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Atypical BCR-ABL1 transcript in mixed phenotype acute leukemia with bone marrow necrosis. 混合表型急性白血病伴骨髓坏死的非典型 BCR-ABL1 转录本。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-11 DOI: 10.1002/mc.23742
Jiarui Liu, Yujie Jiang, Dai Yuan, Zhifen Zhang, Xin Liu, Wenbo Zhao, Hongzhi Xu

Mixed phenotype acute leukemia (MPAL) is a type of acute leukemia in which encompasses mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. Philadelphia chromosome-positive (Ph+) MPAL is a rare subgroup with a poor prognosis and accounts for <1% of adult acute leukemia. Until now, there is still no consensus on how to best treat Ph+ MPAL. Here, we report a 62-year-old male with Ph+ (atypical e13a2 BCR-ABL1 fusion protein) MPAL. This patient presented with recurrent and intense bone pain due to bone marrow necrosis (BMN). Besides, he did not achieve a complete remission for the first two chemotherapies, until he received flumatinib combined with hyper-CVAD (B) (a dose-intensive regimen include methotrexate and cytarabine). To our knowledge, this is the first report to describe the coexistence of BMN and atypical e13a2 BCR-ABL1 transcripts in patients with MPAL. This finding will bring new understandings in the diagnosis and treatment of Ph+ MPAL.

混合表型急性白血病(MPAL)是一种急性白血病,其中包含髓系、T淋巴细胞和/或B淋巴细胞分化的混合特征。费城染色体阳性(Ph+)MPAL 是一种罕见的亚群,预后较差,占成人急性白血病的 1%。迄今为止,关于如何最佳治疗 Ph+ MPAL 仍未达成共识。在此,我们报告了一名患有 Ph+(非典型 e13a2 BCR-ABL1 融合蛋白)MPAL 的 62 岁男性患者。该患者因骨髓坏死(BMN)而反复出现剧烈骨痛。此外,他在接受氟马替尼联合超CVAD(B)(一种包括甲氨蝶呤和阿糖胞苷的剂量强化方案)治疗之前,前两次化疗均未取得完全缓解。据我们所知,这是第一份描述MPAL患者同时存在BMN和非典型e13a2 BCR-ABL1转录本的报告。这一发现将为Ph+ MPAL的诊断和治疗带来新的认识。
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引用次数: 0
Sulforaphane impaired immune checkpoint blockade therapy through activating ΔNP63α/PD-L1 axis in gastric cancer. 绿叶素通过激活胃癌中的ΔNP63α/PD-L1轴来损害免疫检查点阻断疗法
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-23 DOI: 10.1002/mc.23749
Qi Zhang, Chenying Yang, Zhijian Ma, Liangwen Ye, Yunfeng Wu, Caiyun Zhong, Ye Shi, Mingming Zhu

Sulforaphane (SFN) exerts anticancer effect on various cancers including gastric cancer. However, the regulatory effect of SFN on programmed death-ligand 1 (PD-L1) and checkpoint blockade therapy in gastric cancer have not been elucidated. Here we demonstrated that SFN suppressed gastric cancer cell growth both in vitro and in vivo study. SFN upregulated PD-L1 expression through activating ΔNP63α in gastric cancer cells. Further, we found that SFN impaired the anticancer effect of anti-PD-L1 monoclonal antibody (α-PD-L1 mab) on gastric cancer cells. These results uncover a novel PD-L1 regulatory mechanism and the double-edged role of SFN in gastric cancer intervention.

红豆杉(SFN)对包括胃癌在内的多种癌症具有抗癌作用。然而,SFN 对胃癌中程序性死亡配体 1(PD-L1)和检查点阻断疗法的调节作用尚未阐明。在这里,我们证实了 SFN 在体外和体内研究中都能抑制胃癌细胞的生长。SFN 通过激活胃癌细胞中的ΔNP63α来上调 PD-L1 的表达。此外,我们还发现 SFN 会削弱抗 PD-L1 单克隆抗体(α-PD-L1 mab)对胃癌细胞的抗癌作用。这些结果揭示了一种新的 PD-L1 调节机制以及 SFN 在胃癌干预中的双刃作用。
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引用次数: 0
The promotion of non-small cell lung cancer progression by collagen and calcium binding EGF domain 1 is mediated through the regulation of ERK/JNK/P38 phosphorylation by reactive oxygen species. 胶原蛋白和钙结合EGF结构域1通过活性氧调节ERK/JNK/P38磷酸化来促进非小细胞肺癌的进展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-10 DOI: 10.1002/mc.23736
Chunji Chen, Dongfang Tang, Shangwei Xu, Lujie Xiang, Bin Wang, Yuanshan Yao, Zheng Li, Siyun Lin, Saitian Li, Xin Shi, Chang Gu, Wen Gao

Reactive oxygen species (ROS) are metabolic by-products of cells, and abnormal changes in their levels are often associated with tumor development. Our aim was to determine the role of collagen and calcium binding EGF domain 1 (CCBE1) in oxidative stress and tumorigenesis in non-small cell lung cancer cells (NSCLC). We investigated the tumorigenic potential of CCBE1 in NSCLC using in vitro and in vivo models of CCBE1 overexpression and knockdown. Immunohistochemical staining results showed that the expression of CCBE1 in cancer tissues was significantly higher than that in adjacent tissues. Cell counting Kit 8, clonal formation, wound healing, and transwell experiments showed that CCBE1 gene knockdown significantly inhibited the migration, invasion, and proliferation of NSCLC cell lines. In terms of mechanism, the silencing of CCBE1 can significantly promote the morphological abnormalities of mitochondria, significantly increase the intracellular ROS level, and promote cell apoptosis. This change of oxidative stress can affect cell proliferation, migration, and invasion by regulating the phosphorylation level of ERK/JNK/P38 MAPK. Specifically, the downregulation of CCBE1 inhibits the phosphorylation of ERK/P38 and promotes the phosphorylation of JNK in NSCLC, and this regulation can be reversed by the antioxidant NAC. In vivo experiments confirmed that downregulating CCBE1 gene could inhibit the growth of NSCLC in BALB/c nude mice. Taken together, our results confirm the tumorigenic role of CCBE1 in promoting tumor invasion and migration in NSCLC, and reveal the molecular mechanism by which CCBE1 regulates oxidative stress and the ERK/JNK/P38 MAPK pathway.

活性氧(ROS)是细胞的代谢副产物,其水平的异常变化往往与肿瘤的发展有关。我们的目的是确定胶原蛋白和钙结合EGF结构域1(CCBE1)在非小细胞肺癌细胞(NSCLC)氧化应激和肿瘤发生中的作用。我们利用体外和体内CCBE1过表达和基因敲除模型研究了CCBE1在NSCLC中的致瘤潜能。免疫组化染色结果显示,CCBE1在癌组织中的表达明显高于邻近组织。细胞计数试剂盒8、克隆形成、伤口愈合和透孔实验表明,CCBE1基因敲除能明显抑制NSCLC细胞株的迁移、侵袭和增殖。从机制上看,CCBE1 基因沉默能明显促进线粒体形态异常,显著增加细胞内 ROS 水平,促进细胞凋亡。这种氧化应激的变化可通过调节 ERK/JNK/P38 MAPK 的磷酸化水平来影响细胞的增殖、迁移和侵袭。具体来说,在NSCLC中,下调CCBE1可抑制ERK/P38的磷酸化,促进JNK的磷酸化,而抗氧化剂NAC可逆转这种调控。体内实验证实,下调CCBE1基因可抑制BALB/c裸鼠NSCLC的生长。综上所述,我们的研究结果证实了CCBE1在促进NSCLC肿瘤侵袭和迁移中的致瘤作用,并揭示了CCBE1调控氧化应激和ERK/JNK/P38 MAPK通路的分子机制。
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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 : 2024-07-09 DOI: 10.1002/mc.23577
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引用次数: 0
Loss of PTPRS elicits potent metastatic capability and resistance to temozolomide in glioblastoma. 在胶质母细胞瘤中,PTPRS的缺失会导致强大的转移能力和对替莫唑胺的耐药性。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-03-22 DOI: 10.1002/mc.23720
Yihua Zhang, Liugang Chang, Ping Huang, Min Cao, Rujun Hong, Xinhu Zhao, Xuzhi He, Lunshan Xu

Glioblastoma (GBM) is the most aggressive brain tumor type with worse clinical outcome due to the hallmarks of strong invasiveness, high rate of recurrence, and therapeutic resistance to temozolomide (TMZ), the first-line drug for GBM, representing a major challenge for successful GBM therapeutics. Understanding the underlying mechanisms that drive GBM progression will shed novel insight into therapeutic strategies. Receptor-type tyrosine-protein phosphatase S (PTPRS) is a frequently mutated gene in human cancers, including GBM. Its role in GBM has not yet been clarified. Here, inactivating PTPRS mutation or deficiency was frequently found in GBM, and deficiency in PTPRS significantly induced defects in the G2M checkpoint and limited GBM cells proliferation, leading to potent resistance to TMZ treatment in vitro and in vivo. Surprisingly, loss of PTPRS triggered an unexpected mesenchymal phenotype that markedly enhances the migratory capabilities of GBM cells through upregulating numerous matrix metalloproteinases via MAPK-MEK-ERK signaling. Therefore, this work provides a therapeutic window for precisely excluding PTPRS-mutated patients who do not respond to TMZ.

胶质母细胞瘤(GBM)是侵袭性最强的脑肿瘤类型,由于具有侵袭性强、复发率高以及对治疗 GBM 的一线药物替莫唑胺(TMZ)耐药等特点,临床疗效较差,是成功治疗 GBM 的主要挑战。了解推动 GBM 进展的潜在机制将为治疗策略提供新的视角。受体型酪氨酸蛋白磷酸酶 S(PTPRS)是人类癌症(包括 GBM)中的一种常见突变基因。它在 GBM 中的作用尚未明确。在本研究中,GBM中经常发现灭活的PTPRS突变或缺失,PTPRS的缺失会显著诱导G2M检查点的缺陷,限制GBM细胞的增殖,导致体外和体内对TMZ治疗的强耐药性。令人惊讶的是,PTPRS 的缺失引发了意想不到的间充质表型,通过 MAPK-MEK-ERK 信号转导上调多种基质金属蛋白酶,显著增强了 GBM 细胞的迁移能力。因此,这项工作为精确排除对 TMZ 无应答的 PTPRS 突变患者提供了一个治疗窗口。
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引用次数: 0
ENO1 contributes to the gemcitabine resistance of pancreatic cancer through the YAP1 signaling pathway. ENO1通过YAP1信号通路导致胰腺癌对吉西他滨产生耐药性。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-03-22 DOI: 10.1002/mc.23719
Hongqin Ma, Lulu Kong, Li Liu, Yusheng Du, Xinguo Zhu, Ji Wang, Wenxing Zhao

Pancreatic cancer (PC), a leading cause of cancer-related deaths, has a 5-year survival rate of approximately 10%. α-Enolase (ENO1) is a junction channel protein involved in tumor cell apoptosis and chemoresistance. However, the role of ENO1 in PC remains unclear. The expression and prognosis of ENO1 levels were determined in PC using public databases based on The Cancer Genome Atlas (TCGA) data sets. Cell viability, half maximal inhibitory concentration (IC50), autophagy, apoptosis, and autophagy markers were examined using cell counting kit-8 (CCK-8), transmission electron microscope, flow cytometry assays, and immunoblot, respectively. Using the Gene Expression Omnibus (GEO) and TCGA data sets, we found that ENO1 was significantly enriched in PC tumor tissues, and high expression levels of ENO1 were associated with an unfavorable prognosis. Whereas ENO1 silencing suppressed proliferation, autophagy, and induced cell apoptosis in PC cells, and inhibited tumor growth in vivo. Mechanistically, knockdown of ENO1 enhanced cellular cytotoxicity of gemcitabine (GEM), as well as reducing the expression of yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway in vitro. YAP1 promoted autophagy and protected PC cells from GEM-induced apoptotic cell death. Furthermore, YAP1 overexpression attenuated the inhibition effects of ENO1 silencing. Our results suggest that ENO1 overexpression promotes cell growth and tumor progression by increasing the expression of YAP1 in PC. Further studies are required to understand the detailed mechanisms between ENO1 and YAP1 in PC.

胰腺癌(PC)是癌症相关死亡的主要原因之一,其 5 年生存率约为 10%。α-烯醇化酶(ENO1)是一种交界通道蛋白,参与肿瘤细胞凋亡和化疗抵抗。然而,ENO1在PC中的作用仍不清楚。研究人员利用基于癌症基因组图谱(TCGA)数据集的公共数据库确定了ENO1在PC中的表达水平和预后。利用细胞计数试剂盒-8(CCK-8)、透射电子显微镜、流式细胞术检测和免疫印迹分别检测了细胞活力、半数最大抑制浓度(IC50)、自噬、凋亡和自噬标记物。通过基因表达总库(GEO)和TCGA数据集,我们发现ENO1在PC肿瘤组织中明显富集,且ENO1的高表达水平与预后不良相关。而沉默ENO1能抑制PC细胞的增殖、自噬和诱导细胞凋亡,并抑制肿瘤在体内的生长。从机理上讲,敲除ENO1能增强吉西他滨(GEM)的细胞毒性,同时还能降低体外Hippo通路的主要下游效应物--yes-associated protein 1(YAP1)的表达。YAP1能促进自噬,保护PC细胞免受GEM诱导的细胞凋亡。此外,YAP1的过表达还减弱了ENO1沉默的抑制作用。我们的研究结果表明,ENO1 的过表达会通过增加 PC 中 YAP1 的表达促进细胞生长和肿瘤进展。要了解ENO1和YAP1在PC中的详细机制,还需要进一步的研究。
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引用次数: 0
Deciphering CD4+ T cell-mediated responses against cancer. 破解 CD4+ T 细胞介导的抗癌反应。
IF 4.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-07-01 Epub Date: 2024-05-09 DOI: 10.1002/mc.23730
Catherine Kirkpatrick, Yong-Chen William Lu

It's been long thought that CD8+ cytotoxic T cells play a major role in T cell-mediated antitumor responses, whereas CD4+ T cells merely provide some assistance to CD8+ T cells as the "helpers." In recent years, numerous studies support the notion that CD4+ T cells play an indispensable role in antitumor responses. Here, we summarize and discuss the current knowledge regarding the roles of CD4+ T cells in antitumor responses and immunotherapy, with a focus on the molecular and cellular mechanisms behind these observations. These new insights on CD4+ T cells may pave the way to further optimize cancer immunotherapy.

长期以来,人们一直认为 CD8+ 细胞毒性 T 细胞在 T 细胞介导的抗肿瘤反应中发挥着主要作用,而 CD4+ T 细胞作为 "助手 "只是为 CD8+ T 细胞提供一些帮助。近年来,大量研究支持 CD4+ T 细胞在抗肿瘤反应中发挥不可或缺的作用这一观点。在此,我们总结并讨论了目前有关 CD4+ T 细胞在抗肿瘤反应和免疫疗法中作用的知识,重点是这些观察结果背后的分子和细胞机制。这些关于 CD4+ T 细胞的新见解可能会为进一步优化癌症免疫疗法铺平道路。
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引用次数: 0
VDX-111, a novel small molecule, induces necroptosis to inhibit ovarian cancer progression. 新型小分子 VDX-111 可诱导坏死,从而抑制卵巢癌的进展。
IF 4.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-07-01 Epub Date: 2024-04-01 DOI: 10.1002/mc.23721
Christianne Persenaire, Beatrice Babbs, Tomomi M Yamamoto, Morgan Nebbia, Kimberly R Jordan, Sarah Adams, James R Lambert, Benjamin G Bitler

Epithelial ovarian cancers that are nonhomologous recombination deficient, as well as those that are recurrent and in a platinum-resistant state, have limited therapeutic options. The objectives of this study were to characterize the mechanism of action and investigate the therapeutic potential of a small molecule, VDX-111, against ovarian cancer. We examined the ability of VDX-111 to inhibit the growth of a panel of ovarian cancer cell lines, focusing on BRCA wild-type lines. We found that VDX-111 causes a dose-dependent loss of cell viability across ovarian cancer cell lines. Reverse phase protein array (RPPA) analysis was used to identify changes in cell signaling in response to VDX-111 treatment. An RPPA analysis performed on cells treated with VDX-111 detected changes in cell signaling related to autophagy and necroptosis. Immunoblots of OVCAR3 and SNU8 cells confirmed a dose-dependent increase in LC3A/B and RIPK1. Incucyte live cell imaging was used to measure cell proliferation and death in response to VDX-111 alone and with inhibitors of apoptosis, necroptosis, and autophagy. Annexin/PI assays suggested predominantly nonapoptotic cell death, while real-time kinetic imaging of cell growth indicated the necroptosis inhibitor, necrostatin-1, attenuates VDX-111-induced loss of cell viability, suggesting a necroptosis-dependent mechanism. Furthermore, VDX-111 inhibited tumor growth in patient-derived xenograft and syngeneic murine models. In conclusion, the cytotoxic effects of VDX-111 seen in vitro and in vivo appear to occur in a necroptosis-dependent manner and may promote an antitumor immune response.

非同源重组缺陷的上皮性卵巢癌以及复发性卵巢癌和铂类耐药的卵巢癌的治疗方案有限。本研究的目的是描述小分子 VDX-111 的作用机制,并研究其对卵巢癌的治疗潜力。我们研究了 VDX-111 抑制卵巢癌细胞系生长的能力,重点是 BRCA 野生型细胞系。我们发现,VDX-111 会导致卵巢癌细胞株的细胞活力下降,而这种下降是剂量依赖性的。我们利用反相蛋白质阵列(RPPA)分析来确定细胞信号传导对 VDX-111 处理的反应变化。对经 VDX-111 处理的细胞进行的 RPPA 分析检测到了与自噬和坏死有关的细胞信号变化。OVCAR3 和 SNU8 细胞的免疫印迹证实了 LC3A/B 和 RIPK1 的增加具有剂量依赖性。使用 Incucyte 活细胞成像技术测量细胞增殖和死亡对 VDX-111 单独作用以及与细胞凋亡、坏死和自噬抑制剂一起作用的反应。Annexin/PI检测表明主要是非凋亡性细胞死亡,而细胞生长的实时动力学成像表明坏死抑制剂necrostatin-1能减轻VDX-111诱导的细胞活力丧失,这表明这是一种坏死依赖性机制。此外,VDX-111 还能抑制患者异种移植和合成鼠模型中的肿瘤生长。总之,VDX-111 在体外和体内的细胞毒性作用似乎是以依赖坏死的方式发生的,并可能促进抗肿瘤免疫反应。
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引用次数: 0
Reactivation of methylation-silenced PAX1 inhibits cervical cancer proliferation and migration via the WNT/TIMELESS pathway. 重新激活甲基化沉默的 PAX1 可通过 WNT/TIMELESS 途径抑制宫颈癌的增殖和迁移。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 Epub Date: 2024-05-07 DOI: 10.1002/mc.23728
Wenfan Zhang, Huixi Wang, Shuang Chen, Xueting Fan, Yuqing Liu, Shujuan Shi, Rong Wang

Although aberrant methylation of PAX1 is closely associated with cervical cancer (CC), PAX1 methylation (PAX1m) and its role in CC remain to be elucidated. Here, we clarified the biological function of PAX1 in CC. First, PAX1m in ThinPrep cytologic test samples was measured via quantitative methylation-specific PCR. The results showed that PAX1 promoter methylation levels were significantly increased in CC patients (p < 0.001). We also found that PAX1 promoter methylation levels were positively correlated with tumor purity but negatively correlated with immune-infiltration via public databases. Then, CRISPR-based methylation perturbation tools (dCas9-Tet1) were constructed to further demonstrate that DNA methylation participates in the regulation of PAX1 expression directly. Gain- and loss-of-function experiments were used to show that PAX1 overexpression restrained proliferation, migration and improved cisplatin sensitivity by interfering with the WNT/TIMELESS axis in CC cells. Additionally, Co-immunoprecipitation assays further confirmed the interaction between PAX1 and TCF7L2. Taken together, our results suggested that a tumor suppressor role of PAX1 in CC and that CRISPR-based PAX1 demethylation editing might be a promising therapeutic strategy for CC.

虽然 PAX1 的异常甲基化与宫颈癌(CC)密切相关,但 PAX1 甲基化(PAX1m)及其在 CC 中的作用仍有待阐明。在此,我们阐明了 PAX1 在 CC 中的生物学功能。首先,我们通过甲基化特异性定量 PCR 检测了 ThinPrep 细胞学检测样本中的 PAX1m。结果显示,PAX1启动子甲基化水平在CC患者中明显升高(P < 0.001)。我们还通过公共数据库发现,PAX1启动子甲基化水平与肿瘤纯度呈正相关,但与免疫浸润呈负相关。随后,我们构建了基于CRISPR的甲基化扰乱工具(dCas9-Tet1),进一步证明DNA甲基化直接参与了PAX1的表达调控。功能增益和功能缺失实验表明,PAX1 的过表达通过干扰 CC 细胞的 WNT/TIMELESS 轴,抑制了细胞的增殖和迁移,并提高了顺铂的敏感性。此外,共免疫沉淀实验进一步证实了 PAX1 与 TCF7L2 之间的相互作用。综上所述,我们的研究结果表明,PAX1在CC中具有肿瘤抑制作用,基于CRISPR的PAX1去甲基化编辑可能是一种治疗CC的有效策略。
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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 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-11 DOI: 10.1002/mc.23576
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引用次数: 0
期刊
Molecular Carcinogenesis
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