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Delta-Like Homolog 2 Facilitates Malignancy of Hepatocellular Carcinoma via Activating EGFR/PKM2 Signaling Pathway. Delta-Like同源物2通过激活表皮生长因子受体/PKM2信号通路促进肝细胞癌恶变
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1002/mc.23836
Xiangye Liu, Tingting Li, Yuting Wang, Xiaoge Gao, Feitong Wang, Yang Chen, Kaisheng Wang, Weiming Luo, Fanyun Kong, Yanbo Kou, Hongjuan You, Delong Kong, Qing Zhang, Renxian Tang

Delta-like homolog 2 (DLK2) plays a crucial role in adipogenesis, chondrogenic differentiation, and the progression of certain cancers. However, the key roles of DLK2 underlying the progression of hepatocellular carcinoma (HCC) remain ambiguous. In the current study, we demonstrate that DLK2 is upregulated in HCC, significantly correlated with clinicopathological variables and serves as an independent diagnostic marker. Functional assays reveal that DLK2 facilitates malignant progression of HCC in vitro and in vivo models. Mechanistically, DLK2 binds to EGFR resulting in its auto-phosphorylation, which activates NK-κB pathway leading to P65-dependent transcriptional upregulation of PKM2. Furthermore, that elevates both enzyme-dependent and -independent activities of PKM2 contributing to cancer proliferation and metastasis. In summary, our findings demonstrate a novel pro-tumoral role and mechanism of DLK2 in the regulation of HCC malignant progression, suggesting its potential as a clinical diagnostic marker and therapeutic target.

德尔塔样同源物 2(Delta-like homolog 2,DLK2)在脂肪生成、软骨分化和某些癌症的进展中起着至关重要的作用。然而,DLK2 在肝细胞癌(HCC)进展中的关键作用仍不明确。在本研究中,我们发现 DLK2 在 HCC 中上调,与临床病理变量显著相关,是一种独立的诊断标志物。功能测试显示,DLK2 在体外和体内模型中促进了 HCC 的恶性进展。从机理上讲,DLK2 与表皮生长因子受体结合,导致表皮生长因子受体自身磷酸化,从而激活 NK-κB 通路,导致 P65 依赖性 PKM2 转录上调。此外,这还会提高 PKM2 的酶依赖性和非依赖性活性,导致癌症增殖和转移。总之,我们的研究结果证明了 DLK2 在调控 HCC 恶性进展中的一种新的促肿瘤作用和机制,表明它有可能成为一种临床诊断标志物和治疗靶点。
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引用次数: 0
FOS-Mediated PLCB1 Induces Radioresistance and Weakens the Antitumor Effects of CD8+ T Cells in Triple-Negative Breast Cancer. FOS 介导的 PLCB1 在三阴性乳腺癌中诱导放射抗性并削弱 CD8+ T 细胞的抗肿瘤作用
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1002/mc.23834
Yuxian Shu, Jun Lan, Huijing Luo, Huiying Fu, Xuhuang Xiao, Liping Yang

Radioresistance and immune evasion are interactive and crucial events leading to treatment failure and progression of human malignancies. This research studies the role of phospholipase C beta 1 (PLCB1) in these events in triple-negative breast cancer (TNBC) and the regulatory mechanism. PLCB1 was bioinformatically predicted as a dysregulated gene potentially linked to radioresistance in TNBC. Parental TNBC cell lines were exposed to fractionated radiation for 6 weeks. PLCB1 expression was decreased in the first 2 weeks but gradually increased from Week 3. PLCB1 knockdown increased the radiosensitivity of the cells, as manifested by a decreased half-inhibitory dose of irradiation, reduced cell proliferation, apoptosis resistance, mobility, and tumorigenesis in mice. The FOS transcription factor promoted PLCB1 transcription and activated the PI3K/AKT signaling. Knockdown of FOS similarly reduced radioresistance and T cells-mediated immune evasion. However, the radiosensitivity of TNBC cells and the antitumor effects of CD8+ T cells could be affected by a PI3K/AKT activator or by the PLCB1 upregulation. The PLCB1 or FOS knockdown also suppressed radioresistance and tumorigenesis of the TNBC cells in mice. In conclusion, FOS-mediated PLCB1 induces radioresistance and weakens the antitumor effects of CD8+ T cells in TNBC by activating the PI3K/AKT signaling pathway.

放射抗性和免疫逃避是导致治疗失败和人类恶性肿瘤进展的相互作用的关键事件。本研究探讨了磷脂酶C beta 1(PLCB1)在三阴性乳腺癌(TNBC)中这些事件中的作用及其调控机制。根据生物信息学预测,PLCB1 是一种可能与 TNBC 放射抗性有关的失调基因。亲代 TNBC 细胞系暴露于分次辐射 6 周。PLCB1的表达在前两周下降,但从第3周开始逐渐上升。PLCB1基因敲除增加了细胞的放射敏感性,表现为照射的半抑制剂量降低、细胞增殖减少、抗凋亡性降低、移动性降低以及小鼠肿瘤发生。FOS 转录因子促进了 PLCB1 的转录并激活了 PI3K/AKT 信号转导。敲除 FOS 同样会降低放射抗性和 T 细胞介导的免疫逃避。然而,TNBC细胞的放射敏感性和CD8+ T细胞的抗肿瘤作用可能会受到PI3K/AKT激活剂或PLCB1上调的影响。PLCB1或FOS敲除也能抑制小鼠TNBC细胞的放射抗性和肿瘤发生。总之,FOS介导的PLCB1通过激活PI3K/AKT信号通路诱导TNBC的放射抗性并削弱CD8+T细胞的抗肿瘤作用。
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引用次数: 0
FAM20C Promotes Papillary Thyroid Cancer Proliferation and Metastasis via Epithelial-Mesenchymal Transition. FAM20C 通过上皮-间质转化促进甲状腺乳头状癌的增殖和转移
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-22 DOI: 10.1002/mc.23833
Bangyi Lin, Xuejuan Jiang, Adheesh Bhandari, Qi Chen, Yin Pan

Thyroid cancer (TC) is the prevailing malignancy that impacts the endocrine system, accounting for 1% of all recently diagnosed malignancies in humans. The incidence of TC has been continuously increasing, which can be attributed to advancements in clinical diagnostic technology. However, the mechanisms behind the development of TC are still not well understood. TC is classified into four pathological forms: medullary thyroid cancer, papillary thyroid cancer (PTC), follicular thyroid cancer, and poorly differentiated TC. PTC constitutes more than 80% of all TC cases globally. Current research indicates that complex genetic and cellular processes could be responsible for the growth and spread of TC. Next-generation sequencing (RNA-seq) of 79 PTC samples and their corresponding normal thyroid tissues was performed to investigate the molecular mechanisms of PTC. An analysis of RNA-seq data from a local cohort from The Cancer Genome Atlas (TCGA) revealed that, compared with normal tissues, PTC tissues presented elevated FAM20C expression levels. In vitro, the function of FAM20C was validated with small interfering RNA (siRNA). Gene set enrichment analysis (GSEA) revealed the pathways influenced by FAM20C. A western blot experiment was used to investigate protein expression levels associated with epithelial‒mesenchymal transition (EMT). In conclusion, by regulating EMT, FAM20C facilitates PTC cell proliferation and metastasis.

甲状腺癌(TC)是影响内分泌系统的主要恶性肿瘤,占人类近期诊断出的所有恶性肿瘤的 1%。甲状腺癌的发病率持续上升,这可归因于临床诊断技术的进步。然而,人们对TC的发病机制仍不甚了解。甲状腺囊肿分为四种病理形态:甲状腺髓样癌,甲状腺乳头状癌(PTC),甲状腺滤泡癌和分化不良的甲状腺囊肿。PTC占全球TC病例总数的80%以上。目前的研究表明,复杂的基因和细胞过程可能是导致甲状腺癌生长和扩散的原因。为了研究PTC的分子机制,我们对79个PTC样本及其相应的正常甲状腺组织进行了新一代测序(RNA-seq)。对来自癌症基因组图谱(TCGA)本地队列的RNA-seq数据进行分析后发现,与正常组织相比,PTC组织的FAM20C表达水平升高。在体外,用小干扰 RNA(siRNA)验证了 FAM20C 的功能。基因组富集分析(GSEA)揭示了受FAM20C影响的通路。Western印迹实验用于研究与上皮-间质转化(EMT)相关的蛋白质表达水平。总之,FAM20C通过调节EMT促进了PTC细胞的增殖和转移。
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引用次数: 0
Sohlh2 Promotes the Progression of Hepatocellular Carcinoma via TGM2-Mediated Autophagy. Sohlh2 通过 TGM2 介导的自噬促进肝细胞癌的进展
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-22 DOI: 10.1002/mc.23832
Xuyue Liu, Ruihong Zhang, Lanlan Liu, Sujuan Zhi, Xiaoning Feng, Ying Shen, Liyan Wang, Qi Zhang, Yanru Chen, Jing Hao

Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for 85% of liver cancer-related deaths. Autophagy controls HCC cell growth, invasion, metastasis, drug resistance, and stemness. Spermatogenesis and oogenesis basic helix-loop-helix transcription factor 2 (Sohlh2) can bind to the E-boxes in the promoter regions of target genes, which are involved in multiple neoplasms. In this study, Sohlh2 was highly expressed in HCC tissues and was related to poor prognosis. Moreover, Sohlh2 overexpression promoted the proliferation, migration, invasion, and metastasis of HCC cells in vivo and in vitro. However, Sohlh2 silencing inhibited proliferation, migration, invasion, and metastasis of HCC cells in vivo and in vitro. Mechanistically, Sohlh2 could bind to the promoter of TGM2 and enhance its transcriptional activity, thereby enhancing the autophagy of HCC cells. Furthermore, Sohlh2 protein levels were positively associated with TGM2 expression in HCC tissues. Taken together, these results demonstrate that Sohlh2 can promote HCC progression via TGM2-mediated autophagy, implying that Sohlh2 is a promising candidate for HCC treatment.

肝癌是全球癌症相关死亡的第三大原因,其中肝细胞癌(HCC)占肝癌相关死亡的 85%。自噬控制着 HCC 细胞的生长、侵袭、转移、耐药性和干性。精子发生和卵子生成碱性螺旋-环-螺旋转录因子2(Sohlh2)可与靶基因启动子区的E-框结合,而靶基因与多种肿瘤有关。本研究发现,Sohlh2 在 HCC 组织中高表达,且与预后不良有关。此外,Sohlh2 的过表达可促进 HCC 细胞在体内和体外的增殖、迁移、侵袭和转移。然而,沉默 Sohlh2 会抑制 HCC 细胞在体内和体外的增殖、迁移、侵袭和转移。从机理上讲,Sohlh2 可与 TGM2 的启动子结合并增强其转录活性,从而提高 HCC 细胞的自噬能力。此外,Sohlh2 蛋白水平与 HCC 组织中 TGM2 的表达呈正相关。综上所述,这些结果表明,Sohlh2 可通过 TGM2 介导的自噬作用促进 HCC 的进展,这意味着 Sohlh2 是一种治疗 HCC 的有前途的候选药物。
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引用次数: 0
Energy Metabolic Profile in Oral Potentially Malignant Disorders and Oral Squamous Cell Carcinoma: A Preliminary Landscape of Warburg Effect in Oral Cancer. 口腔潜在恶性疾病和口腔鳞状细胞癌的能量代谢概况:口腔癌中沃伯格效应的初步图谱
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-16 DOI: 10.1002/mc.23831
Francisca Aurina Gonçalves, Leonardo da Silva Bittencourt, Silvia Barbosa, Leonardo Francisco Diel, Lisiane Bernardi, Cristiane Matte, Marcelo Lazzaron Lamers

We hypothesized that cell energy metabolic profiles correlate with normal, dysplastic, and tumor cell/tissue statuses and may be indicators of aggressiveness in oral squamous cell carcinoma (OSCC) cells. The energy-related proteins that were differentially expressed in human OSCC fragments (n = 3) and their adjacent epithelial tissue (TAE) were verified using mass spectrometry (MS). Immunohistochemistry for 4-hydroxynonenal (4-HNE) was performed to evaluate the oxidative stress patterns in OSCC (n = 10), epithelial dysplasia (n = 9), and normal epithelial (n = 4) biopsies. The metabolic energy profile of OSCC aggressiveness was investigated in human OSCC cell lines with different levels of epithelial-mesenchymal transition proteins. The genes associated with the proteins found by MS in this study were analyzed using survival analysis (OS), whereas the genes associated with a poorer prognosis were analyzed using context-specific expression, Gene Ontology (GO) and Cancer Hallmarks for function enrichment analysis. The rationale for all experimental approach was to investigate whether the variation in energy metabolism profile accompanies the different phenotypes (from epithelial to mesenchymal) during the epithelial-mesenchymal transition. All OSCC fragments exhibited an increase in glycolysis-related proteins and a decrease in mitochondrial activity compared to the TAE region (p < 0.05), probably due to the downregulation of pyruvate dehydrogenase and antioxidant proteins. Additionally, the OSCC cell lines with a mesenchymal profile (SCC4, SCC9, and SCC25) had a lower mitochondrial mass and membrane potential and generated lower levels of reactive oxygen and nitrogen species than the TAE region. When we analyzed 4-HNE, the reactive species levels were increased in the epithelial regions of OSCC and potentially malignant lesions. A decrease in the levels of 4-HNE/reactive species was observed in the connective tissue underlying the dysplastic regions and the OSCC invasion zone. Based on this scenario, aggressive OSCC is associated with high glycolytic and oxidative metabolism and low mitochondrial and antioxidant activities, which vary according to the differentiation level of the tumor cells and the stage of carcinogenesis.

我们假设细胞能量代谢特征与正常、发育不良和肿瘤细胞/组织状态相关,并可能是口腔鳞状细胞癌(OSCC)细胞侵袭性的指标。利用质谱法(MS)验证了在人类 OSCC 片段(n = 3)及其邻近上皮组织(TAE)中有差异表达的能量相关蛋白。对4-羟基壬烯醛(4-HNE)进行免疫组化,以评估OSCC(10例)、上皮发育不良(9例)和正常上皮(4例)活检组织的氧化应激模式。在具有不同水平上皮-间质转化蛋白的人类 OSCC 细胞系中,研究了 OSCC 侵袭性的代谢能谱。本研究利用生存分析(OS)分析了与MS发现的蛋白质相关的基因,而利用上下文特异性表达、基因本体(GO)和癌症标志物功能富集分析了与较差预后相关的基因。所有实验方法的基本原理都是为了研究在上皮-间质转化过程中,能量代谢谱的变化是否伴随着不同的表型(从上皮到间质)。与 TAE 区域相比,所有 OSCC 片段都表现出糖酵解相关蛋白的增加和线粒体活性的降低(p
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引用次数: 0
Hepatitis B Virus X Protein Contributes to Hepatocellular Carcinoma via Upregulation of KIAA1429 Methyltransferase and mRNA m6A Hypermethylation of HSPG2/Perlecan. 乙型肝炎病毒 X 蛋白通过上调 KIAA1429 甲基转移酶和 mRNA m6A 对 HSPG2/Perlecan 的超甲基化作用诱发肝细胞癌
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-16 DOI: 10.1002/mc.23830
Enakshi Sivasudhan, Jingxian Zhou, Jiongming Ma, Yuanyuan Wang, Siying Liu, Faez Iqbal Khan, Zhiliang Lu, Jia Meng, Neil Blake, Rong Rong

Chronic hepatitis B virus (HBV) remains to be the most common risk factor of hepatocellular carcinoma (HCC). While previous work has primarily focussed on understanding the direct and indirect mechanisms of Hepatitis B virus X protein (HBx)-mediated hepatocarcinogenesis, from genetic and epigenetic perspectives, its influence on RNA modification mediated onset of liver malignancies is less well understood. This study explored the role of HBV-encoded HBx in altering the m6A methylome profile and its implications on the pathogenesis of HCC. We established HBx-expressing stable HCC cell lines, Huh7-HBx and HepG2-HBx, and explored the transcriptomic and epitranscriptomic profiles by RNA-seq and MeRIP-seq, respectively. Preliminary results suggest that HBx promotes liver cell proliferation, migration, survival and overall m6A methylation in HCC cells and is involved in modulating the extracellular matrix. We show that HBx mediates liver cell transformation by upregulating KIAA1429 methyltransferase. HBx also drives the expression and hypermethylation of the extracellular matrix protein HSPG2/Perlecan and promotes tumourigenesis. Furthermore, we observed a potential interaction between KIAA1429 and HSPG2 in HCC liver cancer cells and demands further investigation.

慢性乙型肝炎病毒(HBV)仍然是肝细胞癌(HCC)最常见的风险因素。以往的研究主要侧重于从遗传和表观遗传学的角度了解乙型肝炎病毒 X 蛋白(HBx)介导的肝癌发生的直接和间接机制,但对其对 RNA 修饰介导的肝脏恶性肿瘤发病的影响了解较少。本研究探讨了 HBV 编码的 HBx 在改变 m6A 甲基组图谱中的作用及其对 HCC 发病机制的影响。我们建立了表达 HBx 的稳定 HCC 细胞系 Huh7-HBx 和 HepG2-HBx,并分别通过 RNA-seq 和 MeRIP-seq 对转录组和表转录组进行了研究。初步结果表明,HBx 促进 HCC 细胞的肝细胞增殖、迁移、存活和整体 m6A 甲基化,并参与调节细胞外基质。我们发现,HBx 通过上调 KIAA1429 甲基转移酶介导肝细胞转化。HBx 还能驱动细胞外基质蛋白 HSPG2/Perlecan 的表达和高甲基化,促进肿瘤发生。此外,我们还观察到 KIAA1429 和 HSPG2 在 HCC 肝癌细胞中可能存在相互作用,这需要进一步研究。
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引用次数: 0
Integrating Multi-Omics Data to Uncover Prostate Tissue DNA Methylation Biomarkers and Target Genes for Prostate Cancer Risk. 整合多指标数据,揭示前列腺组织 DNA 甲基化生物标记物和前列腺癌风险靶基因。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 DOI: 10.1002/mc.23828
Shuai Liu, Jingjing Zhu, Dylan Green, Hua Zhong, Quan Long, Chong Wu, Liang Wang, Youping Deng, Lang Wu

Previous studies have indicated that specific CpG sites may be linked to the risk of prostate cancer (PCa) by regulating the expression of PCa target genes. However, most existing studies aim to identify DNA methylation (DNAm) biomarkers through blood tissue genetic instruments, which impedes the identification of relevant biomarkers in prostate tissue. To identify PCa risk-associated CpG sites in prostate tissue, we established genetic prediction models of DNAm levels using data from normal prostate samples in the GTEx (N = 108) and assessed associations between genetically predicted DNAm in prostate and PCa risk by studying 122,188 cases and 604,640 controls. We observed significant associations for 3879 CpG sites, including 926 at novel genomic loci. Among them, DNAm levels of 80 CpG sites located at novel loci are significantly associated with expression levels of 45 neighboring genes in normal prostate tissue. Of these genes, 11 further exhibit significant associations with PCa risk for their predicted expression levels in prostate tissue. Intriguingly, a total of 31 CpG sites demonstrate consistent association patterns across the methylation-gene expression-PCa risk pathway. Our findings suggest that specific CpG sites may be related to PCa risk by modulating the expression of nearby target genes.

以往的研究表明,特定的 CpG 位点可能通过调节 PCa 靶基因的表达而与前列腺癌(PCa)的风险有关。然而,现有的大多数研究旨在通过血液组织基因仪器鉴定DNA甲基化(DNAm)生物标志物,这阻碍了前列腺组织中相关生物标志物的鉴定。为了确定前列腺组织中与 PCa 风险相关的 CpG 位点,我们利用 GTEx(N = 108)中正常前列腺样本的数据建立了 DNAm 水平的遗传预测模型,并通过研究 122,188 例病例和 604,640 例对照,评估了前列腺中遗传预测 DNAm 与 PCa 风险之间的关联。我们观察到 3879 个 CpG 位点存在显着关联,包括 926 个新基因组位点。其中,位于新基因组位点的 80 个 CpG 位点的 DNAm 水平与正常前列腺组织中 45 个邻近基因的表达水平显著相关。在这些基因中,有 11 个基因在前列腺组织中的预测表达水平与 PCa 风险有显著关联。有趣的是,在甲基化-基因表达-PCa 风险通路中,共有 31 个 CpG 位点表现出一致的关联模式。我们的研究结果表明,特定的 CpG 位点可能通过调节附近靶基因的表达与 PCa 风险有关。
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引用次数: 0
microRNA-2117 Negatively Regulates Liver Cancer Stem Cells Expansion and Chemoresistance Via Targeting SOX2. microRNA-2117通过靶向SOX2负向调控肝癌干细胞扩增和化疗抗性
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 DOI: 10.1002/mc.23824
Qing Xia, Guanghua Liu, Wenbo Lin, Jin Zhang

Cancer stem cells (CSCs) are involved in the regulation of tumor initiation, progression, recurrence, and chemoresistance. However, the role of microRNAs (miRNAs) in liver CSCs has not been fully understood. Here we show that miR-2117 is downregulated in liver CSCs and predicts the poor prognosis of hepatocellular carcinoma (HCC) patients. Biofunction studies found that knockdown miR-2117 facilitates liver CSCs self-renewal and tumorigenesis. Conversely, forced miR-2117 expression suppresses liver CSCs self-renewal and tumorigenesis. Mechanistically, we find that transcription factor SOX2 is required for miR-2117-mediated liver CSCs expansion. The correlation between miR-2117 and SOX2 was confirmed in human HCC tissues. More importantly, miR-2117 overexpression HCC cells are more sensitive to CDDP treatment. Analysis of patients' cohort further demonstrates that miR-2117 may predict transcatheter arterial chemoembolization benefits in HCC patients. Our findings revealed the crucial role of miR-2117 in liver CSCs expansion, rendering miR-2117 as an optimal therapeutic target for HCC.

癌症干细胞(CSCs)参与调控肿瘤的发生、发展、复发和化疗耐药性。然而,微RNA(miRNA)在肝癌干细胞中的作用尚未完全明了。在这里,我们发现 miR-2117 在肝脏 CSCs 中下调,并可预测肝细胞癌(HCC)患者的不良预后。生物功能研究发现,敲除 miR-2117 会促进肝脏 CSCs 自我更新和肿瘤发生。相反,强制表达 miR-2117 则会抑制肝脏 CSCs 的自我更新和肿瘤发生。从机理上讲,我们发现转录因子 SOX2 是 miR-2117 介导的肝脏 CSCs 扩增所必需的。miR-2117与SOX2之间的相关性在人类HCC组织中得到了证实。更重要的是,miR-2117 过表达的 HCC 细胞对 CDDP 治疗更敏感。对患者队列的分析进一步表明,miR-2117 可预测经导管动脉化疗栓塞对 HCC 患者的益处。我们的研究结果揭示了miR-2117在肝脏干细胞扩增中的关键作用,使miR-2117成为治疗HCC的最佳靶点。
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引用次数: 0
Characterizing Genetic Susceptibility to Colorectal Cancer in Taiwan Through Genome-Wide Association Study. 通过全基因组关联研究确定台湾大肠癌遗传易感性特征
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-11 DOI: 10.1002/mc.23823
Da-Tian Bau, Ting-Yuan Liu, Jai-Sing Yang, William Tzu-Liang Chen, Chia-Wen Tsai, Wen-Shin Chang, Tao-Wei Ke, Chi-Chou Liao, Yu-Chia Chen, Yen-Ting Chang, Fuu-Jen Tsai

We conducted the first genome-wide association study (GWAS) of colorectal cancer (CRC) in Taiwan with 5342 cases and 61,015 controls. Ninety-two SNPs in three genomic regions reached genome-wide significance (p < 5 × 10-8). The lead SNPs in these three regions were: rs12778523 (OR = 1.18, 95% CI, 1.15-1.23, p = 4.51 × 10-13), an intergenic SNP between RNA5SP299 and LINC02676 at chromosome 10p14; rs647161 (OR = 1.14, 95% CI, 1.09-1.19, p = 2.21 × 10-9), an intronic SNP in PITX1 at 5q31.1, and rs10427139 (OR = 1.20, 95% CI, 1.14-1.28, p = 3.62 × 10-9), an intronic SNP in GPATCH1 at 19q13.1. We further validated CRC susceptibility SNPs previously identified through GWAS in other populations. A total of 61 CRC susceptibility SNPs were confirmed in Taiwanese. The top validated putative CRC susceptibility genes included: POU2AF2, HAO1, LAMC1, EIF3H, BMP2, ZMIZ1, BMP4, POLD3, CDKN1A, PREX1, CDKN2B, CDH1, and LRIG1. The top enriched pathways included TGF-β signaling, BMP signaling, extracellular matrix organization, DNA repair, and cell cycle control. We could not validate SNPs in HLA-G at 6p22.1 and in NOTCH4 at 6p21.32. We generated a weighted genetic risk score (GRS) using the 61 SNPs and constructed receiver operating characteristic (ROC) curves using the GRS to predict CRC. The area under the ROC curve (AUC) was 0.589 for GRS alone and 0.645 for GRS, sex, and age. These susceptibility SNPs and genes provide important insights into the molecular mechanisms of CRC development and help identify high-risk individuals for CRC in Taiwan.

我们在台湾进行了首次大肠癌(CRC)全基因组关联研究(GWAS),共有 5342 例病例和 61 015 例对照。三个基因组区域的 92 个 SNP 达到全基因组显著性(p -8)。这三个区域的主要 SNPs 是:rs12778523(OR = 1.18,95% CI,1.15-1.23,p = 4.51 × 10-13),位于染色体 10p14 的 RNA5SP299 和 LINC02676 之间的基因间 SNP;rs647161(OR = 1.14,95% CI,1.09-1.19,p = 2.21 × 10-9)和位于 19q13.1 的 GPATCH1 的内含子 SNP rs10427139(OR = 1.20,95% CI,1.14-1.28,p = 3.62 × 10-9)。我们进一步验证了之前在其他人群中通过 GWAS 发现的 CRC 易感 SNPs。在台湾人中,共确认了 61 个 CRC 易感 SNPs。最主要的已验证假定的 CRC 易感基因包括POU2AF2、HAO1、LAMC1、EIF3H、BMP2、ZMIZ1、BMP4、POLD3、CDKN1A、PREX1、CDKN2B、CDH1和LRIG1。富集最多的通路包括 TGF-β 信号传导、BMP 信号传导、细胞外基质组织、DNA 修复和细胞周期控制。我们无法验证位于 6p22.1 的 HLA-G 和位于 6p21.32 的 NOTCH4 中的 SNPs。我们利用这 61 个 SNPs 生成了加权遗传风险评分(GRS),并利用 GRS 构建了预测 CRC 的接收者操作特征曲线(ROC)。仅 GRS 的 ROC 曲线下面积(AUC)为 0.589,GRS、性别和年龄的 ROC 曲线下面积(AUC)为 0.645。这些易感 SNPs 和基因为了解 CRC 发生的分子机制提供了重要信息,有助于识别台湾的 CRC 高危人群。
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引用次数: 0
Functional Analysis of BARD1 Missense Variants on Homology-Directed Repair in Ovarian and Breast Cancers. BARD1错义变异对卵巢癌和乳腺癌同源定向修复的功能分析
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-10 DOI: 10.1002/mc.23829
Wenjing Li, Guansheng Chen, Yongjun Wang, Yuening Jiang, Nanlin Wu, Mingjie Hu, Taju Wu, Wei Yue

Women with germline BRCA1 mutations face an increased risk of developing breast and ovarian cancers. BARD1 (BRCA1 associated RING domain 1) is an essential heterodimeric partner of BRCA1, and mutations in BARD1 are also associated with these cancers. While BARD1 mutations are recognized for their cancer susceptibility, the exact roles of numerous BARD1 missense mutations remain unclear. In this study, we conducted functional assays to assess the homology-directed DNA repair (HDR) activity of all BARD1 missense substitutions identified in 55 breast and ovarian cancer samples, using the real-world data from the COSMIC and cBioPortal databases. Seven BARD1 variants (V85M, P187A, G491R, R565C, P669L, T719R, and Q730L) were confirmed to impair DNA damage repair. Furthermore, cells harboring these BARD1 variants exhibited increased sensitivity to the chemotherapeutic drugs, cisplatin, and olaparib, compared to cells expressing wild-type BARD1. These findings collectively suggest that these seven missense BARD1 variants are likely pathogenic and may respond well to cisplatin-olaparib combination therapy. This study not only enhances our understanding of BARD1's role in DNA damage repair but also offers valuable insights into predicting therapy responses in patients with specific BARD1 missense mutations.

BRCA1 基因突变的妇女罹患乳腺癌和卵巢癌的风险会增加。BARD1(BRCA1 相关 RING 结构域 1)是 BRCA1 的重要异源二聚体伙伴,BARD1 的突变也与这些癌症有关。虽然 BARD1 突变被认为具有癌症易感性,但许多 BARD1 错义突变的确切作用仍不清楚。在这项研究中,我们利用 COSMIC 和 cBioPortal 数据库中的真实世界数据进行了功能测定,以评估在 55 个乳腺癌和卵巢癌样本中发现的所有 BARD1 错义置换的同源定向 DNA 修复(HDR)活性。七个 BARD1 变异(V85M、P187A、G491R、R565C、P669L、T719R 和 Q730L)被证实会损害 DNA 损伤修复。此外,与表达野生型 BARD1 的细胞相比,携带这些 BARD1 变体的细胞对化疗药物顺铂和奥拉帕利的敏感性更高。这些发现共同表明,这7个错义BARD1变体可能是致病的,并可能对顺铂-奥拉帕利联合疗法产生良好反应。这项研究不仅加深了我们对BARD1在DNA损伤修复中作用的了解,还为预测特定BARD1错义突变患者的治疗反应提供了有价值的见解。
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引用次数: 0
期刊
Molecular Carcinogenesis
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