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Triiodothyronine (T3) suppresses hepatic tumorigenesis and development by inhibiting the phosphorylation of ERK. 三碘甲状腺原氨酸(T3)通过抑制 ERK 的磷酸化,抑制肝脏肿瘤的发生和发展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-19 DOI: 10.1002/mc.23788
Lili Dong, Nan Zhang, Jun Chen, Penghui Dong, Nan Mao, Huiling Li, Aiguo Wang

The effect of triiodothyronine (T3) on the phosphorylation of ERK and the occurrence and development of hepatocellular carcinoma (HCC) is controversial and remains to be clarified. In the present study, both in vitro (hepatoma cell lines) and in vivo (wild-type mice [WT] and mouse models of HCC [HrasG12Vand KrasG12Dtransgenic mice (Hras-Tg and Kras-Tg)]) systems were used to investigate the effect of T3 on p-ERK and hepatocarcinogenesis. The results showed that, in vitro, T3 treatment elevated the levels of p-ERK in hepatoma cells within 30 min. However, p-ERK levels returned to normal after 1 h with no significant effects on cellular proliferation or apoptosis. Interestingly, in vivo, T3 induced early rapid and transient activation of ERK and later persistent downregulation of p-ERK in liver tissues of WT. In Hras-Tg, liver weight, liver/body weight ratio, hepatic tumor numbers and sizes were significantly reduced withT3treatment compared with the untreated group. Furthermore, the levels of albumin, HrasG12V, and p-ERK in hepatic precancerous and tumor tissues were all significantly downregulated with T3 treatment; however, the levels of endogenous Hras were not affected. In WT, T3 also induced downregulation of Albumin in liver tissues, but without influence on the expression of endogenous Hras and p-MEK. Especially, the inhibitory effect of T3 on p-ERK and hepatic tumorigenesis and development without influence on the levels of KrasG12D and p-MEK was further confirmed in Kras-Tg. In conclusion, T3 suppresses hepatic tumorigenesis and development by independently and substantially inhibiting the phosphorylation of ERK in vivo.

三碘甲状腺原氨酸(T3)对ERK磷酸化以及肝细胞癌(HCC)的发生和发展的影响尚存在争议,仍有待澄清。本研究采用体外(肝癌细胞系)和体内(野生型小鼠[WT]和 HCC 小鼠模型[HrasG12V 和 KrasG12D 转基因小鼠(Hras-Tg 和 Kras-Tg)])系统研究 T3 对 p-ERK 和肝癌发生的影响。结果显示,在体外,T3 处理可在 30 分钟内提高肝癌细胞中 p-ERK 的水平。但 1 小时后,p-ERK 水平恢复正常,对细胞增殖和凋亡无明显影响。有趣的是,在体内,T3 在 WT 的肝组织中诱导 ERK 早期快速和短暂的激活,随后 p-ERK 持续下调。与未处理组相比,Hras-Tg 经 T3 处理后,肝脏重量、肝脏/体重比、肝脏肿瘤数量和大小均显著减少。此外,肝癌前组织和肿瘤组织中的白蛋白、HrasG12V和p-ERK的水平在T3治疗后均明显下调,但内源性Hras的水平不受影响。在 WT 中,T3 也诱导肝组织中 Albumin 的下调,但不影响内源性 Hras 和 p-MEK 的表达。特别是在 Kras-Tg 中进一步证实了 T3 对 p-ERK 和肝肿瘤发生和发展的抑制作用,而对 KrasG12D 和 p-MEK 的水平没有影响。总之,T3通过在体内独立地、实质性地抑制ERK的磷酸化来抑制肝肿瘤的发生和发展。
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引用次数: 0
KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer. 抑制 KDM1A/LSD1 可增强卵巢癌的化疗反应。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-11 DOI: 10.1002/mc.23792
Yihong Chen, Jessica D Johnson, Sridharan Jayamohan, Yi He, Prabhakar P Venkata, Diksha Jamwal, Salvador Alejo, Yi Zou, Zhao Lai, Suryavathi Viswanadhapalli, Ratna K Vadlamudi, Edward Kost, Gangadhara R Sareddy

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

卵巢癌(OCa)是最致命的妇科癌症。卵巢癌的标准治疗方法是铂类化疗,如卡铂或顺铂联合紫杉醇。大多数患者最初对这些治疗方法有反应,但近 90% 的患者会出现复发,并不可避免地死于化疗耐药。最近的研究发现,表观遗传修饰因子赖氨酸特异性组蛋白去甲基化酶1A(KDM1A/LSD1)在OCa中高度过表达。然而,KDM1A在化疗耐药性中的作用以及抑制KDM1A是否会增强OCa的化疗反应仍不确定。对TCGA数据集的分析表明,KDM1A在化疗反应差的患者中高表达。Western印迹分析显示,化疗药物顺铂、卡铂和紫杉醇会增加KDM1A在OCa细胞中的表达。KDM1A敲除(KD)或KDM1A抑制剂NCD38和SP2509能使已建立的和患者来源的OCa细胞对化疗药物敏感,从而降低细胞活力和克隆存活率并诱导细胞凋亡。此外,KDM1A的敲除使卡铂耐药的A2780-CP70细胞对卡铂治疗敏感,使紫杉醇耐药的SKOV3-TR细胞对紫杉醇敏感。RNA-seq分析显示,KDM1A-KD和顺铂联合治疗会导致上皮-间质转化(EMT)相关基因下调。有趣的是,顺铂处理增加了NF-κB通路基因的子集,而KDM1A-KD或KDM1A抑制则逆转了这种效应。重要的是,与单一治疗相比,KDM1A-KD与顺铂联合治疗可显著降低正位滑囊内OCa异种移植模型中的肿瘤生长。总之,这些研究结果表明,KDM1A抑制剂与化疗的结合可能是治疗OCa的一种很有前景的治疗方法。
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引用次数: 0
Targeting Hippo/YAP in intrahepatic cholangiocarcinoma: Promising molecules in cancer therapy. 肝内胆管癌中的 Hippo/YAP 靶向:癌症治疗中的前景分子
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-02 DOI: 10.1002/mc.23791
Xing Ma, Yangyang Zhou, Ruping Li, Xianmin Ding, Deyu Li, Tingting Pan, Fuqiang Zhang, Wenliang Li

The tumorigenesis of intrahepatic cholangiocarcinoma (ICC) has been identified to be exceptionally involved in dysregulated Hippo/Yes-associated protein (YAP) signaling pathway (Hippo/YAP). Hippo/YAP functions as a master regulator engaged in a plethora of physiological and oncogenic processes as well. Therefore, the aberrant Hippo/YAP could serve as an Achilles' heel regarding the molecular therapeutic avenues for ICC patients. Herein, we comprehensively review the recent studies about the underlying mechanism of disrupted Hippo/YAP in ICC, how diagnostic values could be utilized upon the critical genes in this pathway, and what opportunities could be given upon this target pathway.

肝内胆管癌(ICC)的肿瘤发生已被证实与失调的希波/耶斯相关蛋白(YAP)信号通路(Hippo/YAP)密切相关。Hippo/YAP作为主调节因子参与了大量的生理和致癌过程。因此,Hippo/YAP的异常可能成为ICC患者分子治疗途径的致命弱点。在此,我们将全面回顾近期有关 ICC 中 Hippo/YAP 紊乱的潜在机制、如何利用该通路中的关键基因进行诊断以及如何利用该靶通路的机会等方面的研究。
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引用次数: 0
Plakophilin 1 in carcinogenesis. Plakophilin 1 在致癌过程中的作用
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-06-18 DOI: 10.1002/mc.23779
Qiang Luo, Xiaojia Li, Keping Xie

Plakophilin 1 (PKP1) belongs to the desmosome family as an anchoring junction protein in cellular junctions. It localizes at the interface of the cell membrane and cytoplasm. Although PKP1 is a non-transmembrane protein, it may become associated with the cell membrane via transmembrane proteins such as desmocollins and desmogleins. Homozygous deletion of PKP1 results in ectodermal dysplasia-skin fragility syndrome (EDSF) and complete knockout of PKP1 in mice produces comparable symptoms to EDSF in humans, although mice do not survive more than 24 h. PKP1 is not limited to expression in desmosomal structures, but is rather widely expressed in cytoplasm and nucleus, where it assumes important cellular functions. This review will summarize distinct roles of PKP1 in the cell membrane, cytoplasm, and nucleus with an overview of relevant studies on its function in diverse types of cancer.

Plakophilin 1(PKP1)属于脱膜小体家族,是细胞连接处的锚定连接蛋白。它定位于细胞膜和细胞质的交界处。虽然 PKP1 是一种非跨膜蛋白,但它可能通过跨膜蛋白(如脱绒毛球蛋白和脱绒毛球蛋白)与细胞膜结合。PKP1的同基因缺失会导致外胚层发育不良-皮肤脆弱综合征(EDSF),在小鼠中完全敲除PKP1会产生与人类EDSF相似的症状,尽管小鼠存活时间不会超过24小时。本综述将总结 PKP1 在细胞膜、细胞质和细胞核中的不同作用,并概述其在不同类型癌症中功能的相关研究。
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引用次数: 0
Downregulation of ALDH5A1 suppresses cisplatin resistance in esophageal squamous cell carcinoma by regulating ferroptosis signaling pathways. 下调ALDH5A1可通过调节铁变态信号通路抑制食管鳞癌的顺铂耐药性
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-06-24 DOI: 10.1002/mc.23778
Kewei Song, Chenhui Ma, Ewetse Paul Maswikiti, Baohong Gu, Bofang Wang, Na Wang, Pei Jiang, Hao Chen

This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe2+, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe2+ content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.

本研究探讨了ALDH5A1在食管鳞状细胞癌(ESCC)化疗耐药性中的特殊作用及其内在机制。通过免疫荧光评估了裂解的caspase-3、4-羟基壬烯醛(4-HNE)、细胞内Fe2+和脂质活性氧(ROS)的水平。细胞活力和迁移分别通过细胞计数试剂盒-8测定法和伤口愈合测定法进行量化。流式细胞仪用于分析细胞凋亡和 ROS 的产生。用酶联免疫吸附法测定丙二醛(MDA)和还原型谷胱甘肽的浓度。蛋白质组分析采用数据独立采集法进行。此外,还建立了 ESCC 异种移植小鼠模型,以研究 ALDH5A1 表达与顺铂(DDP)体内耐药机制之间的关系。ALDH5A1在ESCC患者和ESCC/DDP细胞中均有过表达。沉默 ALDH5A1 能显著增强 DDP 处理对 KYSE30/DDP 和 KYSE150/DDP 细胞活力和迁移的抑制作用,并促进细胞凋亡。此外,它还能增强 DDP 对裸鼠肿瘤体积和重量的抑制作用。基因本体生物学过程分析表明,铁突变在 KYSE30/DDP 细胞和转染 si-ALDH5A1 的 KYSE30/DDP 细胞中都起着至关重要的作用。我们的体外和体内实验证明,DDP 处理会促进 ROS、脂质 ROS、MDA、LPO 和细胞内 Fe2+ 含量的积累,提高促进铁变态反应的蛋白(ACSL4 和 FTH1)的水平,降低抗铁变态反应蛋白(SLC7A11、FTL 和 GPX4)的表达。沉默 ALDH5A1 会进一步扩大 DDP 在体外和体内的调节作用。ALDH5A1 有可能是 ESCC 化疗耐药性的致癌基因。沉默ALDH5A1可通过促进铁变态信号通路降低ESCC对DDP的耐药性。这些发现为临床实践中治疗 ESCC 提供了一种前景广阔的策略。
{"title":"Downregulation of ALDH5A1 suppresses cisplatin resistance in esophageal squamous cell carcinoma by regulating ferroptosis signaling pathways.","authors":"Kewei Song, Chenhui Ma, Ewetse Paul Maswikiti, Baohong Gu, Bofang Wang, Na Wang, Pei Jiang, Hao Chen","doi":"10.1002/mc.23778","DOIUrl":"10.1002/mc.23778","url":null,"abstract":"<p><p>This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe<sup>2+</sup>, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe<sup>2+</sup> content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458118","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
FAP positive cancer-associated fibroblasts promote tumor progression and radioresistance in esophageal squamous cell carcinoma by transferring exosomal lncRNA AFAP1-AS1. FAP阳性癌相关成纤维细胞通过转移外泌体lncRNA AFAP1-AS1促进食管鳞状细胞癌的肿瘤进展和放射抗性。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-06-27 DOI: 10.1002/mc.23782
Xilei Zhou, Yusuo Tong, Changhua Yu, Juan Pu, Weiguo Zhu, Yun Zhou, Yuandong Wang, Yaozu Xiong, Xinchen Sun

Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP+ CAFs and FAP- CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP+ CAFs and FAP- CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP+ CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP- CAFs. Importantly, FAP+ CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP+ CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.

癌症相关成纤维细胞(CAFs)是肿瘤微环境中丰富的异质性基质细胞,它们通过向癌细胞转移外泌体,在调控肿瘤进展和耐药性方面发挥着重要作用。然而,人们对CAFs如何调节食管鳞状细胞癌(ESCC)的进展和放射抗性仍不甚了解。我们对174例接受手术的ESCC患者和78例接受明确化放疗的ESCC患者的预处理活检标本进行了免疫组化,评估了CAFs中成纤维细胞活化蛋白(FAP)的表达。我们根据FAP的表达对CAFs进行了分类,并收集了条件培养基(CM)来培养ESCC细胞。我们测量了FAP+ CAFs和FAP- CAFs的外泌体中几种被认为调控ESCC进展和/或放射抗性的lncRNAs的表达水平。随后,进行了细胞计数试剂盒-8、5-乙炔基-2'-脱氧尿苷、Transwell、集落形成和异种移植试验,以研究FAP+ CAFs和FAP- CAFs之间的功能差异。最后,一系列体外和体内试验被用来评估 AFAP1-AS1 对 ESCC 细胞放射敏感性的影响。基质CAFs中FAP的表达与神经侵袭、血管侵袭、侵袭深度、淋巴结转移、缺乏临床完全反应和生存率低呈正相关。与用CM/FAP+ CAFs培养ESCC细胞相比,用CM/FAP- CAFs培养ESCC细胞可显著增加癌细胞的增殖、迁移、侵袭和放射抗性。重要的是,FAP+ CAFs通过外泌体将功能性lncRNA AFAP1-AS1直接转移到ESCC细胞,从而发挥其作用。功能性研究表明,AFAP1-AS1通过增强ESCC细胞的DNA损伤修复能力来促进其放射抗性。在临床上,血浆中高水平的AFAP1-AS1与ESCC患者对dCRT的不良反应相关。我们的研究结果表明,FAP+ CAFs通过转移外泌体lncRNA AFAP1-AS1促进了ESCC细胞的放射抗性;这可能是ESCC治疗的一个潜在治疗靶点。
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引用次数: 0
γ-Tocotrienol enhances autophagy of gastric cancer cells by the regulation of GSK3β/β-Catenin pathway. γ-生育三烯酚通过调控GSK3β/β-Catenin通路增强胃癌细胞的自噬作用
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-09 DOI: 10.1002/mc.23790
Hao Zhu, Fa-Lin Wang, Shuang Zhang, Li Xue, Guang-Qiang Gao, Hong-Wei Dong, Qi Wang, Wen-Guang Sun, Jia-Ren Liu

γ-Tocotrienol (γ-T3) is a major subtype of vitamin E, mainly extracted from palm trees, barley, walnuts, and other plants. γ-T3 has effects on anti-inflammation, anti-oxidation, and potential chemoprevention against malignancies. It is still uncompleted to understand the effect of γ-T3 on the inhibitory mechanism of cancer. This study aimed to investigate whether γ-T3 enhanced autophagy in gastric cancer and the underlying molecular mechanism. The results showed that γ-T3 (0-90 μmol/L) inhibited the proliferation of gastric cancer MKN45 cells and AGS cells, and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Autophagy was increased in MKN45 cells treated with γ-T3 (0-45 μmol/L), especially at a dose of 30 μmol/L for 24 h. These effects were reversed by 3-methyladenine pretreatment. Furthermore, γ-T3 (30 μmol/L) also significantly downregulated the expression of pGSK-3β (ser9) and β-catenin protein in MKN45 cells, and γ-T3 (20 mg/kg b.w.) effectively decreased the growth of MKN45 cell xenografts in BABL/c mice. GSK-3β inhibitor-CHIR-99021 reversed the negative regulation of GSK-3β/β-Catenin signaling and autophagy. Our findings indicated that γ-T3 enhances autophagy in gastric cancer cells mediated by GSK-3β/β-Catenin signaling, which provides new insights into the role of γ-T3 enhancing autophagy in gastric cancer.

γ-生育三烯酚(γ-T3)是维生素 E 的一种主要亚型,主要从棕榈树、大麦、核桃和其他植物中提取。γ-T3具有抗炎、抗氧化和潜在的化学预防恶性肿瘤的作用。关于γ-T3对癌症抑制机制的影响,目前尚无定论。本研究旨在探讨γ-T3是否能增强胃癌的自噬作用及其分子机制。结果表明,γ-T3(0-90 μmol/L)可抑制胃癌MKN45细胞和AGS细胞的增殖,并使细胞周期停滞在G0/G1期,且呈剂量依赖性。用γ-T3(0-45 μmol/L)处理 MKN45 细胞 24 小时后,自噬增加,尤其是在剂量为 30 μmol/L 时。此外,γ-T3(30 μmol/L)还能显著下调MKN45细胞中pGSK-3β(ser9)和β-catenin蛋白的表达,而且γ-T3(20 mg/kg b.w.)能有效降低MKN45细胞异种移植在BABL/c小鼠体内的生长。GSK-3β抑制剂-CHIR-99021逆转了GSK-3β/β-Catenin信号转导和自噬的负调控。我们的研究结果表明,γ-T3可通过GSK-3β/β-Catenin信号转导增强胃癌细胞的自噬作用,这为γ-T3增强自噬在胃癌中的作用提供了新的见解。
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引用次数: 0
SYT7 as a Potential Prognostic Marker Promotes the Metastasis of Epithelial Ovarian Cancer Cells by Activating the STAT3 Pathway. 作为潜在预后标志物的 SYT7 通过激活 STAT3 通路促进上皮性卵巢癌细胞的转移
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-27 DOI: 10.1002/mc.23821
Yinguang Li, Fengping Shao, Ying Huang, Qian Yin, Jun Liu, Yunhe Zhao, Linjing Yuan

The study aimed to investigate the impact of synaptotagmin 7 (SYT7) on the metastasis of epithelial ovarian cancer (EOC) and its potential mechanisms. This was achieved through the analysis of SYT7 expression levels and clinical relevance in EOC using bioinformatics analysis from TCGA. Additionally, the study examined the influence of SYT7 on the migration and invasion of EOC cells, as well as explored its molecular mechanisms using in vitro EOC cell lines and in vivo mouse xenograft models. Our research revealed that human EOC tissues exhibit significantly elevated levels of SYT7 compared to normal ovarian tissues, and that SYT7 expression is inversely correlated with overall survival. Suppression of SYT7 effectively impeded the migratory and invasive capabilities of CAOV3 cells, whereas overexpression of SYT7 notably accelerated tumor progression in A2780 cells. Mechanistic investigations demonstrated that SYT7 upregulates p-STAT3 and MMP2 in EOC cells. Importantly, treatment with the STAT3 inhibitor niclosamide effectively counteracted the oncogenic effects of SYT7 in EOC. The inhibition of SYT7 was found to significantly reduce in vivo tumor metastasis in a nude mouse xenograft model. Our findings suggest that the upregulation of SYT7 in EOC is associated with a negative prognosis, as it enhances tumor migration and invasion by activating the STAT3 signaling pathway. Thus, SYT7 might be utilized as a EOC prognostic marker and treatment target.

该研究旨在探讨突触表位素7(SYT7)对上皮性卵巢癌(EOC)转移的影响及其潜在机制。为此,研究人员利用 TCGA 的生物信息学分析方法,分析了 SYT7 在 EOC 中的表达水平和临床相关性。此外,研究还考察了SYT7对EOC细胞迁移和侵袭的影响,并利用体外EOC细胞系和体内小鼠异种移植模型探索了其分子机制。我们的研究发现,与正常卵巢组织相比,人类EOC组织的SYT7水平明显升高,而且SYT7的表达与总生存率成反比。抑制SYT7能有效抑制CAOV3细胞的迁移和侵袭能力,而过表达SYT7则会明显加速A2780细胞的肿瘤进展。机理研究表明,SYT7 能上调 EOC 细胞中的 p-STAT3 和 MMP2。重要的是,STAT3抑制剂尼可刹米能有效抵消SYT7在EOC中的致癌作用。在裸鼠异种移植模型中,发现抑制SYT7能显著减少体内肿瘤转移。我们的研究结果表明,SYT7在EOC中的上调与不良预后有关,因为它通过激活STAT3信号通路来增强肿瘤的迁移和侵袭。因此,SYT7可作为EOC预后标志物和治疗靶点。
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引用次数: 0
Dysregulated BCL9 Controls Tumorigenicity and Ferroptosis Susceptibility by Binding With Nrf2 in Thyroid Carcinoma 调控失调的 BCL9 通过与甲状腺癌中的 Nrf2 结合控制肿瘤致病性和铁中毒易感性
IF 4.6 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1002/mc.23816
Bin Wang, Zhihao Yao, Zhenhua Wang, Shenzhen Yao, Xiaoxia Cen, Wei Zhang
Thyroid carcinoma (TC) is the most common malignant tumor of the endocrine system with increasing incidence. In this study, we found that BCL9 is markedly upregulated in human TC tumors and its expression is positively corrected with the process of TC. Functionally, we found that overexpression of BCL9 promoted the proliferation and migration of TC cells, while reduced the sensitivity of TC cells to ferroptosis, a form of cell death driven by iron‐dependent lipid peroxidation and implicated as a novel cancer therapeutic strategy. Mechanistically, the co‐immunoprecipitation assay determined that BCL9 could bind to Nrf2 which has been confirmed to play an important role in ferroptosis. Furthermore, we demonstrated that silence of BCL9 could decrease Nrf2 expression, and then affect the expression of the downstream genes of Nrf2, ultimately induce ferroptosis. Importantly, we confirmed the effects of BCL9 on TC tumors in vivo. Overall, this study unveils the functional role and clinical significance of BCL9 in TC progression, and highlights the potential of targeting BCL9/Nrf2 ferroptosis axis as a novel therapeutic strategy for TC treatment.
甲状腺癌(TC)是内分泌系统最常见的恶性肿瘤,发病率呈上升趋势。本研究发现,BCL9在人类TC肿瘤中明显上调,且其表达与TC的进程呈正相关。在功能上,我们发现BCL9的过表达促进了TC细胞的增殖和迁移,同时降低了TC细胞对铁凋亡的敏感性,铁凋亡是一种由铁依赖的脂质过氧化驱动的细胞死亡形式,被认为是一种新型的癌症治疗策略。从机理上讲,共免疫沉淀实验确定了BCL9能与Nrf2结合,而Nrf2已被证实在铁跃迁中发挥重要作用。此外,我们还证明了沉默BCL9可降低Nrf2的表达,进而影响Nrf2下游基因的表达,最终诱导铁变态反应。重要的是,我们证实了 BCL9 对体内 TC 肿瘤的影响。总之,本研究揭示了BCL9在TC进展中的功能作用和临床意义,并强调了靶向BCL9/Nrf2铁凋亡轴作为TC治疗新策略的潜力。
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引用次数: 0
ICAT-Mediated Crosstalk Between Cervical Cancer Cells and Macrophages Promotes M2-Like Macrophage Polarization to Reinforce Tumor Malignant Behaviors. ICAT 介导的宫颈癌细胞与巨噬细胞之间的串联促进了 M2 类巨噬细胞的极化,从而加强了肿瘤的恶性行为。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.1002/mc.23820
Deyu Liao, Shiyu Yang, Ling Zhao, Wei Ren, Shiyan Liu, Huomei Yu, Yuanxiang Chen, Tao Yu, Tao Zeng, Lan Zhou, Yan Zhang

Inhibitor of β-catenin and T-cell factor (ICAT) is a classical inhibitor of the Wnt signaling pathway. Nonetheless, our previous work found that ICAT is overexpressed in cervical cancer (CC), resulting in the augmentation of migration and invasion capabilities of CC cells. It remains unclear what molecular mechanism underlies this phenomenon. The interaction between cancer cells and the tumor microenvironment (TME) promotes the outgrowth and metastasis of tumors. Tumor-associated macrophages (TAMs) are a major constituent of the TME and have a significant impact on the advancement of CC. Consequently, our inquiry pertains to the potential of ICAT to facilitate tumor development through its modulation of the cervical TME. In this study, we first verified that ICAT regulated the secretion of cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in CC cells, leading to M2-like macrophage polarization and enhancement of the migration and invasion of CC cells. Furthermore, the system of co-culturing human umbilical vein endothelial cells (HUVECs) with macrophages revealed that depending on the CC cells' overexpression or inhibition of ICAT, the vascular tube formation by HUVECs can be either increased or decreased. Overall, our study indicates that ICAT stimulates M2-like polarization of TAMs via upregulating IL-10 and TGF-β, which results in increased neovascularization, tumor metastasis, and immunosuppression in CC. In upcoming times, inhibiting crosstalk between CC cells and TAMs may be a possible strategy for CC therapy.

β-catenin和T细胞因子抑制剂(ICAT)是Wnt信号通路的经典抑制剂。然而,我们之前的研究发现,ICAT 在宫颈癌(CC)中过度表达,导致 CC 细胞的迁移和侵袭能力增强。目前仍不清楚这一现象的分子机制是什么。癌细胞与肿瘤微环境(TME)之间的相互作用促进了肿瘤的生长和转移。肿瘤相关巨噬细胞(TAMs)是肿瘤微环境的主要组成部分,对CC的发展有重要影响。因此,我们的研究涉及 ICAT 通过调节宫颈 TME 促进肿瘤发展的潜力。在这项研究中,我们首先验证了 ICAT 可调节 CC 细胞中白细胞介素-10(IL-10)和转化生长因子-β(TGF-β)的分泌,从而导致 M2 样巨噬细胞极化并增强 CC 细胞的迁移和侵袭。此外,人脐静脉内皮细胞(HUVECs)与巨噬细胞共培养的系统显示,根据 CC 细胞过表达或抑制 ICAT 的情况,HUVECs 的血管管形成会增加或减少。总之,我们的研究表明,ICAT通过上调IL-10和TGF-β刺激TAMs的M2样极化,从而导致CC中血管新生、肿瘤转移和免疫抑制的增加。今后,抑制CC细胞和TAMs之间的串联可能是治疗CC的一种可行策略。
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引用次数: 0
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Molecular Carcinogenesis
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