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MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells by binding ITGB4/LAMB3 to activate the AKT signaling pathway. MDFI 通过结合 ITGB4/LAMB3 激活 AKT 信号通路,促进结直肠癌细胞的增殖和对化疗的耐受性。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-20 DOI: 10.1080/15384047.2024.2314324
Ding Ma, Shuwen Liu, Kua Liu, Lingkai Kong, Lingjun Xiao, Qilei Xin, Chunping Jiang, Junhua Wu

Colorectal cancer (CRC) is one of the most lethal cancers. Single-cell RNA sequencing (scRNA-seq) and protein-protein interactions (PPIs) have enabled the systematic study of CRC. In our research, the activation of the AKT pathway in CRC was analyzed by KEGG using single-cell sequencing data from the GSE144735 dataset. The correlation and PPIs of MDFI and ITGB4/LAMB3 were examined. The results were verified in the TCGA and CCLE and further tested by coimmunoprecipitation experiments. The effect of MDFI on the AKT pathway via ITGB4/LAMB3 was validated by knockdown and lentiviral overexpression experiments. The effect of MDFI on oxaliplatin/fluorouracil sensitivity was probed by colony formation assay and CCK8 assay. We discovered that MDFI was positively associated with ITGB4/LAMB3. In addition, MDFI was negatively associated with oxaliplatin/fluorouracil sensitivity. MDFI upregulated the AKT pathway by directly interacting with LAMB3 and ITGB4 in CRC cells, and enhanced the proliferation of CRC cells via the AKT pathway. Finally, MDFI reduced the sensitivity of CRC cells to oxaliplatin and fluorouracil. In conclusion, MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells, partially through the activation of the AKT signaling pathway by the binding to ITGB4/LAMB3. Our findings provide a possible molecular target for CRC therapy.

结肠直肠癌(CRC)是致死率最高的癌症之一。单细胞 RNA 测序(scRNA-seq)和蛋白-蛋白相互作用(PPIs)使得对 CRC 的系统研究成为可能。在我们的研究中,利用 GSE144735 数据集中的单细胞测序数据,通过 KEGG 分析了 CRC 中 AKT 通路的激活情况。研究还考察了 MDFI 和 ITGB4/LAMB3 的相关性和 PPIs。这些结果在TCGA和CCLE中得到了验证,并通过共免疫沉淀实验进行了进一步检验。通过敲除和慢病毒过表达实验验证了MDFI通过ITGB4/LAMB3对AKT通路的影响。通过菌落形成实验和CCK8实验检测了MDFI对奥沙利铂/氟尿嘧啶敏感性的影响。我们发现,MDFI与ITGB4/LAMB3呈正相关,与奥沙利铂/氟尿嘧啶敏感性呈负相关。MDFI通过与CRC细胞中的LAMB3和ITGB4直接相互作用,上调AKT通路,并通过AKT通路增强CRC细胞的增殖。最后,MDFI降低了CRC细胞对奥沙利铂和氟尿嘧啶的敏感性。总之,MDFI能促进结直肠癌细胞的增殖和对化疗的耐受性,部分原因是通过与ITGB4/LAMB3结合激活了AKT信号通路。我们的发现为 CRC 治疗提供了一个可能的分子靶点。
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引用次数: 0
The predictors of lymphopenia and its effects on survival in locally advanced esophageal squamous cell carcinoma. 局部晚期食管鳞状细胞癌淋巴细胞减少的预测因素及其对生存期的影响。
IF 4.4 4区 医学 Q2 ONCOLOGY Pub Date : 2024-12-31 Epub Date: 2024-07-01 DOI: 10.1080/15384047.2024.2371632
Danjing Luo, Qiulu Zhong, Haiying Yue, Jue Wang, Qianfu Liang, Wenqi Liu, Xiaodong Zhu

To investigate the impact of the effective radiation dose to immune cells (EDIC) and gross tumor volume (GTV) on lymphopenia and survival in patients with locally advanced esophageal squamous cell carcinoma (LAESCC). Between January 2013 and December 2020, 272 LAESCC patients were treated with definitive radiotherapy in two institutions. Based on radiation doses to the lungs, heart, and body region scanned, EDIC was calculated as an equal uniform dose to the total blood considering blood flow and fraction effect. The radiotherapy plan was used to calculate the GTVs. Lymphopenia was graded based on the lowest lymphocyte count during RT. The overall survival (OS), progress-free survival (PFS), and local recurrence-free survival (LRFS) were analyzed statistically. The lowest lymphocyte count was significantly correlated with EDIC (r= -0.389, p < .001) and GTV (r= -0.211, p < .001). Lymphopenia, EDIC, and GTV are risk factors for patients with ESCC. In a Kaplan-Meier analysis with EDIC and GTV as stratification factors, lymphopenia was not associated with OS in the EDIC>12.9 Gy group (p = .294)and EDIC ≤ 12.9 Gy group, and it was also not associated with OS in GTV>68.8 cm3 group (p = .242) and GTV ≤ 68.8 cm3 group(p = .165). GTV and EDIC had an impact on the relationship between lymphopenia and OS in patients with LAESCC undergoing definitive RT. Poorer OS, PFS, and LRFS are correlated with lymphopenia, higher EDIC, and larger GTV.

研究免疫细胞有效辐射剂量(EDIC)和肿瘤总体积(GTV)对局部晚期食管鳞状细胞癌(LAESCC)患者淋巴细胞减少症和生存期的影响。2013年1月至2020年12月期间,两家机构共对272名LAESCC患者进行了确定性放疗。根据肺部、心脏和身体扫描区域的辐射剂量,考虑到血流量和分数效应,EDIC被计算为总血液中的等量均匀剂量。放疗计划用于计算GTV。淋巴细胞减少症根据放疗期间的最低淋巴细胞计数进行分级。对总生存期(OS)、无进展生存期(PFS)和无局部复发生存期(LRFS)进行了统计分析。最低淋巴细胞计数与 EDIC(r= -0.389,p < .001)和 GTV(r= -0.211,p < .001)显著相关。淋巴细胞减少症、EDIC和GTV是ESCC患者的危险因素。在以EDIC和GTV为分层因素的Kaplan-Meier分析中,淋巴细胞减少与EDIC>12.9 Gy组(p = .294)和EDIC≤12.9 Gy组的OS无关,与GTV>68.8 cm3组(p = .242)和GTV≤68.8 cm3组(p = .165)的OS也无关。GTV和EDIC对接受确定性RT治疗的LAESCC患者淋巴细胞减少与OS之间的关系有影响。较差的OS、PFS和LRFS与淋巴细胞减少、较高的EDIC和较大的GTV相关。
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引用次数: 0
Fusobacterium nucleatum in tumors: from tumorigenesis to tumor metastasis and tumor resistance. 肿瘤中的核分枝杆菌:从肿瘤发生到肿瘤转移和肿瘤抗药性。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-01-30 DOI: 10.1080/15384047.2024.2306676
Chun Ye, Xiao Liu, Zilun Liu, Chuxuan Pan, Xiaowei Zhang, Zhanyi Zhao, Haitao Sun

Fusobacterium nucleatum, an anaerobic Gram-negative bacterium primarily residing in the oral cavity, has garnered significant attention for its emerging role in cancer progression and prognosis. While extensive research has revealed mechanistic links between Fusobacterium nucleatum and colorectal cancer, a comprehensive review spanning its presence and metastatic implications in cancers beyond colorectal origin is conspicuously absent. This paper broadens our perspective from colorectal cancer to various malignancies associated with Fusobacterium nucleatum, including oral, pancreatic, esophageal, breast, and gastric cancers. Our central focus is to unravel the mechanisms governing Fusobacterium nucleatum colonization, initiation, and promotion of metastasis across diverse cancer types. Additionally, we explore Fusobacterium nucleatum's adverse impacts on cancer therapies, particularly within the domains of immunotherapy and chemotherapy. Furthermore, this paper underscores the clinical research significance of Fusobacterium nucleatum as a potential tumor biomarker and therapeutic target, offering a novel outlook on its applicability in cancer detection and prognostic assessment.

核叉杆菌是一种厌氧革兰阴性菌,主要栖息于口腔,因其在癌症进展和预后中的新作用而备受关注。尽管广泛的研究揭示了核酸镰刀菌与结直肠癌之间的机理联系,但关于核酸镰刀菌在结直肠癌以外的癌症中的存在和转移影响的全面综述却明显缺乏。本文将我们的视角从结直肠癌扩大到与核酸镰刀菌相关的各种恶性肿瘤,包括口腔癌、胰腺癌、食管癌、乳腺癌和胃癌。我们的研究重点是揭示核酸镰刀菌在不同癌症类型中定植、引发和促进转移的机制。此外,我们还探讨了核团镰刀菌对癌症疗法的不利影响,尤其是在免疫疗法和化疗领域。此外,本文还强调了核酸镰刀菌作为潜在肿瘤生物标记物和治疗靶点的临床研究意义,为其在癌症检测和预后评估中的应用提供了新的前景。
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引用次数: 0
Correction. 更正。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-13 DOI: 10.1080/15384047.2024.2318833
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引用次数: 0
Neuroendocrine gene subsets are uniquely dysregulated in prostate adenocarcinoma. 神经内分泌基因亚群在前列腺癌中出现独特的失调。
IF 4.4 4区 医学 Q2 ONCOLOGY Pub Date : 2024-12-31 Epub Date: 2024-06-26 DOI: 10.1080/15384047.2024.2364433
Nicole M Naranjo, Anne Kennedy, Anna Testa, Cecilia E Verrillo, Adrian D Altieri, Rhonda Kean, D Craig Hooper, Jindan Yu, Jonathan Zhao, Oliver Abinader, Maxwell W Pickles, Adam Hawkins, William K Kelly, Ramkrishna Mitra, Lucia R Languino

Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP is enriched in small extracellular vesicles (sEVs) derived from plasma of PRAD patients, but it is absent in sEVs derived from plasma of healthy donors. Similarly, classical sEV markers are enriched in sEVs derived from plasma of prostate cancer patients, but weakly detectable in sEVs derived from plasma of healthy donors. Overall, our results pave the way to explore new strategies to diagnose these diseases based on the neuroendocrine gene expression in patient tumors or plasma sEVs.

前列腺癌的生长模式多种多样,当其发展为神经内分泌表型时,预后最差。通过生物信息学分析,我们评估了神经内分泌基因在五种不同类型癌症(前列腺癌、乳腺癌、肾嗜铬细胞瘤、肾透明细胞癌和肾乳头状细胞癌)中的 RNA 表达。我们的研究结果表明,特定的神经内分泌基因在这些肿瘤中明显失调,表明它们在癌症进展中发挥着积极作用。其中,突触素(SYP)作为一种传统的神经内分泌标志物,在前列腺癌(PRAD)和乳腺癌(BRCA)中上调。我们的分析表明,SYP 在 PRAD 患者血浆中的小细胞外囊泡 (sEV) 中富集,但在健康供体血浆中的小细胞外囊泡中却没有。同样,前列腺癌患者血浆中富含经典的 sEV 标记,但在健康捐献者血浆中只能检测到微弱的 sEV。总之,我们的研究结果为探索基于患者肿瘤或血浆 sEV 中神经内分泌基因表达诊断这些疾病的新策略铺平了道路。
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引用次数: 0
BRG1 promotes liver cancer cell proliferation and metastasis by enhancing mitochondrial function and ATP5A1 synthesis through TOMM40. BRG1 通过 TOMM40 增强线粒体功能和 ATP5A1 合成,从而促进肝癌细胞增殖和转移。
IF 4.4 4区 医学 Q2 ONCOLOGY Pub Date : 2024-12-31 Epub Date: 2024-07-08 DOI: 10.1080/15384047.2024.2375440
Yongfeng Hui, Junzhi Leng, Dong Jin, Genwang Wang, Kejun Liu, Yang Bu, Qi Wang

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.

肝细胞癌(HCC)是全球致死率最高的恶性肿瘤之一。梵天相关基因 1(BRG1)是一种催化 ATP 酶,是基因表达的主要调控因子,已知在 HCC 中会发生突变和过表达。本研究的目的是探讨 BRG1 在 HCC 细胞中的作用机制。在我们的研究中,BRG1 在人类 HCC 细胞系中被沉默或过表达。透孔试验和伤口愈合试验用于分析细胞的侵袭性和迁移性。线粒体膜电位(MMP)和线粒体通透性转换孔(mPTP)检测用于评估HCC细胞的线粒体功能。集落形成和细胞凋亡试验用于评估 BRG1/TOMM40/ATP5A1 对 HCC 细胞增殖和凋亡/死亡的影响。免疫细胞化学(ICC)、免疫荧光(IF)染色和 Western 印迹分析用于确定 BRG1 对 HCC 细胞中 TOMM40、ATP5A1 通路的影响。结果表明,敲除BRG1能明显抑制HCC细胞的增殖和侵袭,促进细胞凋亡,而过表达BRG1则能逆转上述效应。过表达BRG1可上调MMP水平,抑制mPTP开放,激活TOMM40、ATP5A1的表达。我们的研究结果表明,BRG1作为一种癌基因,通过调节TOMM40影响线粒体功能和ATP5A1的合成来促进HCC的进展。靶向 BRG1 可能是预防 HCC 发展的一种新的有效方法。
{"title":"BRG1 promotes liver cancer cell proliferation and metastasis by enhancing mitochondrial function and ATP5A1 synthesis through TOMM40.","authors":"Yongfeng Hui, Junzhi Leng, Dong Jin, Genwang Wang, Kejun Liu, Yang Bu, Qi Wang","doi":"10.1080/15384047.2024.2375440","DOIUrl":"10.1080/15384047.2024.2375440","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558159","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 relationship between long non-coding gene CASC21 polymorphisms and cervical cancer. 长非编码基因 CASC21 多态性与宫颈癌的关系
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-03-11 DOI: 10.1080/15384047.2024.2322207
Lili Han, Jing Liu, Mireayi Shataer, Chengyong Wu, Mayinuer Niyazi

Background: CASC21 was reported to be a hotspot gene in cervical cancer. The relationship between CASC21 genetic polymorphisms and cervical cancer has not been reported. Genetic factors influence the occurrence of cervical cancer. Thus, we explored the correlation between CASC21 polymorphisms and cervical cancer.

Methods: A total of 973 participants within 494 cervical cancer cases and 479 healthy controls were recruited. Five single nucleotide polymorphisms (SNPs) in the CASC21 gene were genotyped using the Agena MassARRAY platform. Chi-squared test, logistic regression analysis, odds ratio (OR), multifactor dimensionality reduction (MDR), and 95% confidence interval (95%CI) were used for data analysis.

Results: In the overall analysis, rs16902094 (p = .014, OR = 1.86, 95% CI = 1.12-3.08) and rs16902104 (p = .014, OR = 1.86, 95% CI = 1.12-3.09) had the risk-increasing correlation with the occurrence of cervical cancer. Stratification analysis showed that rs16902094 and rs16902104 were still associated with cervical cancer risk in the subgroups with age > 51, BMI < 24 kg/m2, smokers, and patients with cervical squamous cell carcinoma. MDR analysis displayed that rs16902094 (.49%) and rs16902104 (.52%) were the main influential attribution factor for cervical cancer risk.

Conclusion: Our finding firstly determined that two CASC21 SNPs (rs16902094, rs16902104) were associated with an increased risk of cervical cancer, which adds to our knowledge regarding the effect of CASC21 on cervical carcinogenesis.

背景:据报道,CASC21 是宫颈癌的热点基因。CASC21 基因多态性与宫颈癌之间的关系尚未见报道。遗传因素会影响宫颈癌的发生。因此,我们探讨了 CASC21 基因多态性与宫颈癌之间的相关性:方法:在 494 例宫颈癌病例和 479 例健康对照中招募了 973 名参与者。使用 Agena MassARRAY 平台对 CASC21 基因中的五个单核苷酸多态性(SNPs)进行了基因分型。数据分析采用了卡方检验、逻辑回归分析、几率比(OR)、多因素降维(MDR)和95%置信区间(95%CI):在总体分析中,rs16902094(p = .014,OR = 1.86,95% CI = 1.12-3.08)和rs16902104(p = .014,OR = 1.86,95% CI = 1.12-3.09)与宫颈癌的发生具有风险递增相关性。分层分析表明,在年龄大于 51 岁、体重指数为 2、吸烟者和宫颈鳞状细胞癌患者的亚组中,rs16902094 和 rs16902104 仍与宫颈癌风险相关。MDR分析显示,rs16902094(.49%)和rs16902104(.52%)是宫颈癌风险的主要影响因素:我们的发现首次确定了两个CASC21 SNPs(rs16902094和rs16902104)与宫颈癌风险的增加相关,这增加了我们关于CASC21对宫颈癌发生影响的知识。
{"title":"The relationship between long non-coding gene <i>CASC21</i> polymorphisms and cervical cancer.","authors":"Lili Han, Jing Liu, Mireayi Shataer, Chengyong Wu, Mayinuer Niyazi","doi":"10.1080/15384047.2024.2322207","DOIUrl":"10.1080/15384047.2024.2322207","url":null,"abstract":"<p><strong>Background: </strong><i>CASC21</i> was reported to be a hotspot gene in cervical cancer. The relationship between <i>CASC21</i> genetic polymorphisms and cervical cancer has not been reported. Genetic factors influence the occurrence of cervical cancer. Thus, we explored the correlation between <i>CASC21</i> polymorphisms and cervical cancer.</p><p><strong>Methods: </strong>A total of 973 participants within 494 cervical cancer cases and 479 healthy controls were recruited. Five single nucleotide polymorphisms (SNPs) in the <i>CASC21</i> gene were genotyped using the Agena MassARRAY platform. Chi-squared test, logistic regression analysis, odds ratio (OR), multifactor dimensionality reduction (MDR), and 95% confidence interval (95%CI) were used for data analysis.</p><p><strong>Results: </strong>In the overall analysis, rs16902094 (<i>p</i> = .014, OR = 1.86, 95% CI = 1.12-3.08) and rs16902104 (<i>p</i> = .014, OR = 1.86, 95% CI = 1.12-3.09) had the risk-increasing correlation with the occurrence of cervical cancer. Stratification analysis showed that rs16902094 and rs16902104 were still associated with cervical cancer risk in the subgroups with age > 51, BMI < 24 kg/m<sup>2</sup>, smokers, and patients with cervical squamous cell carcinoma. MDR analysis displayed that rs16902094 (.49%) and rs16902104 (.52%) were the main influential attribution factor for cervical cancer risk.</p><p><strong>Conclusion: </strong>Our finding firstly determined that two <i>CASC21</i> SNPs (rs16902094, rs16902104) were associated with an increased risk of cervical cancer, which adds to our knowledge regarding the effect of <i>CASC21</i> on cervical carcinogenesis.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10936591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140093448","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
Influence of genetic polymorphisms in vascular endothelial-related genes on the clinical outcome of axitinib in patients with metastatic renal cell carcinoma. 血管内皮相关基因的遗传多态性对转移性肾细胞癌患者服用阿西替尼的临床疗效的影响
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-07 DOI: 10.1080/15384047.2024.2312602
Kazuyuki Numakura, Ryoma Igarashi, Makoto Takahashi, Taketoshi Nara, Sohei Kanda, Mitsuru Saito, Shintaro Narita, Takamitsu Inoue, Takenori Niioka, Masatomo Miura, Tomonori Habuchi

Objective: Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients.

Methods: This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function.

Results: Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p  = .045 and p =  0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p  = .025 and p =  0.036, respectively).

Conclusions: Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

目的:阿西替尼是一种口服多靶点酪氨酸激酶抑制剂,用于治疗肾细胞癌(RCC)。由于阿西替尼会引起严重的不良反应(AEs),因此患者往往需要减少剂量或停止使用,这突出表明需要有效的生物标志物来评估疗效和/或AEs。本研究旨在调查转移性RCC(mRCC)患者中参与阿西替尼药效学作用的基因的单核苷酸多态性(SNPs)与临床预后和AEs之间的关系:本研究纳入了80例接受一线、二线或三线阿西替尼(5毫克,口服,每天两次)治疗的mRCC患者。对 75 例患者(男性 53 例,女性 22 例)的临床参数和基因多态性进行了研究。我们对血管紧张素转换酶(ACE)、一氧化氮合酶3(NOS3)和血管紧张素II受体1型(AT1R)这三个候选基因中的三个SNPs进行了评估,所有这些基因都参与了阿西替尼对血管内皮功能的影响:结果:携带ACE缺失等位基因的阿西替尼治疗患者更常出现手足综合征和肾功能恶化(分别为p = 0.045和p = 0.005),而携带NOS3 G等位基因的患者更常出现蛋白尿和多重AEs(分别为p = 0.025和p = 0.036):我们的研究发现,ACE缺失等位基因和NOS3 G等位基因与AEs增加有关。
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引用次数: 0
Role of transforming growth factor-β1 pathway in angiogenesis induced by chronic stress in colorectal cancer. 转化生长因子-β1通路在慢性应激诱导结直肠癌血管生成中的作用
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-06-10 DOI: 10.1080/15384047.2024.2366451
Jie Zhang, Yao-Tiao Deng, Jie Liu, Lu Gan, Yu Jiang

Background: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood.

Methods: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) in vitro. TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested.

Results: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion.

Conclusions: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.

背景:慢性应激可诱导与应激有关的激素;去甲肾上腺素(NE)被认为是最有可能诱发癌症的激素。NE 可刺激缺氧诱导因子-1α(HIF-1α)的表达,HIF-1α 与血管内皮生长因子(VEGF)分泌和肿瘤血管生成有关。然而,人们对其基本机制还知之甚少:方法:对携带肿瘤的小鼠施加慢性束缚应激,并用生理盐水、人单克隆 VEGF-A 中和抗体贝伐珠单抗或β-肾上腺素能受体(β-AR)拮抗剂(普萘洛尔)进行治疗。此外,还对肿瘤生长和血管密度进行了评估。在体外用 NE、普萘洛尔或转化生长因子-β(TGF-β)受体 I 型激酶抑制剂(Ly2157299)处理人结直肠腺癌细胞。小鼠血清和细胞培养上清液中的 TGF-β1 用酶联免疫吸附法进行定量。采用 Real time-PCR 和 Western 印迹法测定 HIF-1α 的表达。对细胞迁移和侵袭进行了检测:结果:在结直肠肿瘤模型中,慢性束缚应激削弱了贝伐珠单抗的疗效,促进了肿瘤生长和血管生成。普萘洛尔阻断了这种效应,并抑制了慢性束缚应激或NE引起的TGF-β1升高。NE会上调HIF-1α的表达,普萘洛尔或Ly2157299可逆转这种上调。普萘洛尔和 Ly2157199 阻止了 NE 刺激的癌细胞迁移和侵袭:我们的研究结果证明了 NE 对肿瘤血管生成的影响以及 TGF-β1 信号在这一过程中的关键作用。此外,β-AR/TGF-β1 信号/HIF-1α/VEGF 也是一条潜在的信号通路。这项研究还表明,社会心理压力可能是削弱抗血管生成疗法疗效的一个风险因素。
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引用次数: 0
The prognostic marker KRT81 is involved in suppressing CD8 + T cells and predicts immunotherapy response for triple-negative breast cancer. 预后标志物 KRT81 参与抑制 CD8 + T 细胞,并预测三阴性乳腺癌的免疫疗法反应。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-05-22 DOI: 10.1080/15384047.2024.2355705
Zhideng Yan, Zhihui Zhong, Chuanke Shi, Muyin Feng, Xiaoqiang Feng, Tong Liu

Triple-negative breast Cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors. Known for limited targeted therapies, it poses challenges and requires personalized treatment strategies. Differential analysis revealed a significant decrease in keratin 81 (KRT81) expression in non-TNBC samples and an increase in TNBC samples, lower KRT81 expression correlated with better TNBC patient outcomes. It emerged as an independent predictive factor for TNBC, with associations found between its expression and clinically relevant features. We further developed a nomogram for survival probability assessment based on Cox regression results, demonstrating its accuracy through calibration curves. Gene annotation analysis indicated that KRT81 is involved in immune-related pathways and tumor cell adhesion. KRT81 is associated with immune cell infiltration of Follicular helper T cells (Tfh) and CD8 + T cells, suggesting its potential impact on the immunological microenvironment. The study delved into KRT81's predictive value for immunotherapy responses, high expression of KRT81 was associated with greater potential for immune evasion. Single-cell RNA sequencing analysis pinpointed KRT81 expression within a specific malignant subtype which was a risk factor for TNBC. Furthermore, KRT81 promoted TNBC cell proliferation, migration, invasion, and adhesion was confirmed by gene knockout or overexpression assay. Co-culture experiments further indicated KRT81's potential role in inhibiting CD8 + T cells, and correlation analysis implied KRT81 was highly correlated with immune checkpoint CD276, providing insights into its involvement in the immune microenvironment via CD276. In conclusion, this comprehensive study positions KRT81 as a promising prognostic marker for predicting tumor progression and immunotherapy responses in TNBC.

三阴性乳腺癌(TNBC)是一种缺乏雌激素、孕激素和 HER2 受体的侵袭性亚型。由于靶向治疗手段有限,它带来了挑战,需要个性化的治疗策略。差异分析显示,角蛋白 81(KRT81)在非 TNBC 样本中的表达量显著下降,而在 TNBC 样本中的表达量则显著上升,较低的 KRT81 表达量与 TNBC 患者较好的预后相关。KRT81是TNBC的独立预测因子,其表达与临床相关特征之间存在关联。我们根据 Cox 回归结果进一步开发了用于生存概率评估的提名图,并通过校准曲线证明了其准确性。基因注释分析表明,KRT81 参与了免疫相关通路和肿瘤细胞粘附。KRT81与免疫细胞浸润滤泡辅助T细胞(Tfh)和CD8 + T细胞有关,表明它对免疫微环境有潜在影响。研究深入探讨了 KRT81 对免疫疗法反应的预测价值,KRT81 的高表达与免疫逃避的更大可能性相关。单细胞 RNA 测序分析确定了 KRT81 在特定恶性亚型中的表达,而该亚型是 TNBC 的风险因素。此外,基因敲除或过表达实验证实,KRT81 能促进 TNBC 细胞的增殖、迁移、侵袭和粘附。共培养实验进一步表明了 KRT81 在抑制 CD8 + T 细胞方面的潜在作用,相关性分析表明 KRT81 与免疫检查点 CD276 高度相关,这为 KRT81 通过 CD276 参与免疫微环境提供了启示。总之,这项综合研究将 KRT81 定位为预测 TNBC 肿瘤进展和免疫治疗反应的一种有前途的预后标志物。
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Cancer Biology & Therapy
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