 DOI: 10.21873/cgp.20426
Masato Yoshizawa, Atsushi Shiozaki, Eishi Ashihara

Background/aim: Pancreatic cancer is one of the most lethal malignant cancers worldwide and the seventh most common cause of cancer-related death in both sexes. Herein, we analyzed open access data and discovered that expression of a gene called deoxynucleotidyltransferase terminal-interacting protein 2 (DNTTIP2) is linked to prognosis of pancreatic ductal adenocarcinoma (PDAC). We then elucidated the role of DNTTIP2 in the proliferation of pancreatic cancer cells in vitro.

Materials and methods: A WST-8 assay, cell cycle analysis, Annexin-V staining, quantitative reverse transcription-PCR, and western blot analysis were conducted to assess cell proliferation, cell cycle, apoptosis, and expression of DNTTIP2 mRNA and protein, respectively, in DNTTIP2-depleteted MIA-PaCa-2 and PK-1 cells.

Results: Depletion of DNTTIP2 induced G1 arrest in MIA-PaCa-2 cells by decreasing expression of special AT-rich sequence binding protein 1 (SATB1) and cyclin-dependent kinase 6 (CDK6). In addition, depletion of DNTTIP2 induced G2 arrest in PK-1 cells by decreasing expression of CDK1. Depletion of DNTTIP2 did not induce apoptosis in MIA-PaCa-2 or PK-1 cells.

Conclusion: DNTTIP2 is involved in proliferation of pancreatic cancer cells. Thus, DNTTIP2 is a potential target for inhibiting progression of pancreatic cancers.

背景/目的:胰腺癌是全球致死率最高的恶性肿瘤之一,也是导致男女癌症相关死亡的第七大常见原因。在此,我们分析了公开获取的数据,发现一种名为脱氧核苷酸转移酶末端互作蛋白 2(DNTTIP2)的基因的表达与胰腺导管腺癌(PDAC)的预后有关。我们随后阐明了 DNTTIP2 在体外胰腺癌细胞增殖中的作用:通过WST-8检测、细胞周期分析、Annexin-V染色、定量反转录-PCR和Western印迹分析,分别评估了DNTTIP2耗竭的MIA-PaCa-2和PK-1细胞的细胞增殖、细胞周期、细胞凋亡以及DNTTIP2 mRNA和蛋白的表达情况:结果:DNTTIP2耗竭通过降低特殊富AT序列结合蛋白1(SATB1)和细胞周期蛋白依赖性激酶6(CDK6)的表达,诱导MIA-PaCa-2细胞G1停滞。此外,通过减少 CDK1 的表达,消耗 DNTTIP2 可诱导 PK-1 细胞 G2 期停滞。在 MIA-PaCa-2 或 PK-1 细胞中,DNTTIP2 的耗竭不会诱导细胞凋亡:结论:DNTTIP2 参与了胰腺癌细胞的增殖。因此,DNTTIP2 是抑制胰腺癌进展的潜在靶点。
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引用次数: 0
SNHG3/WISP2 Axis Promotes Hela Cell Migration and Invasion via Activating Wnt/β-Catenin Signaling. SNHG3/WISP2轴通过激活Wnt/β-Catenin信号传导促进Hela细胞迁移和侵袭
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20421
Dengfei Xu, Hao Feng, Zirui Ren, Xiang Li, Chenyang Jiang, Yuming Chen, Lina Liu, Wenchao Chen, Zhilei Cui, Shundong Cang

Background/aim: Cervical cancer (CC) poses a significant threat to women's health and has a relatively poor prognosis due to local invasion and metastasis. It is, therefore, crucial to elucidate the molecular mechanisms of CC metastasis. SNHG3 has been implicated in various tumor metastasis processes, but its involvement in CC has not been thoroughly studied. Our study aimed to investigate the role of SNHG3 in metastasis and elucidate its underlying mechanisms in CC.

Materials and methods: LncRNA SNHG3 expression in CC tissues was analyzed using TCGA and GSE27469 databases. Normal cervical epithelial cells and CC cell lines were used to detect mRNA expression of SNHG3 via quantitative reverse transcription polymerase chain reaction (qRT-PCR). With RNA interference (RNAi) technology, antisense oligonucleotides (ASO) can act on HeLa cells to knockdown target gene expression. The influence of SNHG3 on cell migration and invasion were determined by wound healing and transwell assays. Transcriptome sequencing (RNA-seq) was used to seek abnormally expressed genes between SNHG3 knockdown cells and control cells. The expressions of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling related proteins were detected using western blot.

Results: SNHG3 was obviously up-regulated in CC tissues and cell lines, and ectopic expression of SNHG3 was associated with lymph node metastasis of CC. Knockdown of SNHG3 significantly inhibited cell migration and invasion in CC. Further molecular mechanism studies showed that SNHG3 knockdown could down-regulate the expression of WNT1 Inducible Signaling Pathway Protein 2 (WISP2) so as to inhibit the activation of the Wnt/β-catenin signaling pathway, and regulated the expression of EMT-related markers, that promoted the protein expression of E-cadherin, as well as decreased the expression of N-cadherin and vimentin.

Conclusion: SNHG3 appears to exert a pro-metastatic effect in CC, as evidenced by inhibition of cell migration and invasion upon SNHG3 knockdown. EMT also appears to be attenuated. Of interest is the down-regulation of WISP2 following SNHG3 knockdown leads to the inactivation of the Wnt/β-catenin signaling pathway.

背景/目的:宫颈癌(Cervical cancer, CC)是一种严重威胁妇女健康的疾病,由于其局部侵袭和转移,预后较差。因此,阐明CC转移的分子机制是至关重要的。SNHG3参与多种肿瘤转移过程,但其在CC中的作用尚未被深入研究。本研究旨在探讨SNHG3在CC转移中的作用及其机制。材料和方法:采用TCGA和GSE27469数据库分析LncRNA SNHG3在CC组织中的表达。采用定量反转录聚合酶链反应(qRT-PCR)检测正常宫颈上皮细胞和CC细胞株SNHG3 mRNA的表达。通过RNA干扰(RNAi)技术,反义寡核苷酸(ASO)可以作用于HeLa细胞,敲低靶基因的表达。通过创面愈合和transwell实验测定SNHG3对细胞迁移和侵袭的影响。利用转录组测序(RNA-seq)在SNHG3敲低细胞和对照细胞之间寻找异常表达基因。western blot检测上皮间质转化(epithelial-mesenchymal transition, EMT)和Wnt/β-catenin信号相关蛋白的表达。结果:SNHG3在CC组织和细胞系中表达明显上调,SNHG3异位表达与CC淋巴结转移有关,敲低SNHG3可显著抑制CC细胞的迁移和侵袭,进一步的分子机制研究表明,敲低SNHG3可下调WNT1诱导信号通路蛋白2 (WISP2)的表达,从而抑制Wnt/β-catenin信号通路的激活,调控emt相关标志物的表达。促进E-cadherin蛋白的表达,降低N-cadherin和vimentin的表达。结论:SNHG3在CC中具有促进转移的作用,表达SNHG3可抑制细胞迁移和侵袭。EMT似乎也减弱了。令人感兴趣的是,SNHG3敲低后WISP2的下调导致Wnt/β-catenin信号通路失活。
{"title":"SNHG3/WISP2 Axis Promotes Hela Cell Migration and Invasion <i>via</i> Activating Wnt/β-Catenin Signaling.","authors":"Dengfei Xu, Hao Feng, Zirui Ren, Xiang Li, Chenyang Jiang, Yuming Chen, Lina Liu, Wenchao Chen, Zhilei Cui, Shundong Cang","doi":"10.21873/cgp.20421","DOIUrl":"10.21873/cgp.20421","url":null,"abstract":"<p><strong>Background/aim: </strong>Cervical cancer (CC) poses a significant threat to women's health and has a relatively poor prognosis due to local invasion and metastasis. It is, therefore, crucial to elucidate the molecular mechanisms of CC metastasis. SNHG3 has been implicated in various tumor metastasis processes, but its involvement in CC has not been thoroughly studied. Our study aimed to investigate the role of SNHG3 in metastasis and elucidate its underlying mechanisms in CC.</p><p><strong>Materials and methods: </strong>LncRNA SNHG3 expression in CC tissues was analyzed using TCGA and GSE27469 databases. Normal cervical epithelial cells and CC cell lines were used to detect mRNA expression of SNHG3 via quantitative reverse transcription polymerase chain reaction (qRT-PCR). With RNA interference (RNAi) technology, antisense oligonucleotides (ASO) can act on HeLa cells to knockdown target gene expression. The influence of SNHG3 on cell migration and invasion were determined by wound healing and transwell assays. Transcriptome sequencing (RNA-seq) was used to seek abnormally expressed genes between SNHG3 knockdown cells and control cells. The expressions of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling related proteins were detected using western blot.</p><p><strong>Results: </strong>SNHG3 was obviously up-regulated in CC tissues and cell lines, and ectopic expression of SNHG3 was associated with lymph node metastasis of CC. Knockdown of SNHG3 significantly inhibited cell migration and invasion in CC. Further molecular mechanism studies showed that SNHG3 knockdown could down-regulate the expression of WNT1 Inducible Signaling Pathway Protein 2 (WISP2) so as to inhibit the activation of the Wnt/β-catenin signaling pathway, and regulated the expression of EMT-related markers, that promoted the protein expression of E-cadherin, as well as decreased the expression of N-cadherin and vimentin.</p><p><strong>Conclusion: </strong>SNHG3 appears to exert a pro-metastatic effect in CC, as evidenced by inhibition of cell migration and invasion upon SNHG3 knockdown. EMT also appears to be attenuated. Of interest is the down-regulation of WISP2 following SNHG3 knockdown leads to the inactivation of the Wnt/β-catenin signaling pathway.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"20 6suppl","pages":"744-753"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138458024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
(S)-3-(3-Fluoro-4-Methoxybenzyl)-5,6,7-Trimethoxychroman-4-One Suppresses the Proliferation of Huh7 Cells by Up-regulating P21 and Inducing G2/M Phase Arrest. (S)-3-(3-氟-4-甲氧基苄基)-5,6,7-三甲氧基铬-4- one通过上调P21诱导G2/M期阻滞抑制Huh7细胞增殖
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20422
Haelim Yoon, Junho Lee, Sangil Kwon, Seung-Yong Seo, Sayeon Cho

Background/aim: Hepatocellular carcinoma (HCC) is a prevalent type of cancer worldwide. Although sorafenib is the only chemotherapy agent used for HCC, there is a need to discover a more potent anticancer agent with reduced side-effects. The compound, (S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (FMTC), was designed to inhibit tubulin assembly but its specific mechanisms of action have not been previously investigated. Herein, we investigated the regulation mechanisms by which FMTC affects the proliferation of the HCC cell line, Huh7.

Materials and methods: The effects of FMTC on cell viability and growth were analyzed in the HCC cell line, Huh7. Cell cycle and apoptosis regulated by FMTC were analyzed using flow cytometry. To verify the regulation of mRNA and protein expression of cell proliferation-related factors by FMTC in Huh7 cells, RT-qPCR and western blot analyses were employed.

Results: FMTC suppressed cell division dose-dependently by triggering cell cycle arrest at the G2/M phase via p21 up-regulation. The increased phosphorylation of histone H3 on Ser-10 and the condensation of chromatin in FMTC-treated cells indicated mitotic arrest. Prolonged FMTC-induced cell cycle arrest triggered apoptosis.

Conclusion: FMTC inhibits the proliferation of human liver cancer cells by up-regulating p21, thereby inducing cell cycle arrest at the G2/M phase. These findings highlight FMTC as a novel agent for HCC treatment.

背景/目的:肝细胞癌(HCC)是世界范围内常见的一种癌症。虽然索拉非尼是唯一用于HCC的化疗药物,但需要发现一种副作用更小的更有效的抗癌药物。化合物(S)-3-(3-氟-4-甲氧基苄基)-5,6,7-三甲氧基铬-4-酮(FMTC)被设计用于抑制微管蛋白组装,但其具体的作用机制尚未被研究。在此,我们研究了FMTC影响HCC细胞系Huh7增殖的调控机制。材料与方法:分析FMTC对HCC细胞株Huh7细胞活力和生长的影响。流式细胞术分析FMTC对细胞周期和凋亡的调控作用。为了验证FMTC对Huh7细胞中细胞增殖相关因子mRNA和蛋白表达的调控作用,采用RT-qPCR和western blot分析。结果:FMTC通过上调p21在G2/M期触发细胞周期阻滞,呈剂量依赖性地抑制细胞分裂。在fmtc处理的细胞中,Ser-10上组蛋白H3磷酸化的增加和染色质的凝聚表明有丝分裂停止。延长fmtc诱导的细胞周期阻滞触发细胞凋亡。结论:FMTC通过上调p21抑制人肝癌细胞增殖,从而诱导细胞周期阻滞在G2/M期。这些发现突出了FMTC作为HCC治疗的一种新型药物。
{"title":"(S)-3-(3-Fluoro-4-Methoxybenzyl)-5,6,7-Trimethoxychroman-4-One Suppresses the Proliferation of Huh7 Cells by Up-regulating P21 and Inducing G<sub>2</sub>/M Phase Arrest.","authors":"Haelim Yoon, Junho Lee, Sangil Kwon, Seung-Yong Seo, Sayeon Cho","doi":"10.21873/cgp.20422","DOIUrl":"10.21873/cgp.20422","url":null,"abstract":"<p><strong>Background/aim: </strong>Hepatocellular carcinoma (HCC) is a prevalent type of cancer worldwide. Although sorafenib is the only chemotherapy agent used for HCC, there is a need to discover a more potent anticancer agent with reduced side-effects. The compound, (S)-3-(3-fluoro-4-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (FMTC), was designed to inhibit tubulin assembly but its specific mechanisms of action have not been previously investigated. Herein, we investigated the regulation mechanisms by which FMTC affects the proliferation of the HCC cell line, Huh7.</p><p><strong>Materials and methods: </strong>The effects of FMTC on cell viability and growth were analyzed in the HCC cell line, Huh7. Cell cycle and apoptosis regulated by FMTC were analyzed using flow cytometry. To verify the regulation of mRNA and protein expression of cell proliferation-related factors by FMTC in Huh7 cells, RT-qPCR and western blot analyses were employed.</p><p><strong>Results: </strong>FMTC suppressed cell division dose-dependently by triggering cell cycle arrest at the G<sub>2</sub>/M phase via p21 up-regulation. The increased phosphorylation of histone H3 on Ser-10 and the condensation of chromatin in FMTC-treated cells indicated mitotic arrest. Prolonged FMTC-induced cell cycle arrest triggered apoptosis.</p><p><strong>Conclusion: </strong>FMTC inhibits the proliferation of human liver cancer cells by up-regulating p21, thereby inducing cell cycle arrest at the G<sub>2</sub>/M phase. These findings highlight FMTC as a novel agent for HCC treatment.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"20 6suppl","pages":"754-762"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138458077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Bayesian Approaches in Exploring Gene-environment and Gene-gene Interactions: A Comprehensive Review. 贝叶斯方法在基因-环境和基因-基因相互作用研究中的应用综述。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20414
N A Sun, Y U Wang, Jiadong Chu, Qiang Han, Yueping Shen

Rapid advancements in high-throughput biological techniques have facilitated the generation of high-dimensional omics datasets, which have provided a solid foundation for precision medicine and prognosis prediction. Nonetheless, the problem of missing heritability persists. To solve this problem, it is essential to explain the genetic structure of disease incidence risk and prognosis by incorporating interactions. The development of the Bayesian theory has provided new approaches for developing models for interaction identification and estimation. Several Bayesian models have been developed to improve the accuracy of model and identify the main effect, gene-environment (G×E) and gene-gene (G×G) interactions. Studies based on single-nucleotide polymorphisms (SNPs) are significant for the exploration of rare and common variants. Models based on the effect heredity principle and group-based models are relatively flexible and do not require strict constraints when dealing with the hierarchical structure between the main effect and interactions (M-I). These models have a good interpretability of biological mechanisms. Machine learning-based Bayesian approaches are highly competitive in improving prediction accuracy. These models provide insights into the mechanisms underlying the occurrence and progression of complex diseases, identify more reliable biomarkers, and develop higher predictive accuracy. In this paper, we provide a comprehensive review of these Bayesian approaches.

高通量生物技术的快速发展促进了高维组学数据集的生成,为精准医学和预后预测提供了坚实的基础。尽管如此,缺失遗传性的问题依然存在。为了解决这一问题,必须通过结合相互作用来解释疾病发病率、风险和预后的遗传结构。贝叶斯理论的发展为建立相互作用识别和估计模型提供了新的途径。为了提高模型的准确性,建立了几个贝叶斯模型,并确定了主效应、基因-环境(G×E)和基因-基因(G×G)的相互作用。基于单核苷酸多态性(SNPs)的研究对于探索罕见和常见变异具有重要意义。基于效应遗传原理的模型和基于群体的模型在处理主效应与交互作用(M-I)之间的层次结构时相对灵活,不需要严格的约束。这些模型具有良好的生物学机制解释性。基于机器学习的贝叶斯方法在提高预测精度方面具有很强的竞争力。这些模型提供了对复杂疾病发生和发展的机制的见解,确定了更可靠的生物标志物,并开发了更高的预测准确性。在本文中,我们提供了这些贝叶斯方法的全面回顾。
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引用次数: 0
Effect of NFATc2- and Sp1-mediated TNFalpha Regulation on the Proliferation and Migration Behavior of Pancreatic Cancer Cells. NFATc2-和sp1介导的TNFalpha调控对胰腺癌细胞增殖和迁移行为的影响
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20417
Manuela Malsy, Bernhard Graf, Elisabeth Bruendl, Constantin Maier-Stocker, Anika Bundscherer

Background/aim: One in two people will develop a tumor during their lifetime. Adenocarcinoma of the pancreas is one of the most aggressive types of cancer in humans with very poor long-term survival. A central role in the carcinogenesis of pancreatic cancer has been attributed to NFAT transcription factors. Previous studies have identified the transcription factor Sp1 as a binding partner of NFATc2 in pancreatic cancer. Using expression profile analysis, our group was able to identify the tumor necrosis factor TNFalpha as a target gene of the interaction between NFATc2 and Sp1. The present study investigated the effect of TNFalpha over-expression via the transcription factors NFATc2 and Sp1 on the pancreatic cancer cell lines PaTu 8988t and PANC-1.

Materials and methods: Transient transfection of NFATc2, Sp1, and TNFalpha siRNAs and their effects on the expression were investigated with immunoblot. Cell proliferation was measured with the ELISA BrdU assay. Cell migration was assayed with a Cell Migration Assay Kit using a Boyden chamber.

Results: Inhibition of the transfection factors NFATc2, Sp1, or TNFalpha by siRNA significantly inhibited proliferation, which was exacerbated when using the combination of NFATc2 and Sp1. TNFalpha was able to counterbalance this effect. In contrast to proliferation, migration of pancreatic cancer cells was increased by inhibiting these transfection factors.

Conclusion: Tumor progression is strongly influenced by transcriptional changes in signaling cascades and oncogene mutations as well as by changes in tumor suppressor genes. Further studies are needed to understand the underlying mechanisms of these processes.

背景/目的:每两个人中就有一个会在一生中患上肿瘤。胰腺腺癌是人类最具侵袭性的癌症之一,长期生存率很低。NFAT转录因子在胰腺癌的癌变中起着核心作用。先前的研究已经确定转录因子Sp1是胰腺癌中NFATc2的结合伴侣。通过表达谱分析,我们小组能够确定肿瘤坏死因子TNFalpha是NFATc2和Sp1相互作用的靶基因。本研究通过转录因子NFATc2和Sp1研究了TNFalpha过表达对胰腺癌细胞系PaTu 8988t和PANC-1的影响。材料和方法:用免疫印迹法观察瞬时转染NFATc2、Sp1和TNFalpha sirna及其对表达的影响。采用ELISA BrdU法检测细胞增殖。使用细胞迁移测定试剂盒(Cell migration Assay Kit)检测细胞迁移。结果:siRNA抑制转染因子NFATc2、Sp1或TNFalpha均能显著抑制细胞增殖,且NFATc2与Sp1联合使用时,抑制作用更明显。TNFalpha能够抵消这种影响。与增殖相反,抑制这些转染因子可增加胰腺癌细胞的迁移。结论:肿瘤的进展受信号级联和癌基因突变的转录变化以及肿瘤抑制基因的变化的强烈影响。需要进一步的研究来了解这些过程的潜在机制。
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引用次数: 0
Orexins and Prostate Cancer: State of the Art and Potential Experimental and Therapeutic Perspectives. 食欲素和前列腺癌:最新进展和潜在的实验和治疗前景。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20412
Anna Costagliola, Renato Lombardi, Giovanna Liguori, Andrea Morrione, Antonio Giordano

Prostate cancer (PCa) is the second most common cancer in humans. Peptides have recently been used as targeted therapeutics in cancers, due to their extensive multi-functional applications. Two hypothalamic peptides, orexins A (OXA) and B (OXB) and their specific receptors, orexin receptor 1 (OX1R) and 2 (OX2R), orchestrate several biological processes in the central nervous system and peripheral organs. However, in addition to their role in physiological responses, orexins are involved in numerous inflammatory and/or neoplastic pathologies. The presence and expression of orexins in different cancer models, including prostate cancer, and their role in inducing pro- or anti-apoptotic responses in tumor cell lines, suggest that the orexinergic system might have potential therapeutic action or function as a diagnostic marker in PCa. In addition to the traditional animal models for studying human PCa, the canine model might also serve as an additional tool, due to its clinical similarities with human prostate cancer.

前列腺癌(PCa)是人类第二大常见癌症。肽由于其广泛的多功能应用,近年来已被用作癌症的靶向治疗药物。两种下丘脑肽,食欲素A (OXA)和B (OXB)及其特异性受体,食欲素受体1 (OX1R)和2 (OX2R),在中枢神经系统和外周器官中协调多种生物过程。然而,除了它们在生理反应中的作用外,食欲素还参与许多炎症和/或肿瘤病理。食欲素在包括前列腺癌在内的不同癌症模型中的存在和表达,以及它们在肿瘤细胞系中诱导促或抗凋亡反应的作用,表明食欲素系统可能具有潜在的治疗作用或作为前列腺癌的诊断标志物。除了研究人类前列腺癌的传统动物模型外,犬类模型也可以作为一种额外的工具,因为它与人类前列腺癌具有临床相似性。
{"title":"Orexins and Prostate Cancer: State of the Art and Potential Experimental and Therapeutic Perspectives.","authors":"Anna Costagliola, Renato Lombardi, Giovanna Liguori, Andrea Morrione, Antonio Giordano","doi":"10.21873/cgp.20412","DOIUrl":"10.21873/cgp.20412","url":null,"abstract":"<p><p>Prostate cancer (PCa) is the second most common cancer in humans. Peptides have recently been used as targeted therapeutics in cancers, due to their extensive multi-functional applications. Two hypothalamic peptides, orexins A (OXA) and B (OXB) and their specific receptors, orexin receptor 1 (OX1R) and 2 (OX2R), orchestrate several biological processes in the central nervous system and peripheral organs. However, in addition to their role in physiological responses, orexins are involved in numerous inflammatory and/or neoplastic pathologies. The presence and expression of orexins in different cancer models, including prostate cancer, and their role in inducing pro- or anti-apoptotic responses in tumor cell lines, suggest that the orexinergic system might have potential therapeutic action or function as a diagnostic marker in PCa. In addition to the traditional animal models for studying human PCa, the canine model might also serve as an additional tool, due to its clinical similarities with human prostate cancer.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"20 6suppl","pages":"637-645"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138458021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
The Combination of Methioninase and Ethionine Exploits Methionine Addiction to Selectively Eradicate Osteosarcoma Cells and Not Normal Cells and Synergistically Down-regulates the Expression of C-MYC. 蛋氨酸酶和蛋氨酸联合利用蛋氨酸依赖性选择性根除骨肉瘤细胞和非正常细胞并协同下调C-MYC的表达。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20415
Yusuke Aoki, Yutaro Kubota, Qinghong Han, Noriyuki Masaki, Koya Obara, Michael Bouvet, Sant P Chawla, Yasunori Tome, Kotaro Nishida, Robert M Hoffman

Background/aim: The fundamental and general hallmark of cancer cells, methionine addiction, termed the Hoffman effect, is due to overuse of methionine for highly-increased transmethylation reactions. In the present study, we tested if the combination efficacy of recombinant methioninase (rMETase) and a methionine analogue, ethionine, could eradicate osteosarcoma cells and down-regulate the expression of c-MYC.

Materials and methods: 143B osteosarcoma cells and Hs27 normal human fibroblasts were tested. The efficacy of rMETase alone and ethionine, alone and in their combination, on cell viability was determined with the WST-8 assay on 143B cells and Hs27 cells. c-MYC expression was examined with western immunoblotting and compared in 143B cells treated with/without rMETase, ethionine, or the combination of both rMETase and ethionine.

Results: 143B cells were more sensitive to both rMETase and ethionine than Hs 27 cells, with the following IC50s: rMETase (143B: 0.22 U/ml; Hs27: 0.82 U/ml); ethionine (143B: 0.24 mg/ml; Hs27: 0.42 mg/ml). The combination of rMETase and ethionine synergistically eradicated 143B cells, lowering the IC50 for ethionine 14-fold compared to ethionine alone (p<0.001). In contrast, Hs27 fibroblasts were relatively resistant to the combination. The expression of c-MYC was significantly down-regulated only by the combination of rMETase and ethionine in 143B cells (p<0.001).

Conclusion: In the present study, we showed, for the first time, the synergistic combination efficacy of rMETase and ethionine on osteosarcoma cells in contrast to normal fibroblasts, which were relatively resistant. The combination of rMETase and ethionine down-regulated c-MYC expression in the cancer cells. The present results indicate the combination of rMETase and ethionine may reduce the malignancy of osteosarcoma cells and can be a potential future clinical strategy.

背景/目的:甲硫氨酸成瘾是癌细胞的基本和普遍特征,被称为霍夫曼效应,是由于过度使用蛋氨酸引起高度增加的转甲基化反应。在本研究中,我们测试了重组蛋氨酸酶(rMETase)和蛋氨酸类似物乙硫氨酸(ethionine)联合使用是否能根除骨肉瘤细胞并下调c-MYC的表达。材料和方法:143B骨肉瘤细胞和Hs27正常人成纤维细胞。在143B细胞和Hs27细胞上采用WST-8法测定rMETase单独和蛋氨酸、单独和联合使用对细胞活力的影响。用western免疫印迹法检测c-MYC的表达,并比较在加/不加rMETase、蛋氨酸或rMETase和蛋氨酸联合处理的143B细胞中c-MYC的表达。结果:143B细胞对rMETase和蛋氨酸的敏感性均高于Hs 27细胞,其ic50值如下:rMETase (143B: 0.22 U/ml;Hs27: 0.82 U/ml);乙硫氨酸(143B: 0.24 mg/ml;Hs27: 0.42 mg/ml)。rMETase和ethionine联合使用可协同根除143B细胞,使其IC50比单独使用时降低14倍(p)结论:本研究中,我们首次发现rMETase和ethionine联合使用对骨肉瘤细胞具有协同作用,而对正常成纤维细胞具有相对的耐药性。rMETase和乙硫氨酸联合作用可下调癌细胞中c-MYC的表达。目前的研究结果表明,rMETase和蛋氨酸联合使用可能会降低骨肉瘤细胞的恶性程度,并可能成为未来临床治疗骨肉瘤的一种潜在策略。
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引用次数: 0
Kinase D-interacting Substrate of 220 kDa Is Overexpressed in Gastric Cancer and Associated With Local Invasion. 激酶d相互作用的220 kDa底物在胃癌中过表达并与局部侵袭有关。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20420
Shuo Cai, Zhiwei Sun, Xiangyu Gao, K E Ji, Fiona Ruge, Deepa Shankla, Xiangyi Liu, Wen G Jiang, Lin Ye

Background/aim: Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning protein (ARMS), is a transmembrane scaffold protein. Deregulated Kidins220 has been observed in various malignancies including melanoma, glioma, neuroblastoma, prostate cancer, pancreatic cancer, and ovarian cancer.

Materials and methods: In the current study, Kidins220 expression was determined at transcript and protein levels. A Kidins220 knockdown cell model was established to identify its role in cellular functions including cell cycle, proliferation, and invasion. Cell signalling was analysed by protein array and the TCGA gastric cancer cohort.

Results: Kidins220 transcript levels were significantly increased in gastric tumours, compared with adjacent normal tissues. More advanced tumours (TNMIII and TNMIV) exhibited higher protein levels of Kidins220 compared with early-stage tumours (TNMI and TNMII). Increased expression of Kidins220 in gastric cancer was associated with poorer overall survival. Loss of Kidins220 promoted cell invasion and adhesion of gastric cancer and correlated to epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) signalling. Knockdown of Kidins220 promoted proliferation of gastric cancer cells with an increased population at the G2/M phase.

Conclusion: Our study identified increased expression of Kidins220 in gastric cancer, which is associated with disease progression and poor prognosis. However, Kidins220 presented an inhibitory effect on the proliferation, invasion, and adhesion through a regulation of EMT, MMP and cell cycle.

背景/目的:220 kDa的激酶d相互作用底物(Kidins220),也称为富含锚蛋白重复的膜跨越蛋白(ARMS),是一种跨膜支架蛋白。不受管制的Kidins220已被观察到用于各种恶性肿瘤,包括黑色素瘤、胶质瘤、神经母细胞瘤、前列腺癌、胰腺癌和卵巢癌。材料和方法:在目前的研究中,Kidins220在转录物和蛋白水平上表达。建立了Kidins220敲低细胞模型,以确定其在细胞周期、增殖和侵袭等细胞功能中的作用。通过蛋白阵列和TCGA胃癌队列分析细胞信号传导。结果:与邻近正常组织相比,胃肿瘤中Kidins220转录物水平显著升高。与早期肿瘤(TNMI和TNMII)相比,晚期肿瘤(TNMIII和TNMIV)表现出更高的Kidins220蛋白水平。胃癌中Kidins220的表达增加与较差的总生存期相关。Kidins220的缺失促进了胃癌细胞的侵袭和粘附,并与上皮间质转化(EMT)和基质金属蛋白酶(MMP)信号传导有关。在G2/M期,敲低Kidins220促进了胃癌细胞的增殖,增加了胃癌细胞的数量。结论:我们的研究发现,Kidins220在胃癌中表达增加,与疾病进展和预后不良有关。然而,Kidins220通过调节EMT、MMP和细胞周期对增殖、侵袭和粘附有抑制作用。
{"title":"Kinase D-interacting Substrate of 220 kDa Is Overexpressed in Gastric Cancer and Associated With Local Invasion.","authors":"Shuo Cai, Zhiwei Sun, Xiangyu Gao, K E Ji, Fiona Ruge, Deepa Shankla, Xiangyi Liu, Wen G Jiang, Lin Ye","doi":"10.21873/cgp.20420","DOIUrl":"10.21873/cgp.20420","url":null,"abstract":"<p><strong>Background/aim: </strong>Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning protein (ARMS), is a transmembrane scaffold protein. Deregulated Kidins220 has been observed in various malignancies including melanoma, glioma, neuroblastoma, prostate cancer, pancreatic cancer, and ovarian cancer.</p><p><strong>Materials and methods: </strong>In the current study, Kidins220 expression was determined at transcript and protein levels. A Kidins220 knockdown cell model was established to identify its role in cellular functions including cell cycle, proliferation, and invasion. Cell signalling was analysed by protein array and the TCGA gastric cancer cohort.</p><p><strong>Results: </strong>Kidins220 transcript levels were significantly increased in gastric tumours, compared with adjacent normal tissues. More advanced tumours (TNMIII and TNMIV) exhibited higher protein levels of Kidins220 compared with early-stage tumours (TNMI and TNMII). Increased expression of Kidins220 in gastric cancer was associated with poorer overall survival. Loss of Kidins220 promoted cell invasion and adhesion of gastric cancer and correlated to epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) signalling. Knockdown of Kidins220 promoted proliferation of gastric cancer cells with an increased population at the G<sub>2</sub>/M phase.</p><p><strong>Conclusion: </strong>Our study identified increased expression of Kidins220 in gastric cancer, which is associated with disease progression and poor prognosis. However, Kidins220 presented an inhibitory effect on the proliferation, invasion, and adhesion through a regulation of EMT, MMP and cell cycle.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"20 6suppl","pages":"735-743"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138458019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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