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Preoperative ctDNA Levels Are Associated With Poor Overall Survival in Patients With Ovarian Cancer. 术前ctDNA水平与卵巢癌患者较差的总生存率相关
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20423
Arturas Dobilas, Yilun Chen, Christian Brueffer, Pia Leandersson, Lao H Saal, Christer Borgfeldt

Background/aim: Circulating tumor DNA (ctDNA), which is shed from cancer cells into the bloodstream, offers a potential minimally invasive approach for cancer diagnosis and monitoring. This research aimed to assess the preoperative ctDNA levels in ovarian tumors patients' plasma and establish correlations with clinicopathological parameters and patient prognosis.

Patients and methods: Tumor DNA was extracted from ovarian tumor tissue from 41 patients. Targeted sequencing using a panel of 127 genes recurrently mutated in cancer was performed to identify candidate somatic mutations in the tumor DNA. SAGAsafe digital PCR (dPCR) assays targeting the candidate mutations were used to measure ctDNA levels in patient plasma samples, obtained prior to surgery, to evaluate ctDNA levels in terms of mutant copy number/ml and variant allele frequency.

Results: Somatic mutations were found in 24 tumor samples, 17 of which were from ovarian cancer patients. The most frequently mutated gene was TP53. Preoperative plasma ctDNA levels were detected in 14 of the 24 patients. With higher stage, plasma ctDNA mutant concentration increased (p for trend <0.001). The overall survival of cancer patients with more than 10 ctDNA mutant copies/ml in plasma was significantly worse (p=0.008).

Conclusion: Pre-operative ctDNA measurement in ovarian cancer patients' plasma holds promise as a predictive biomarker for tumor staging and prognosis.

背景/目的:循环肿瘤DNA (ctDNA)从癌细胞转移到血液中,为癌症诊断和监测提供了一种潜在的微创方法。本研究旨在评估卵巢肿瘤患者术前血浆中ctDNA水平,并建立其与临床病理参数和患者预后的相关性。患者和方法:从41例卵巢肿瘤组织中提取肿瘤DNA。使用一组127个在癌症中反复突变的基因进行靶向测序,以确定肿瘤DNA中的候选体细胞突变。针对候选突变的SAGAsafe数字PCR (dPCR)检测用于测量手术前获得的患者血浆样本中的ctDNA水平,以突变拷贝数/ml和变异等位基因频率来评估ctDNA水平。结果:24份肿瘤样本中发现体细胞突变,其中17份来自卵巢癌患者。最常见的突变基因是TP53。24例患者中有14例术前检测血浆ctDNA水平。结论:术前卵巢癌患者血浆ctDNA检测可作为预测肿瘤分期和预后的生物标志物。
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引用次数: 0
Fucoxanthin Inhibits Development of Sigmoid Colorectal Cancer in a PDX Model With Alterations of Growth, Adhesion, and Cell Cycle Signals. 岩藻黄素通过改变生长、粘附和细胞周期信号抑制乙状结肠直肠癌的发展。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-12-01 DOI: 10.21873/cgp.20416
Masaru Terasaki, Kirara Tsuruoka, Takuji Tanaka, Hayato Maeda, Masaki Shibata, Kazuo Miyashita, Yukihide Kanemitsu, Shigeki Sekine, Mami Takahashi, Shigehiro Yagishita, Akinobu Hamada

Background/aim: Fucoxanthin (Fx), a dietary marine xanthophyll, exerts potent anticancer effects in various colorectal cancer (CRC) animal models. However, therapeutic effects of Fx in human cancer tissues remain unclear. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissues from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates.

Materials and methods: Herein, we investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with CRC (CRC-PDX) using LC-MS/MS- and western blot-based proteome analysis.

Results: The tumor in the patient with CRC was a primary adenocarcinoma (T3N0M0, stage II) showing mutations of certain genes that were tumor protein p53 (TP53), AT-rich interaction domain 1A (ARID1A), neuroblastoma RAS viral oncogene homolog (NRAS), and PMS1 homolog 2 (PMS2). Administration of Fx significantly suppressed the tumor growth (0.6-fold) and tended to induce differentiation in CRC-PDX mice. Fx up-regulated glycanated-decorin (Gc-DCN) expression, and down-regulated Kinetochore-associated protein DSN1 homolog (DSN1), phospho(p) focal adhesion kinase (pFAK)(Tyr397), pPaxillin(Tyr31), and c-MYC involved in growth, adhesion, and/or cell cycle, in the tumors of CRC-PDX mice than in control mice. Alterations in the five proteins were consistent with those in human CRC HT-29 and HCT116 cells treated with fucoxanthinol (FxOH, a major metabolite of Fx).

Conclusion: Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals.

背景/目的:岩藻黄素(Fx)是一种膳食中的海洋叶黄素,在多种结直肠癌(CRC)动物模型中具有较强的抗癌作用。然而,Fx在人类癌症组织中的治疗效果尚不清楚。患者来源的异种移植(PDX)小鼠模型移植了患者的癌症组织,被广泛认为是评估候选药物抗癌潜力的最佳临床前模型。材料和方法:在此,我们使用LC-MS/MS-和基于western blot的蛋白质组分析,研究Fx在移植了CRC患者肿瘤组织(CRC-PDX)的PDX小鼠中的抗癌作用。结果:该结直肠癌患者的肿瘤为原发性腺癌(T3N0M0, II期),表现为肿瘤蛋白p53 (TP53)、AT-rich相互作用结构域1A (ARID1A)、神经母细胞瘤RAS病毒癌基因同源物(NRAS)和PMS1同源物2 (PMS2)的某些基因突变。Fx可显著抑制CRC-PDX小鼠的肿瘤生长(0.6倍),并有诱导分化的倾向。与对照小鼠相比,Fx上调了CRC-PDX小鼠肿瘤中glycanateddecorin (Gc-DCN)的表达,下调了kinetochore相关蛋白DSN1同源物(DSN1)、磷酸化(p)局灶黏附激酶(pFAK)(Tyr397)、pPaxillin(Tyr31)和参与生长、黏附和/或细胞周期的c-MYC。这五种蛋白的变化与用岩藻黄嘌呤(FxOH, Fx的主要代谢物)处理的人CRC HT-29和HCT116细胞的变化一致。结论:Fx抑制人样结直肠癌组织的发育,特别是通过生长、粘附和细胞周期信号。
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引用次数: 0
p21 Protein Outperforms Clinico-pathological Criteria in Predicting Liver Metastases in Pancreatic Endocrine Tumors. p21蛋白在预测胰腺内分泌肿瘤肝转移方面优于临床病理标准。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20402
Aejaz Nasir, Malik K Ahmed, James J Saller, Evita B Henderson-Jackson, Mokenge P Malafa, Timothy J Yeatman, Domenico Coppola

Background/aim: P21 is a cyclin-dependent kinase inhibitor regulating the cell cycle as a tumor suppressor. Using a p21 immunohistochemistry (IHC) assay, we compared tumor p21 levels with conventional clinico-pathological criteria in primary pancreatic endocrine tumor subsets with and without liver metastases.

Materials and methods: Sections from tissue microarray (TMA) including 13 archival metastatic primary and 18 non-metastatic primary pancreatic endocrine carcinomas/tumors (MP-PECAs/NMP-PETs) were stained with a monoclonal anti-p21WAFI,CIP primary antibody. Tumor p21 IHCs were scored as the sum of intensity (0-3) and proportion scores (0-5) (Total Allred score: 0-8), and as p21% labelling index in the tumor. ROC curve analysis was used for most optimal p21 score cut-off (4 or >) and Fisher's exact test was used to compare the association among tumor p21 scores, conventional prognostic criteria, and liver metastases.

Results: For PET/PECA patients, mean ages were 55.6 years (27-73) and 49.3 years (28-71), M/F ratios were 7/11 and 7/6. Mean p21 labelling index (%) for MP- PECAs was 24% (range=3-63%) vs. 9% for NMP-PETs (range=1-25%) (p=0.022). The mean p21 index in MP-PECAs was significantly higher (24%) as compared to PIs (7%) (p=0.0047). Using a p21 Allred score of ≥4, high p21 IHC score had strong association with the presence of liver metastases (p-value <0.001). High tumor p21 IHC score had a 93% sensitivity, 68% specificity, 78% predictive accuracy, 66% positive, and 94% negative predictive values.

Conclusion: In patients with primary PETs, p21 IHC is superior to conventional criteria in predicting presence or absence of liver metastases.

背景/目的:P21是一种细胞周期蛋白依赖性激酶抑制剂,作为肿瘤抑制因子调节细胞周期。使用p21免疫组织化学(IHC)检测,我们将有和无肝转移的原发性胰腺内分泌肿瘤亚群的肿瘤p21水平与常规临床病理标准进行了比较。材料和方法:用单克隆抗p21WAFI、CIP一级抗体对组织微阵列(TMA)的切片进行染色,其中包括13个档案转移性原发性胰腺内分泌癌/肿瘤和18个非转移性原发性胰腺内分泌肿瘤(MP PECAs/NMP PETs)。肿瘤p21 IHCs的评分为强度(0-3)和比例评分(0-5)的总和(Allred总分:0-8),以及肿瘤中p21%标记指数。ROC曲线分析用于最佳p21评分截止值(4或>),Fisher精确检验用于比较肿瘤p21评分、常规预后标准和肝转移之间的相关性。结果:PET/PECA患者的平均年龄分别为55.6岁(27-73岁)和49.3岁(28-71岁),M/F比分别为7/11和7/6。MP-PECAs的平均p21标记指数(%)为24%(范围=3-63%),而NMP PET为9%(范围=1-25%)(p=0.022)。MP-PECAs的平均p21指数(24%)明显高于PI(7%)(p=0.0047),高p21 IHC评分与肝转移的存在密切相关(p值)结论:在原发性PETs患者中,p21IHC在预测是否存在肝转移方面优于传统标准。
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引用次数: 0
Potential Common Molecular Mechanisms Between Periodontitis and Hepatocellular Carcinoma: A Bioinformatic Analysis and Validation. 牙周炎和肝细胞癌之间潜在的共同分子机制:生物信息学分析和验证。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20409
Xiaomiao Fan, Zimin Song, Wenguang Qin, Ting Yu, Baogang Peng, Yuqin Shen

Background/aim: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has a poor prognosis. Periodontitis, or tooth loss, is considered to be related to hepatocarcinogenesis and its poor prognosis. This study aimed to explore potential associations and cross-talk mechanisms between periodontitis and HCC.

Materials and methods: Periodontitis and HCC microarray datasets were acquired from the Gene Expression Omnibus (GEO) database and were analyzed to obtain differentially expressed (DE) lncRNAs, miRNAs and mRNAs. Functional enrichment analysis was used to detect the functions of these mRNAs. Then, a ceRNA network of periodontitis-related HCC was constructed. Least absolute shrinkage and selection operator (LASSO) regression, random forest algorithm, and support vector machine-recursive feature elimination (SVM-RFE) were performed to explore the diagnostic significance of mRNAs in periodontitis-related HCC. Cox regression analyses were conducted to screen mRNAs with prognostic significance in HCC. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were conducted to validate the expression of these mRNAs in HCC tissues.

Results: A ceRNA network was constructed. Functional enrichment analysis indicated that the network is associated with immune and inflammatory responses, the cell cycle and liver metabolic function. LASSO, random forest algorithm and SVM-RFE showed the diagnostic significance of DE mRNAs in HCC. Cox regression analyses revealed that MSH2, GRAMD1C and CTHRC1 have prognostic significance for HCC, and qRT-PCR and IHC validated this finding.

Conclusion: Periodontitis may affect the occurrence of HCC by changing the immune and inflammatory response, the cell cycle and liver metabolic function. MSH2, GRAMD1C and CTHRC1 are potential prognostic biomarkers for HCC.

背景/目的:肝细胞癌(HCC)是癌症最常见的原发性肝癌,预后不良。牙周炎或牙齿脱落被认为与肝癌的发生及其不良预后有关。本研究旨在探索牙周炎与HCC之间的潜在关联和串扰机制。材料和方法:从基因表达综合数据库(GEO)中获取牙周炎和HCC微阵列数据集,并进行分析以获得差异表达(DE)的lncRNA、miRNA和mRNA。功能富集分析用于检测这些mRNA的功能。然后,构建了牙周炎相关HCC的ceRNA网络。采用最小绝对收缩选择算子(LASSO)回归、随机森林算法和支持向量机递归特征消除(SVM-RFE)来探讨mRNAs在牙周炎相关HCC中的诊断意义。Cox回归分析用于筛选HCC中具有预后意义的mRNA。定量实时PCR(qRT-PCR)和免疫组织化学(IHC)验证了这些mRNA在HCC组织中的表达。结果:构建了ceRNA网络。功能富集分析表明,该网络与免疫和炎症反应、细胞周期和肝脏代谢功能有关。LASSO、随机森林算法和SVM-RFE显示了DE mRNA对HCC的诊断意义。Cox回归分析显示MSH2、GRAMD1C和CTHRC1对HCC具有预后意义,qRT-PCR和IHC验证了这一发现。结论:牙周炎可能通过改变免疫和炎症反应、细胞周期和肝脏代谢功能来影响HCC的发生。MSH2、GRAMD1C和CTHRC1是HCC的潜在预后生物标志物。
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引用次数: 0
Hepatocellular Carcinoma: Up-regulated Circular RNAs Which Mediate Efficacy in Preclinical In Vivo Models. 肝细胞癌:临床前体内模型中介导疗效的上调环状RNA。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20401
Ulrich H Weidle, Adam Nopora

Hepatocellular carcinoma (HCC) ranges as number two with respect to the incidence of tumors and is associated with a dismal prognosis. The therapeutic efficacy of approved multi-tyrosine kinase inhibitors and checkpoint inhibitors is modest. Therefore, the identification of new therapeutic targets and entities is of paramount importance. We searched the literature for up-regulated circular RNAs (circRNAs) which mediate efficacy in preclinical in vivo models of HCC. Our search resulted in 14 circRNAs which up-regulate plasma membrane transmembrane receptors, while 5 circRNAs induced secreted proteins. Two circRNAs facilitated replication of Hepatitis B or C viruses. Three circRNAs up-regulated high mobility group proteins. Six circRNAs regulated components of the ubiquitin system. Seven circRNAs induced GTPases of the family of ras-associated binding proteins (RABs). Three circRNAs induced redox-related proteins, eight of them up-regulated metabolic enzymes and nine circRNAs induced signaling-related proteins. The identified circRNAs up-regulate the corresponding targets by sponging microRNAs. Identified circRNAs and their targets have to be validated by standard criteria of preclinical drug development. Identified targets can potentially be inhibited by small molecules or antibody-based moieties and circRNAs can be inhibited by small-interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) for therapeutic purposes.

肝细胞癌(HCC)在肿瘤发生率方面排名第二,与预后不佳有关。经批准的多酪氨酸激酶抑制剂和检查点抑制剂的治疗效果是适度的。因此,识别新的治疗靶点和实体至关重要。我们在文献中搜索了上调的环状RNA(circRNA),其在HCC的临床前体内模型中介导疗效。我们的研究发现14个circRNA上调质膜跨膜受体,而5个circRNAs诱导分泌蛋白。两种circRNA促进了乙型肝炎或丙型肝炎病毒的复制。三种circRNA上调高迁移率组蛋白。六个circRNA调节泛素系统的组成部分。七个circRNA诱导ras相关结合蛋白家族的GTP酶。三种circRNA诱导氧化还原相关蛋白,其中八种上调代谢酶,九种circRNAs诱导信号传导相关蛋白。已鉴定的circRNA通过吸收微小RNA上调相应的靶点。已鉴定的circRNA及其靶标必须通过临床前药物开发的标准标准进行验证。已识别的靶点可能被小分子或基于抗体的部分抑制,CircRNA可以被小干扰RNA(siRNA)或短发夹RNA(shRNA)抑制用于治疗目的。
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引用次数: 0
Hsa_circ_0079557 Promotes the Proliferation of Colorectal Cancer Cells Through the hsa_circ_0079557/miR-502-5p/CCND1 Axis. Hsa_circ_07957通过Hsa_cir_0079557/miR-502-5p/CCND1轴促进结直肠癌癌症细胞的增殖。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20406
Chao Yu, Xue Huang, Renli Huang, Peiqi Wang, Zongda Cai, Zeyi Guo, Qingnan Lan, Haodi Cao, Jinlong Yu

Background/aim: Recent studies have demonstrated the crucial regulatory roles of circular RNAs (circRNAs) in cancer initiation and progression. The sponge mechanism of circRNAs has been shown to be widely active in various types of tumors. However, many circRNAs still have not been verified to function through this mechanism. This study aimed to investigate the regulatory mechanism of hsa_circ_0079557 in colorectal cancer (CRC) and its role in CRC progression.

Materials and methods: Raw gene expression profile datasets were downloaded from Gene Expression Omnibus (GEO) and combined to form a new dataset. Hsa_circ_0079557 was found to be highly expressed in CRC. Its role was evaluated in vitro and in vivo through a series of experiments, including quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, colony formation, cell counting kit-8 (CCK-8), transwell assays, scratch wound healing assays, nude mice experiments, and immunohistochemistry (IHC). The association between hsa_circ_0079557 and the identified target microRNAs (miRNA) was confirmed through fluorescence in situ hybridization (FISH) and dual-luciferase reporter assays. The downstream target proteins were predicted using the web-based tool "TargetScan," and their expressions were determined using Western blot (WB).

Results: Hsa_circ_0079557 was found to be relatively up-regulated in CRC tissues and cell lines. Suppression of hsa_circ_0079557 expression inhibited cell proliferation in vitro and in vivo. Additionally, hsa_circ_0079557 acted as a "molecular sponge" for miR-502-5p, up-regulating the expression of Cyclin D1 (CCND1).

Conclusion: In this study, we identify a highly expressed circRNA in CRC and propose a novel pathway of hsa_circ_0079557/miR-502-5p/CCND1 in CRC.

背景/目的:最近的研究证明了环状RNA(circRNA)在癌症发生和发展中的关键调节作用。circRNAs的海绵机制已被证明在各种类型的肿瘤中具有广泛的活性。然而,许多circRNA仍未被证实通过这种机制发挥作用。本研究旨在探讨hsa_cir_0079557在癌症(CRC)中的调节机制及其在CRC进展中的作用。材料和方法:从gene expression Omnibus(GEO)下载原始基因表达谱数据集,并将其组合形成新的数据集。发现Hsa_cir_0079557在CRC中高度表达。通过一系列实验在体外和体内评估了其作用,包括定量实时聚合酶链式反应(qRT-PCR)、流式细胞术、集落形成、细胞计数试剂盒-8(CCK-8)、transwell测定、划痕愈合测定、裸鼠实验和免疫组化(IHC)。通过荧光原位杂交(FISH)和双荧光素酶报告基因测定证实了hsa_cir_0079557与已鉴定的靶微小RNA(miRNA)之间的关联。使用基于网络的工具“TargetScan”预测下游靶蛋白,并使用蛋白质印迹(WB)测定其表达。结果:Hsa_cir_0079557在CRC组织和细胞系中相对上调。抑制hsa_cir_0079557的表达抑制了体外和体内的细胞增殖。此外,hsa_cir_0079557作为miR-502-5p的“分子海绵”,上调细胞周期蛋白D1(CCND1)的表达。
{"title":"Hsa_circ_0079557 Promotes the Proliferation of Colorectal Cancer Cells Through the hsa_circ_0079557/miR-502-5p/CCND1 Axis.","authors":"Chao Yu, Xue Huang, Renli Huang, Peiqi Wang, Zongda Cai, Zeyi Guo, Qingnan Lan, Haodi Cao, Jinlong Yu","doi":"10.21873/cgp.20406","DOIUrl":"10.21873/cgp.20406","url":null,"abstract":"<p><strong>Background/aim: </strong>Recent studies have demonstrated the crucial regulatory roles of circular RNAs (circRNAs) in cancer initiation and progression. The sponge mechanism of circRNAs has been shown to be widely active in various types of tumors. However, many circRNAs still have not been verified to function through this mechanism. This study aimed to investigate the regulatory mechanism of hsa_circ_0079557 in colorectal cancer (CRC) and its role in CRC progression.</p><p><strong>Materials and methods: </strong>Raw gene expression profile datasets were downloaded from Gene Expression Omnibus (GEO) and combined to form a new dataset. Hsa_circ_0079557 was found to be highly expressed in CRC. Its role was evaluated in vitro and in vivo through a series of experiments, including quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, colony formation, cell counting kit-8 (CCK-8), transwell assays, scratch wound healing assays, nude mice experiments, and immunohistochemistry (IHC). The association between hsa_circ_0079557 and the identified target microRNAs (miRNA) was confirmed through fluorescence in situ hybridization (FISH) and dual-luciferase reporter assays. The downstream target proteins were predicted using the web-based tool \"TargetScan,\" and their expressions were determined using Western blot (WB).</p><p><strong>Results: </strong>Hsa_circ_0079557 was found to be relatively up-regulated in CRC tissues and cell lines. Suppression of hsa_circ_0079557 expression inhibited cell proliferation in vitro and in vivo. Additionally, hsa_circ_0079557 acted as a \"molecular sponge\" for miR-502-5p, up-regulating the expression of Cyclin D1 (CCND1).</p><p><strong>Conclusion: </strong>In this study, we identify a highly expressed circRNA in CRC and propose a novel pathway of hsa_circ_0079557/miR-502-5p/CCND1 in CRC.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"20 6","pages":"567-581"},"PeriodicalIF":2.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54227755","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
SUV39H1 Expression as a Guideline for Omitting Radiotherapy in Lymph Node-positive Triple-negative Breast Cancer Patients. SUV39H1表达作为癌症淋巴结阳性三阴性乳腺癌患者省略放射治疗的指南。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20407
Wei-Lun Huang, Chi-Wen Luo, Huei-Shan Lin, Chao-Ming Hung, Fang-Ming Chen, Sin-Hua Moi, Mei-Ren Pan

Background/aim: The role of postoperative radiotherapy (RT) combined with chemotherapy (CT) for lymph node-positive (LN+) triple-negative breast cancer (TNBC) remains controversial. SUV39H1-mediated epigenetic regulation is associated with cancer cell migration, invasion, metastasis, and treatment resistance. This study aims to identify the role of SUV39H1 in TNBCs.

Materials and methods: Overall, 498 TNBCs with SUV39H1 RNA-seq profiles were retrieved from TCGA-BRCA and analyzed; the X-tile algorithm was used to stratify the population into low, intermediate, and high SUV39H1. Furthermore, we performed an in vitro clonogenic cell survival assay using the MDA-MB-231 cell line to assess the effects of SUV39H1 on cellular responses.

Results: The results showed that SUV39H1 was significantly higher in TNBC than normal tissue and luminal subtype breast cancer. Notably, SUV39H1 is significantly expressed in the basal-like 1 (BL1) and immunomodulatory (IM) subgroups, compared to other subtypes. Compared to patients with a low or medium expression of SUV39H1, omitting RT only worsens disease-free survival (DFS) in those with high SUV39H1 expression. The experimental results showed SUV39H1 was suppressed by si-SUV39H1, and SUV39H1 knockdown in MDA-MB-231-IV2-1 cells enhanced the cellular toxicity of doxorubicin and paclitaxel.

Conclusion: Targeting SUV39H1 may provide a potential guiding indication of omitting RT to avoid over-treatment and chemosensitivity for TNBC.

背景/目的:术后放疗(RT)联合化疗(CT)治疗淋巴结阳性(LN+)三阴性癌症(TNBC)的作用仍存在争议。SUV39H1介导的表观遗传学调控与癌症细胞迁移、侵袭、转移和治疗耐药性有关。本研究旨在确定SUV39H1在TNBCs中的作用。材料和方法:从TCGA-BRCA中检索并分析了498个具有SUV39H1RNA-seq图谱的TNBCs;使用X-tile算法将种群分为低、中、高SUV39H1。此外,我们使用MDA-MB-231细胞系进行了体外克隆细胞存活测定,以评估SUV39H1对细胞反应的影响。结果:SUV39H1在TNBC中的表达明显高于正常组织和管腔亚型癌症。值得注意的是,与其他亚型相比,SUV39H1在基底样1(BL1)和免疫调节(IM)亚组中显著表达。与SUV39H1低表达或中等表达的患者相比,省略RT只会恶化SUV39H1高表达患者的无病生存率(DFS)。实验结果表明,SUV39H1被si-SUV39H1抑制,在MDA-MB-231-IV2-1细胞中敲低SUV39H1增强了阿霉素和紫杉醇的细胞毒性。结论:靶向SUV39H1可能为省略RT以避免TNBC的过度治疗和化疗敏感性提供潜在的指导指征。
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引用次数: 0
Pathogenetic Dichotomy in Angioleiomyoma. 血管平滑肌瘤的病因二分术。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20405
Ioannis Panagopoulos, Kristin Andersen, Marta Brunetti, Ludmila Gorunova, Ilyá Kostolomov, Wanja Kildal, Hanne Regine Hognestad, Ingvild Lobmaier, Francesca Micci, Sverre Heim

Background/aim: Angioleiomyoma is a benign tumor, occurs at any age, and arises most frequently in the lower extremities. Genetic information on angioleiomyomas is restricted to six reported abnormal karyotypes, losses in chromosome 22 and gains in Xq found by comparative genomic hybridization, and mutation analysis of notch receptor 2 (NOTCH2), NOTCH3, platelet-derived growth factor receptor beta (PDGFRB), and mediator complex subunit 12 (MED12) in a few tumors. Herein, we report the genetic findings in another three angioleiomyomas.

Materials and methods: The tumors were examined using G-banding and karyotyping, RNA sequencing, reverse transcription-polymerase chain reaction, Sanger sequencing, and expression analysis.

Results: The first tumor carried a t(4;5)(p12;q32) translocation resulting in fusion of the cardiac mesoderm enhancer-associated non-coding RNA (CARMN in 5q32) with the TXK tyrosine kinase gene (TXK in 4p12) leading to overexpression of TXK. To our knowledge, this is the first time that a recurrent chromosome translocation and its resulting fusion gene have been described in angioleiomyomas. The second tumor carried a four-way translocation, t(X;3;4;16)(q22;p11;q11;p13) which fused the myosin heavy chain 11 gene (MYH11 in 16p13) with intergenic sequences from Xq22 that mapped a few kilobase pairs distal to the insulin receptor substrate 4 gene (IRS4), resulting in enhanced IRS4 expression. The third angioleiomyoma carried another rearrangement of chromosome band Xq22, t(X;9)(q22;q32), as the sole cytogenetic aberration, but no material was available for further molecular investigation.

Conclusion: Our data, together with previously reported abnormal karyotypes in angioleiomyomas, show the presence of two recurrent genetic pathways in this tumor type: The first is characterized by presence of the translocation t(4;5)(p12;q32), which generates a CARMN::TXK chimera. The second is recurrent rearrangement of Xq22 resulting in overexpression of IRS4.

背景/目的:血管平滑肌瘤是一种良性肿瘤,发生于任何年龄,最常见于下肢。血管平滑肌瘤的遗传信息仅限于6种报告的异常核型、22号染色体的缺失和Xq的增加,这些都是通过比较基因组杂交和缺口受体2(NOTCH2)、NOTCH3、血小板衍生生长因子受体β(PDGFRB)和介体复合体亚基12(MED12)在少数肿瘤中的突变分析发现的。在此,我们报告了另外三种血管平滑肌瘤的基因发现。材料和方法:应用G带和核型分析、RNA测序、逆转录聚合酶链式反应、Sanger测序和表达分析对肿瘤进行检测。结果:第一个肿瘤携带t(4;5)(p12;q32)易位,导致心脏中胚层增强子相关非编码RNA(5q32中的CARMN)与TXK酪氨酸激酶基因(4p12中的TXK)融合,导致TXK过表达。据我们所知,这是首次在血管平滑肌瘤中描述复发性染色体易位及其产生的融合基因。第二个肿瘤携带四向易位t(X;3;4;16)(q22;p11;q11;p13),其将肌球蛋白重链11基因(16p13中的MYH11)与Xq22的基因间序列融合,该序列定位在胰岛素受体底物4基因(IRS4)远端的几千碱基对,导致IRS4表达增强。第三个血管平滑肌瘤携带另一个染色体带Xq22,t(X;9)(q22;q32)的重排,作为唯一的细胞遗传学畸变,但没有材料可用于进一步的分子研究。结论:我们的数据,加上先前报道的血管平滑肌瘤的异常核型,表明在这种肿瘤类型中存在两种复发性遗传途径:第一种是以易位t(4;5)(p12;q32)的存在为特征,其产生CARMN::TXK嵌合体。第二种是Xq22的复发性重排,导致IRS4的过表达。
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引用次数: 0
Using Comparative Proteomics to Identify Protein Signatures in Clear Cell Renal Cell Carcinoma. 使用比较蛋白质组学鉴定透明细胞肾细胞癌中的蛋白质特征。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20408
Juhee Park, Eun Hye Lee, Hyunchae Sim, Ann-Yae Na, So Young Choi, Jae-Wook Chung, Yun-Sok Ha, Tae Gyun Kwon, Sangkyu Lee, Jun Nyung Lee

Background/aim: Renal cell carcinoma (RCC) is one of the most commonly diagnosed cancers in the world. Approximately 25-30% of patients identified with initial kidney cancer will have metastasized tumors, thus 5-year survival rates for these patients are poor. Therefore, biomarker research is required to identify and predict molecular signatures in RCC.

Materials and methods: To address this, we used a mass spectrometry (MS)-based proteomics approach to identify proteins related to clear cell RCC (ccRCC) tissues from patients with T1G2, T1G3, T3G2, T3G3, and metastatic RCC (mRCC) stages.

Results: We identified and quantified 2,608 and 2,463 proteins, respectively, in ccRCC tissue and identified 1,449 differentially expressed proteins (DEPs). Bioinformatics analysis revealed that serpin family A member 3 (SERPINA3) qualified as biomarker for ccRCC progression. Using indirect enzyme-linked immunosorbent assay (ELISA), immunoblotting, and immunohistochemistry assays it was found that SERPINA3 expression levels in ccRCC tissues were much higher in stages before metastasis.

Conclusion: Comparative proteomics analysis of ccRCC tissues provided new evidence of SERPINA3 association with ccRCC progression.

背景/目的:肾细胞癌(RCC)是世界上最常见的癌症之一。大约25-30%的癌症早期患者会有转移性肿瘤,因此这些患者的5年生存率很低。因此,需要进行生物标志物研究来识别和预测RCC的分子特征。材料和方法:为了解决这一问题,我们使用基于质谱(MS)的蛋白质组学方法来鉴定T1G2、T1G3、T3G2、T3G3和转移性RCC(mRCC)分期患者的透明细胞RCC(ccRCC)组织相关的蛋白质。结果:我们在ccRCC组织中分别鉴定和定量了2608和2463种蛋白质,并鉴定了1449种差异表达蛋白质(DEP)。生物信息学分析显示,serpin家族A成员3(SERPINA3)符合ccRCC进展的生物标志物。使用间接酶联免疫吸附试验(ELISA)、免疫印迹和免疫组织化学试验发现,在转移前的阶段,ccRCC组织中SERPINA3的表达水平要高得多。结论:ccRCC组织的比较蛋白质组学分析为SERPINA3与ccRCC进展的关系提供了新的证据。
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引用次数: 0
Inhibition of Increased Invasiveness of Breast Cancer Cells With Acquired Tamoxifen Resistance by Suppression of CYR61. 通过抑制CYR61抑制具有获得性三苯氧胺耐药性的乳腺癌症细胞侵袭性增加。
IF 2.5 4区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-11-01 DOI: 10.21873/cgp.20403
Gerd Bauerschmitz, Silke Hüchel, Julia Gallwas, Carsten Gründker

Background/aim: Hormone sensitivity-targeted therapy with selective estrogen receptor modulators (SERMs), such as 4-hydroxytamoxifen (4-OHT), is the mainstay of treatment for breast cancers (BCs) that express estrogen receptor α (ERα). However, development of resistance limits this therapy approach. The question arises whether changes associated with 4-OHT resistance could be exploited therapeutically.

Materials and methods: First, 4-OHT-resistant sublines of ERα-positive breast carcinoma cell lines MCF-7 and T47D were generated. Viability was assessed by the Alamar Blue assay. Cell invasion was quantified in modified Boyden chambers with Matrigel. Changes in expression of CYR61, S100A4, and ERα were examined by RT-qPCR. Expression of CYR61 was suppressed by transient gene silencing using siRNA. Successful suppression was verified by western blot. Efficacy of 4-OHT treatment was analyzed by quantification of viability using Alamar Blue assay. Correlation of CYR61 levels in patients with luminal A BC to distant metastases-free survival was determined by Kaplan-Meier analysis.

Results: ERα-positive MCF-7 and T47D BC cells exhibit an extremely weak invasion rate. Acquired tamoxifen resistance significantly increased the invasive behavior of both tamoxifen-resistant MCF-7-TR and T47D-TR sublines. In addition, expression of CYR61 and S100A4 showed significantly increased levels, whereas expression of ERα was decreased. Suppression of CYR61 expression resulted in a significant decreased invasion rate. In addition, expression of S100A4 was reduced, whereas expression of ERα was increased. Furthermore, suppression of CYR61 resulted in re-sensitization to 4-OHT. High CYR61 levels in patients with luminal A BC resulted in reduced distant metastases-free survival.

Conclusion: The prometastatic factor CYR61 appears to play an important role in the increased invasiveness of tamoxifen-resistant ERα-positive BC cells. Its suppression leads to a lower invasion rate. Given the few therapeutic options available for tamoxifen-resistant BC, therapy that reduces CYR61 may improve its treatability in future.

背景/目的:选择性雌激素受体调节剂(SERM),如4-羟基他莫昔芬(4-OHT)的激素敏感性靶向治疗是治疗表达雌激素受体α(ERα)的乳腺癌(BCs)的主要方法。然而,耐药性的发展限制了这种治疗方法。产生的问题是,与4-OHT耐药性相关的变化是否可以用于治疗。材料与方法:首先,从ERα阳性乳腺癌细胞系MCF-7和T47D中筛选出抗4-OHT亚系。通过Alamar Blue测定法评估可行性。用Matrigel在改良的Boyden室中定量细胞侵袭。通过RT-qPCR检测CYR61、S100A4和ERα的表达变化。通过使用siRNA的瞬时基因沉默来抑制CYR61的表达。通过蛋白质印迹验证了成功的抑制。4-OHT治疗的疗效通过使用Alamar蓝测定法定量生存能力来分析。通过Kaplan-Meier分析确定管腔A BC患者的CYR61水平与无远处转移生存率的相关性。结果:ERα阳性的MCF-7和T47D-BC细胞侵袭率极低。获得性三苯氧胺耐药性显著增加了三苯氧碱耐药性MCF-7-TR和T47D-TR亚系的侵袭行为。此外,CYR61和S100A4的表达水平显著升高,而ERα的表达降低。CYR61表达的抑制导致侵袭率显著降低。此外,S100A4的表达减少,而ERα的表达增加。此外,对CYR61的抑制导致对4-OHT的再致敏。管腔A BC患者的高CYR61水平导致无远处转移生存率降低。结论:促增殖因子CYR61在三苯氧胺耐药ERα阳性BC细胞侵袭性增强中起重要作用。它的抑制导致较低的入侵率。鉴于三苯氧胺耐药BC的治疗选择很少,减少CYR61的治疗可能会提高其未来的可治疗性。
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引用次数: 0
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Cancer Genomics & Proteomics
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