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PKP2 induced by YAP/TEAD4 promotes malignant progression of gastric cancer. YAP/TEAD4诱导的PKP2促进胃癌恶性进展
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-28 DOI: 10.1002/mc.23751
Yunyun Liu, Yi Lu, Yuanxin Xing, Wenshuai Zhu, Duanrui Liu, Xiaoli Ma, Yunshan Wang, Yanfei Jia

Gastric cancer (GC) exhibits significant heterogeneity and its prognosis remains dismal. Therefore, it is essential to investigate new approaches for diagnosing and treating GC. Desmosome proteins are crucial for the advancement and growth of cancer. Plakophilin-2 (PKP2), a member of the desmosome protein family, frequently exhibits aberrant expression and is strongly associated with many tumor types' progression. In this study, we found upregulation of PKP2 in GC. Further correlation analysis showed a notable association between increased PKP2 expression and both tumor stage and poor prognosis in individuals diagnosed with gastric adenocarcinoma. In addition, our research revealed that the Yes-associated protein1 (YAP1)/TEAD4 complex could stimulate the transcriptional expression of PKP2 in GC. Elevated PKP2 levels facilitate activation of the AKT/mammalian target of rapamycin signaling pathway, thereby promoting the malignant progression of GC. By constructing a mouse model, we ultimately validated the molecular mechanism and function of PKP2 in GC. Taken together, these discoveries suggest that PKP2, as a direct gene target of YAP/TEAD4 regulation, has the potential to be used as an indication of GC progression and prognosis. PKP2 is expected to be a promising therapeutic target for GC.

胃癌(GC)具有明显的异质性,其预后仍然不容乐观。因此,研究诊断和治疗胃癌的新方法至关重要。脱膜体蛋白对癌症的进展和生长至关重要。Plakophilin-2(PKP2)是脱模体蛋白家族的成员之一,经常表现出异常表达,并与许多肿瘤类型的进展密切相关。在这项研究中,我们发现 PKP2 在 GC 中上调。进一步的相关分析表明,PKP2 表达的增加与胃腺癌患者的肿瘤分期和预后不良都有明显的关联。此外,我们的研究还发现,Yes相关蛋白1(YAP1)/TEAD4复合物可刺激PKP2在胃癌中的转录表达。PKP2 水平的升高会促进 AKT/哺乳动物雷帕霉素靶信号通路的激活,从而促进 GC 的恶性进展。通过构建小鼠模型,我们最终验证了 PKP2 在 GC 中的分子机制和功能。综上所述,这些发现表明,PKP2作为YAP/TEAD4调控的直接基因靶点,有可能被用作GC进展和预后的指示剂。PKP2有望成为GC的治疗靶点。
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引用次数: 0
ZBTB7A interferes with the RPL5-P53 feedback loop and reduces endoplasmic reticulum stress-induced apoptosis of pancreatic cancer cells. ZBTB7A 可干扰 RPL5-P53 反馈环,减少内质网应激诱导的胰腺癌细胞凋亡。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-19 DOI: 10.1002/mc.23772
Jie Tang, Lingling Chen, Yunli Chang, Dongyun Hang, Guoyu Chen, Ying Wang, Lingmei Feng, Ming Xu

Endoplasmic reticulum (ER) stress is a primary mechanism leading to cell apoptosis, making it of great research interests in cancer management. This study delves into the function of ribosomal protein L5 (RPL5) in ER stress within pancreatic cancer (PCa) cells and investigates its regulatory mechanisms. Bioinformatics predictions pinpointed RPL5 as an ER stress-related gene exhibiting diminished expression in PCa. Indeed, RPL5 was found to be poorly expressed in PCa tissues and cells, with this reduced expression correlating with an unfavorable prognosis. Moreover, RPL5 overexpression led to heightened levels of p-PERK, p-eIF2α, and CHOP, bolstering the proapoptotic effect of Tunicamycin, an ER stress activator, on PCa cells. Additionally, the RPL5 overexpression curbed cell proliferation, migration, and invasion. Tunicamycin enhanced the binding between RPL5 and murine double minute 2 (MDM2), thus suppressing MDM2-mediated ubiquitination and degradation of P53. Consequently, P53 augmentation intensified ER stress, which further enhanced the binding between RPL5 and MDM2 through PERK-dependent eIF2α phosphorylation, thereby establishing a positive feedback loop. Zinc finger and BTB domain containing 7A (ZBTB7A), conspicuously overexpressed in PCa samples, repressed RPL5 transcription, thereby reducing P53 expression. Silencing of ZBTB7A heightened ER stress and subdued the malignant attributes of PCa cells, effects counteracted upon RPL5 silencing. Analogous outcomes were recapitulated in vivo employing a xenograft tumor mouse model, where ZBTB7A silencing dampened the tumorigenic potential of PCa cells, an effect reversed by additional RPL5 silencing. In conclusion, this study suggests that ZBTB7A represses RPL5 transcription, thus impeding the RPL5-P53 feedback loop and mitigating ER-induced apoptosis in PCa cells.

内质网(ER)应激是导致细胞凋亡的主要机制,因此在癌症治疗中具有重要的研究意义。本研究探讨了核糖体蛋白 L5(RPL5)在胰腺癌(PCa)细胞ER应激中的功能,并研究了其调控机制。生物信息学预测将 RPL5 定义为在 PCa 中表现出表达减少的 ER 应激相关基因。事实上,RPL5 在 PCa 组织和细胞中的表达量很低,这种表达量的降低与预后不良有关。此外,RPL5 的过表达导致 p-PERK、p-eIF2α 和 CHOP 水平升高,从而增强了ER应激激活剂 Tunicamycin 对 PCa 细胞的促凋亡作用。此外,RPL5 的过表达抑制了细胞的增殖、迁移和侵袭。图尼霉素增强了 RPL5 与小鼠双分化 2(MDM2)之间的结合,从而抑制了 MDM2 介导的 P53 泛素化和降解。因此,P53 的增强加剧了 ER 应激,而 ER 应激又通过 PERK 依赖性 eIF2α 磷酸化进一步增强了 RPL5 与 MDM2 的结合,从而建立了一个正反馈循环。PCa 样本中明显过表达的锌指和含 BTB 结构域的 7A(ZBTB7A)抑制了 RPL5 的转录,从而降低了 P53 的表达。沉默 ZBTB7A 会增加 ER 压力,抑制 PCa 细胞的恶性属性,而沉默 RPL5 则会抵消这种效应。利用异种移植肿瘤小鼠模型在体内再现了类似的结果,沉默 ZBTB7A 可抑制 PCa 细胞的致瘤潜能,而额外的 RPL5 沉默可逆转这种效应。总之,这项研究表明,ZBTB7A 可抑制 RPL5 的转录,从而阻碍 RPL5-P53 的反馈环路,减轻 PCa 细胞中 ER 诱导的细胞凋亡。
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引用次数: 0
LAIR1 promotes hepatocellular carcinoma cell metastasis and induces M2-macrophage infiltration through activating AKT-IKKβ-p65 axis. LAIR1 通过激活 AKT-IKKβ-p65 轴促进肝癌细胞转移并诱导 M2-巨噬细胞浸润。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-17 DOI: 10.1002/mc.23776
Banglun Pan, Shuling Shen, Jun Zhao, Zhu Zhang, Dongjie Ye, Xiaoxia Zhang, Yuxin Yao, Yue Luo, Xiaoqian Wang, Nanhong Tang

LAIR1, a receptor found on immune cells, is capable of binding to collagen and is involved in immune-related diseases. However, the precise contribution of LAIR1 expressed on hepatocellular carcinoma (HCC) cells to tumor microenvironment is still unclear. In our study, bioinformatics analysis and immunofluorescence were employed to study the correlation between LAIR1 levels and clinical indicators. Transwell and scratch tests were used to evaluate how LAIR1 affected the migration and invasion of HCC cells. The chemotactic capacity and alternative activation of macrophages were investigated using RT-qPCR, transwell, and immunofluorescence. To investigate the molecular mechanisms, transcriptome sequencing analysis, Western blot, nucleus/cytoplasm fractionation, ELISA, and cytokine microarray were employed. We revealed a significant correlation between the presence of LAIR1 and an unfavorable outcome in HCC. We indicated that LAIR1 promoted migration and invasion of HCC cells through the AKT-IKKβ-p65 axis. Additionally, the alternative activation and infiltration of tumor-associated macrophages induced by LAIR1 were reliant on the upregulation of IL6 and CCL5 within this axis, respectively. In conclusion, blocking LAIR1 was found to be an effective approach in combating the cancerous advancement of HCC.

LAIR1是免疫细胞上的一种受体,能够与胶原蛋白结合,并参与免疫相关疾病的发生。然而,肝细胞癌(HCC)细胞上表达的 LAIR1 对肿瘤微环境的确切贡献仍不清楚。我们的研究采用生物信息学分析和免疫荧光技术研究 LAIR1 水平与临床指标之间的相关性。我们采用了Transwell和划痕试验来评估LAIR1如何影响HCC细胞的迁移和侵袭。利用 RT-qPCR、transwell 和免疫荧光研究了巨噬细胞的趋化能力和替代性活化。为了研究其分子机制,我们采用了转录组测序分析、Western 印迹、细胞核/细胞质分馏、ELISA 和细胞因子芯片。我们发现 LAIR1 的存在与 HCC 的不良预后之间存在明显的相关性。我们发现 LAIR1 通过 AKT-IKKβ-p65 轴促进了 HCC 细胞的迁移和侵袭。此外,LAIR1 诱导的肿瘤相关巨噬细胞的替代性活化和浸润分别依赖于该轴中 IL6 和 CCL5 的上调。总之,研究发现阻断 LAIR1 是对抗 HCC 癌症发展的有效方法。
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引用次数: 0
Concomitant genomic features stratify prognosis to patients with advanced EGFR mutant lung cancer. 晚期表皮生长因子受体突变肺癌患者预后分层的基因组特征。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-11 DOI: 10.1002/mc.23750
Xiao Liang, Jiali Xu, Yuqin Jiang, Yuqian Yan, Hongshuai Wu, Jiali Dai, Yanan Cui, Chen Zhang, Wei Chen, Zhihong Zhang, Renhua Guo

This study aimed to explore the clinical significance of genomics features including tumor mutation burden (TMB) and copy number alteration (CNA) for advanced EGFR mutant lung cancer. We retrospectively identified 1378 patients with advanced EGFR mutant lung cancer and next-generation sequencing tests from three cohorts. Multiple co-occurring genomics alternations occurred in a large proportion (97%) of patients with advanced EGFR mutant lung cancers. Both TMB and CNA were predictive biomarkers for these patients. A joint analysis of TMB and CNA found that patients with high TMB and high CNA showed worse responses to EGFR-TKIs and predicted worse outcomes. TMBhighCNAhigh, as a high-risk genomic feature, showed predictive ability in most of the subgroups based on clinical characteristics. These patients had larger numbers of metastatic sites, and higher rates of EGFR copy number amplification, TP53 mutations, and cell-cycle gene alterations, which showed more potential survival gain from combination treatment. Furthermore, a nomogram based on genomic features and clinical features was developed to distinguish prognosis. Genomic features could stratify prognosis and guide clinical treatment for patients with advanced EGFR mutant lung cancer.

本研究旨在探索晚期表皮生长因子受体突变肺癌基因组学特征(包括肿瘤突变负荷(TMB)和拷贝数改变(CNA))的临床意义。我们回顾性地鉴定了1378名晚期表皮生长因子受体突变肺癌患者,并从三个队列中进行了新一代测序检测。在很大一部分(97%)晚期表皮生长因子受体突变肺癌患者中,出现了多种共存基因组学变异。TMB和CNA都是这些患者的预测性生物标记物。对 TMB 和 CNA 的联合分析发现,高 TMB 和高 CNA 患者对 EGFR-TKIs 的反应较差,预示着较差的预后。TMB高CNA高作为一种高风险基因组特征,在大多数基于临床特征的亚组中都显示出预测能力。这些患者的转移部位较多,表皮生长因子受体拷贝数扩增、TP53 基因突变和细胞周期基因改变的发生率也较高,这表明联合治疗可获得更多的生存机会。此外,研究人员还根据基因组特征和临床特征绘制了一个提名图来区分预后。基因组特征可对晚期表皮生长因子受体突变肺癌患者的预后进行分层并指导临床治疗。
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引用次数: 0
Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma. CHMP4A和PANX1的潜在功能变异在热蛋白沉积相关途径中可预测非口咽头颈部鳞状细胞癌患者的生存率。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-11 DOI: 10.1002/mc.23767
Xiaozhun Tang, Huiling Wang, Hongliang Liu, Guojun Li, Erich M Sturgis, Sanjay Shete, Qingyi Wei

Background: Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC).

Methods: We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants.

Results: There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels.

Conclusions: Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.

背景:热蛋白沉积与各种癌症的发展有关。触发肿瘤内的热蛋白沉积可增强免疫反应,从而促进抗肿瘤免疫环境的形成。然而,很少有已发表的研究评估了非口咽头颈部鳞状细胞癌(NON-ORO HNSCC)患者的热解相关基因的功能变异与临床预后之间的关联:我们对 985 名非口咽头颈部鳞癌(NON-ORO HNSCC)患者进行了关联研究,这些患者被随机分为两组:发现组(492 人)和复制组(493 人)。我们采用 Cox 比例危险度回归分析法研究了热蛋白变性相关基因的遗传变异与 NON-ORO HNSCC 患者生存率之间的关联。贝叶斯假发现概率(BFDP)用于多重检验校正。对鉴定出的与生存相关的基因变异进行了功能注释:结果:有8254个单核苷酸多态性(SNPs)位于82个热蛋白相关基因中,其中202个SNPs通过了BFDP A和PANX1 rs56175344 C > G的多重检验校正,对总生存率(OS)仍有显著影响,调整后的危险比(HR)分别为1.31(95%置信区间[CI] = 1.09-1.57,p = 0.004)和0.65(95% CI = 0.51-0.83,p = 0.0005)。对合并基因型的进一步分析表明,随着不利基因型数量的增加,OS逐渐恶化(ptrend 结论):热蛋白沉积通路基因的遗传变异可能通过降低基因表达来预测非ORO HNSCC患者的生存率,但我们的研究结果还需要更大规模的研究来验证。
{"title":"Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma.","authors":"Xiaozhun Tang, Huiling Wang, Hongliang Liu, Guojun Li, Erich M Sturgis, Sanjay Shete, Qingyi Wei","doi":"10.1002/mc.23767","DOIUrl":"10.1002/mc.23767","url":null,"abstract":"<p><strong>Background: </strong>Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC).</p><p><strong>Methods: </strong>We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants.</p><p><strong>Results: </strong>There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (p<sub>trend</sub> < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels.</p><p><strong>Conclusions: </strong>Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1712-1721"},"PeriodicalIF":3.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
JMJD2A promotes the development of castration-resistant prostate cancer by activating androgen receptor enhancer and inhibiting the cGAS-STING pathway. JMJD2A 通过激活雄激素受体增强子和抑制 cGAS-STING 通路,促进耐受性前列腺癌的发展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-31 DOI: 10.1002/mc.23753
Xiang Cai, Xiaodong Yu, Tielong Tang, Yi Xu, Tao Wu

Exploring targets for inhibiting androgen receptor (AR) activity is an effective strategy for suppressing the development of castration-resistant prostate cancer (CRPC). Upregulation of histone demethylase JMJD2A activity is an important factor in increasing AR expression in CRPC. Based on our research, we found that the binding affinity between JMJD2A and AR increases in CRPC, while the level of AR histone methylation decreases and the H3K27ac level increases in the AR enhancer region. Further investigations revealed that overexpression of the histone demethylase JMJD2A increased the binding affinity between JMJD2A and AR, decreased AR histone methylation levels, upregulated H3K27ac in the AR enhancer region, and increased AR activity. Conversely, knocking down JMJD2A effectively reversed these effects. Additionally, in CRPC, JMJD2A expression was upregulated, the tumor-intrinsic immune cGAS-STING signaling pathway was suppressed, the tumor microenvironment was altered, and AR expression was upregulated. However, both knocking down JMJD2A and inhibiting the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS-STING) signaling pathway reversed these effects. In summary, our study indicates that in CRPC, JMJD2A can directly bind to AR and activate residual AR enhancers through its demethylation activity, thereby promoting AR expression. Furthermore, upregulation of JMJD2A expression inhibits the innate immune cGAS-STING signaling pathway of the tumor, leading to a decrease in antitumor immune function, and further promoting AR expression.

探索抑制雄激素受体(AR)活性的靶点是抑制去势抵抗性前列腺癌(CRPC)发展的有效策略。组蛋白去甲基化酶 JMJD2A 活性的上调是 CRPC 中 AR 表达增加的一个重要因素。根据我们的研究,我们发现在 CRPC 中,JMJD2A 与 AR 的结合亲和力增加,而 AR 增强子区域的 AR 组蛋白甲基化水平降低,H3K27ac 水平增加。进一步研究发现,过量表达组蛋白去甲基化酶JMJD2A会增加JMJD2A与AR之间的结合亲和力,降低AR组蛋白甲基化水平,上调AR增强子区的H3K27ac,并增加AR的活性。相反,敲除 JMJD2A 能有效逆转这些影响。此外,在 CRPC 中,JMJD2A 表达上调,肿瘤内在免疫 cGAS-STING 信号通路受到抑制,肿瘤微环境发生改变,AR 表达上调。然而,敲除 JMJD2A 和抑制环 GMP-AMP 合成酶/干扰素基因刺激器(cGAS-STING)信号通路都能逆转这些影响。总之,我们的研究表明,在 CRPC 中,JMJD2A 可直接与 AR 结合,并通过其去甲基化活性激活残余的 AR 增强子,从而促进 AR 的表达。此外,JMJD2A表达的上调会抑制肿瘤的先天免疫cGAS-STING信号通路,导致抗肿瘤免疫功能下降,进一步促进AR的表达。
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引用次数: 0
Fisetin induces G2/M phase arrest and caspase-mediated cleavage of p21Cip1 and p27Kip1 leading to apoptosis and tumor growth inhibition in HNSCC. 菲赛汀可诱导 G2/M 期停滞,并在树突酶介导下裂解 p21Cip1 和 p27Kip1,从而导致 HNSCC 细胞凋亡并抑制肿瘤生长。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-27 DOI: 10.1002/mc.23754
Monika Yadav, Kushal Kandhari, Sivapar V Mathan, Mansoor Ali, Rana P Singh

The anticancer potential and associated mechanisms of flavonoid fisetin are yet to be fully investigated on human head and neck squamous cell carcinoma (HNSCC). In the present study, fisetin (25-75 µM for 24-48 h) dose-dependently inhibited growth and induced death in HNSCC Cal33 and UM-SCC-22B cells, without showing any death in normal cells. Fisetin (25-50 µM) induced G2/M phase arrest via decrease in Cdc25C, CDK1, cyclin B1 expression, and an increase in p53(S15). A concentration-dependent increase in fisetin-induced DNA damage and apoptosis in HNSCC cells was authenticated by comet assay, gamma-H2A.X(S139) phosphorylation, and marked cleavage of PARP protein. Interestingly, fisetin-induced cell death occurred independently of p53 and reactive oxygen species production. The activation of JNK and inhibition of PI3K/Akt, ERK1/2, EGFR, and STAT-3 signaling were identified. Further, fisetin-induced apoptosis was mediated, in part, via p21Cip1 and p27Kip1 cleavage by caspase, which was reversed by z-VAD-FMK, a pan-caspase inhibitor. Subsequently, fisetin was also found to induce autophagy; nevertheless, autophagy attenuation exaggerated apoptosis. Oral fisetin (50 mg/kg body weight) treatment to establish Cal33 xenograft in mice for 19 days showed 73% inhibition in tumor volume (p < 0.01) along with a decrease in Ki67-positive cells and an increase in cleaved caspase-3 level in tumors. Consistent with the effect of 50 µM fisetin in vitro, the protein levels of p21Cip1 and P27Kip1 were also decreased by fisetin in tumors. Together, these findings showed strong anticancer efficacy of fisetin against HNSCC with downregulation of EGFR-Akt/ERK1/2-STAT-3 pathway and activation of JNK/c-Jun, caspases and caspase-mediated cleavage of p21Cip1 and p27Kip1.

黄酮类化合物鱼腥草素对人类头颈部鳞状细胞癌(HNSCC)的抗癌潜力和相关机制还有待全面研究。在本研究中,鱼腥草素(25-75 µM,24-48 小时)剂量依赖性地抑制了 HNSCC Cal33 和 UM-SCC-22B 细胞的生长并诱导其死亡,而正常细胞则没有死亡。鱼藤素(25-50 µM)通过减少 Cdc25C、CDK1 和细胞周期蛋白 B1 的表达以及增加 p53(S15) 的表达诱导 G2/M 期停滞。彗星试验、γ-H2A.X(S139)磷酸化和 PARP 蛋白的明显裂解证实了浓度依赖性的鱼藤酮诱导的 HNSCC 细胞 DNA 损伤和凋亡的增加。有趣的是,非西丁诱导的细胞死亡与 p53 和活性氧的产生无关。研究发现,JNK 被激活,PI3K/Akt、ERK1/2、EGFR 和 STAT-3 信号被抑制。此外,非西丁诱导的细胞凋亡部分是通过 caspase 对 p21Cip1 和 p27Kip1 的裂解介导的,而泛 caspase 抑制剂 z-VAD-FMK 能逆转这种裂解。随后还发现,菲赛汀还能诱导自噬;然而,自噬衰减会加剧细胞凋亡。用非西丁(50 毫克/千克体重)口服治疗小鼠 Cal33 异种移植 19 天后,肿瘤体积减少了 73%(非西丁还能减少肿瘤中的 p Cip1 和 P27Kip1)。总之,这些研究结果表明,通过下调表皮生长因子受体-Akt/ERK1/2-STAT-3通路,激活JNK/c-Jun、caspase以及caspase介导的p21Cip1和p27Kip1的裂解,鱼腥草素对HNSCC具有很强的抗癌功效。
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引用次数: 0
HDAC inhibitor regulates the tumor immune microenvironment via pyroptosis in triple negative breast cancer. HDAC 抑制剂通过三阴性乳腺癌的热蛋白沉积调节肿瘤免疫微环境
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-11 DOI: 10.1002/mc.23773
Xue Yang, Xiaoqing Cui, Ge Wang, Mengying Zhou, Yonglin Wu, Yaying Du, Xingrui Li, Tao Xu

Pyroptosis, an inflammatory form of cell death, promotes the release of immunogenic substances and stimulates immune cell recruitment, a process, which could turn cold tumors into hot ones. Thus, instigating pyroptosis in triple-negative breast cancer (TNBC) serves as a viable method for restoring antitumor immunity. We analyzed the effects of Histone Deacetylase Inhibitors (HDACi) on TNBC cells using the Cell Counting Kit-8 and colony formation assay. Apoptosis and lactate dehydrogenase (LDH) release assays were utilized to determine the form of cell death. The pyroptotic executor was validated by quantitative real-time polymerase chain reaction and western blot. Transcriptome was analyzed to investigate pyroptosis-inducing mechanisms. A subcutaneously transplanted tumor model was generated in BALB/c mice to evaluate infiltration of immune cells. HDACi significantly diminished cell proliferation, and pyroptotic "balloon"-like cells became apparent. HDACi led to an intra and extracellular material exchange, signified by the release of LDH and the uptake of propidium iodide. Among the gasdermin family, TNBC cells expressed maximum quantities of GSDME, and expression of GSDMA, GSDMB, and GSDME were augmented post HDACi treatment. Pyroptosis was instigated via the activation of the caspase 3-GSDME pathway with the potential mechanisms being cell cycle arrest and altered intracellular REDOX balance due to aberrant glutathione metabolism. In vivo experiments demonstrated that HDACi can activate pyroptosis, limit tumor growth, and escalate CD8+ lymphocyte and CD11b+ cell infiltration along with an increased presence of granzyme B in tumors. HDACi can instigate pyroptosis in TNBC, promoting infiltration of immune cells and consequently intensifying the efficacy of anticancer immunity.

热蛋白沉积是细胞死亡的一种炎症形式,可促进免疫原性物质的释放并刺激免疫细胞的招募,这一过程可将冷肿瘤变成热肿瘤。因此,在三阴性乳腺癌(TNBC)中激发热休克是恢复抗肿瘤免疫力的一种可行方法。我们使用细胞计数试剂盒-8和集落形成试验分析了组蛋白去乙酰化酶抑制剂(HDACi)对TNBC细胞的影响。我们利用细胞凋亡和乳酸脱氢酶(LDH)释放试验来确定细胞死亡的形式。通过定量实时聚合酶链反应和免疫印迹验证了热凋亡执行者。对转录组进行了分析,以研究诱导热休克的机制。在 BALB/c 小鼠中建立了皮下移植肿瘤模型,以评估免疫细胞的浸润情况。HDACi明显减少了细胞增殖,出现了明显的热凋亡 "气球 "样细胞。HDACi 导致了细胞内外的物质交换,LDH 的释放和碘化丙啶的摄取都表明了这一点。在gasdermin家族中,TNBC细胞表达了最大量的GSDME,而GSDMA、GSDMB和GSDME的表达在HDACi处理后有所增加。通过激活caspase 3-GSDME通路引发了细胞凋亡,其潜在机制是细胞周期停滞和谷胱甘肽代谢异常导致的细胞内REDOX平衡改变。体内实验表明,HDACi 可以激活肿瘤的化脓过程、限制肿瘤生长、增加 CD8+ 淋巴细胞和 CD11b+ 细胞浸润以及增加肿瘤中颗粒酶 B 的存在。HDACi能促进TNBC的热变态反应,促进免疫细胞的浸润,从而增强抗癌免疫的效果。
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引用次数: 0
Issue Information ‐ Ed Board 发行信息 - 教育委员会
IF 4.6 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1002/mc.23578
{"title":"Issue Information ‐ Ed Board","authors":"","doi":"10.1002/mc.23578","DOIUrl":"https://doi.org/10.1002/mc.23578","url":null,"abstract":"","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":"24 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142221636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
M6A-mediated hsa_circ_0061179 inhibits DNA damage in ovarian cancer cells via miR-143-3p/TIMELESS. M6A 介导的 hsa_circ_0061179 通过 miR-143-3p/TIMELESS 抑制卵巢癌细胞的 DNA 损伤。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-15 DOI: 10.1002/mc.23744
Yuhong Zhang, Yuhong Wu, Xiu Shi, Hongmei Ding, Ying Zhou, Hanqing Chen, Fangrong Shen, Youguo Chen, Jinhua Zhou, Dingjie Zhou, Juan Wang

Ovarian cancer (OC) is among the most common and deadly solid malignancies in women. Despite many advances in OC research, the incidence of OC continues to rise, and its pathogenesis remains largely unknown. Herein, we elucidated the function of hsa_circ_0061179 in OC. The levels of hsa_circ_0061179, miR-143-3p, TIMELESS, and DNA damage repair-related proteins in OC or normal ovarian tissues and cells were measured using real-time quantitative polymerase chain reaction and immunoblotting. The biological effects of hsa_circ_0061179 and miR-143-3p on proliferation, clone formation, DNA damage, and apoptosis of OC cells were detected by the cell counting kit-8 assay, 5-methylethyl-2'-deoxyuridine, flow cytometry, the comet assay, and immunofluorescence staining combined with the confocal microscopy. The interaction among hsa_circ_0061179, miR-143-3p, and TIMELESS was validated by the luciferase reporter assay. Mice tumor xenograft models were used to evaluate the influence of hsa_circ_0061179 on OC growth in vivo. We found that human OC biospecimens expressed higher levels of hsa_circ_0061179 and lower levels of miR-143-3p. Hsa_circ_0061179 was found to bind with miR-143-3p, which directly targets TIMELESS. Hsa_circ_0061179 knockdown or miR-143-3p overexpression suppressed the proliferation and clone formation of OC cells and increased DNA damage and apoptosis of OC cells via the miR-143-3p/TIMELESS axis. Furthermore, we demonstrated that METTL3 could direct the formation of has_circ_0061179 through a specific m6A modification site. YTHDC1 facilitated the cytoplasmic transfer of has_circ_0061179 by directly binding to the modified m6A site. Our findings suggest that hsa_circ_0061179 acts as the sponge of miR-143-3p to activate TIMELESS signaling and inhibits DNA damage and apoptosis in OC cells.

卵巢癌(OC)是女性最常见、最致命的实体恶性肿瘤之一。尽管卵巢癌的研究取得了许多进展,但卵巢癌的发病率仍在持续上升,其发病机理在很大程度上仍不清楚。在此,我们阐明了hsa_circ_0061179在OC中的功能。采用实时定量聚合酶链反应和免疫印迹法测定了 OC 或正常卵巢组织和细胞中 hsa_circ_0061179、miR-143-3p、TIMELESS 和 DNA 损伤修复相关蛋白的水平。采用细胞计数试剂盒-8、5-甲基乙基-2'-脱氧尿苷、流式细胞术、彗星试验和免疫荧光染色结合共聚焦显微镜检测了hsa_circ_0061179和miR-143-3p对OC细胞增殖、克隆形成、DNA损伤和凋亡的生物学效应。荧光素酶报告实验验证了 hsa_circ_0061179、miR-143-3p 和 TIMELESS 之间的相互作用。小鼠肿瘤异种移植模型用于评估 hsa_circ_0061179 对体内 OC 生长的影响。我们发现人类 OC 生物样本表达了较高水平的 hsa_circ_0061179,而 miR-143-3p 水平较低。我们发现 Hsa_circ_0061179 与 miR-143-3p 结合,而 miR-143-3p 直接靶向 TIMELESS。通过 miR-143-3p/TIMELESS 轴,Hsa_circ_0061179 敲除或 miR-143-3p 过表达抑制了 OC 细胞的增殖和克隆形成,增加了 OC 细胞的 DNA 损伤和凋亡。此外,我们还证明 METTL3 可以通过一个特定的 m6A 修饰位点引导 has_circ_0061179 的形成。YTHDC1 通过直接与修饰的 m6A 位点结合,促进了 has_circ_0061179 的细胞质转移。我们的研究结果表明,hsa_circ_0061179可作为miR-143-3p的海绵激活TIMELESS信号,抑制OC细胞的DNA损伤和凋亡。
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Molecular Carcinogenesis
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