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Oncogenic fusion of CD63-BCAR4 contributes cancer stem cell-like properties via ALDH1 activity. CD63-BCAR4 的致癌融合通过 ALDH1 的活性产生类似癌症干细胞的特性。
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-13 DOI: 10.1002/mc.23808
Kieun Bae, Dong Eon Kim, Jin Hee Kim, Ja Young Lee, Kyong-Ah Yoon

Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.

基因融合是癌症中常见的体细胞改变,具有致癌特征的融合基因已被确定为新的癌症驱动因素和治疗靶点。很少有研究确定融合基因的致癌能力是否与诱导细胞的干性有关。癌症干细胞(CSC)是导致癌症进展、转移和复发的细胞亚群,是癌症侵袭性特征的关键组成部分。在这里,我们研究了 CD63-BCAR4 融合基因诱导的 CSC 类特性,CD63-BCAR4 融合基因以前曾被报道为一种致癌融合基因,它对增强转移性的潜在贡献是 CD63-BCAR4 的一个显著特征。CD63-BCAR4 的过表达促进了永生化支气管上皮细胞球的形成。沉默 BCAR4 可抑制 CD63-BCAR4 过表达细胞在异种移植小鼠肿瘤衍生细胞中明显增强的球形成活性。RNA 微阵列分析显示,BCAR4 融合过表达细胞中的 ALDH1A1 上调。与空载体相比,CD63-BCAR4过表达细胞球内观察到ALDH1A1的活性和表达增加。BCAR4融合过表达细胞中的CD133和CD44水平也有所升高。在注射了CD63-BCAR4过表达细胞的小鼠转移性肿瘤细胞中,观察到NANOG、SOX2和OCT-3/4蛋白水平升高。此外,ALDH1A1 抑制剂 DEAB 能降低 CD63-BCAR4 诱导的迁移活性和球形成活性。我们的研究结果表明,CD63-BCAR4融合可通过上调ALDH1A1诱导类似CSC的特性,而ALDH1A1是导致其转移特性的原因。
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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 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub 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
ROR2 promotes cell cycle progression and cell proliferation through the PI3K/AKT signaling pathway in gastric cancer. ROR2 通过 PI3K/AKT 信号通路促进胃癌细胞周期进展和细胞增殖。
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-16 DOI: 10.1002/mc.23811
Qi Liu, Xin Zhao, Xiaowen Shao, Ping Cheng, Jingyi Cui, Shuyi Han

Proliferation is a critical characteristic of the progression of gastric cancer (GC). Receptor tyrosine kinase-like orphan receptor 2 (ROR2), the orphan receptor tyrosine kinase-like receptor, exhibits effects on tumor growth due to its abnormal expression in cancer. The goal of our study was to assess the potential regulatory role exerted by the ROR2 on GC cells. Through previous bioinformatics analysis, we discovered an association between ROR2 and the G2/M phase of the GC cell cycle. However, little is known about the link between ROR2 and the G2/M phase cell cycle in GC. Here, the findings of our study indicate that ROR2, after transcribed expression by Twist1, activates the PI3K/AKT/mTOR/S6K signal transduction pathway, thus leading to the acceleration of the G2/M phase and subsequent promotion of cell proliferation in GC. Furthermore, the functional link among ROR2, Twist1, and G2/M phase of cell cycle was also confirmed in mouse xenograft tissues and human tissues. ROR2 expression was correlated with Twist expression and lower survival in vivo. Notably, our suggestion is that focusing on ROR2 as a potential therapeutic approach could show potential for the management of GC.

增殖是胃癌(GC)进展的一个关键特征。受体酪氨酸激酶样孤儿受体 2(ROR2)是一种孤儿受体酪氨酸激酶样受体,因其在癌症中的异常表达而对肿瘤生长产生影响。我们的研究旨在评估 ROR2 对 GC 细胞的潜在调控作用。通过之前的生物信息学分析,我们发现 ROR2 与 GC 细胞周期的 G2/M 阶段有关联。然而,人们对 ROR2 与 GC 细胞周期 G2/M 期之间的联系知之甚少。在此,我们的研究结果表明,ROR2在通过Twist1转录表达后,会激活PI3K/AKT/mTOR/S6K信号转导途径,从而导致GC中G2/M期的加速,进而促进细胞增殖。此外,ROR2、Twist1 和细胞周期 G2/M 期之间的功能联系也在小鼠异种移植组织和人体组织中得到了证实。ROR2 的表达与 Twist 的表达和体内存活率的降低相关。值得注意的是,我们的建议是,将 ROR2 作为一种潜在的治疗方法,可以显示出治疗 GC 的潜力。
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引用次数: 0
The efficacy and safety of pH-responsive and photothermal-sensitive multifunctional nanoparticles loaded with cryptotanshinone for the treatment of gastric cancer. 载入隐丹参酮的 pH 响应和光热敏感多功能纳米粒子治疗胃癌的有效性和安全性。
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-26 DOI: 10.1002/mc.23814
Dan Wu, MingHang Chen, Nan Zheng, Ying Lu, Xiang Wang, Chuan Jiang, HongTao Xu

A multifunctional polydopamine/mesoporous silica nanoparticles loaded cryptotanshinone (PDA/MSN@CTS) was synthesized and subjected to investigating its physicochemical properties and anti-gastric cancer (GC) effects. Utilizing network pharmacology and molecular docking techniques, CTS was identified as our final research target. The structural morphology and physicochemical properties of PDA/MSN@CTS were examined. Near-infrared (NIR) laser was employed to evaluate the photothermal properties of the PDA/MSN@CTS, along with pH-responsive and NIR-triggered release assessments. In vitro experiments evaluated the impact of PDA/MSN@CTS on the malignant behavior of AGS gastric cells. A subcutaneous tumor model was further established to evaluate the in vivo safety of PDA/MSN@CTS. Furthermore, the in vivo photothermal efficacy of PDA/MSN@CTS, in addition to its combined effect with photothermal therapy (PTT), was investigated. Uniform and stable PDA/MSN@CTS had been successfully synthesized and demonstrated efficient release under tumor environment and NIR irradiation. Upon increasing NIR laser conditions, in vivo cytotoxicity, apoptosis rate, reactive oxygen species scavenging ability, and suppression of migration and invasion of AGS cells by PDA/MSN@CTS were significantly enhanced. In vivo assessments revealed excellent blood compatibility and biosafety of PDA/MSN@CTS, alongside robust tumor tissue targeting. Combining nanoparticles with PTT facilitated the anti-GC effects of PDA/MSN@CTS. Compared to free drugs, PDA/MSN@CTS exhibits higher selectivity towards cancer cells, demonstrating effective anticancer activity and biocompatibility both in vitro and in vivo. Furthermore, our nanomaterial possesses excellent photothermal properties, and under NIR conditions, PDA/MSN@CTS exhibits synergistic therapeutic effects.

我们合成了一种负载隐丹参酮的多功能多巴胺/介孔二氧化硅纳米粒子(PDA/MSN@CTS),并对其理化性质和抗胃癌(GC)作用进行了研究。利用网络药理学和分子对接技术,CTS 被确定为我们的最终研究目标。我们研究了 PDA/MSN@CTS 的结构形态和理化性质。利用近红外(NIR)激光评估了 PDA/MSN@CTS 的光热特性,以及 pH 响应和 NIR 触发的释放评估。体外实验评估了 PDA/MSN@CTS 对 AGS 胃细胞恶性行为的影响。为了评估 PDA/MSN@CTS 在体内的安全性,还进一步建立了皮下肿瘤模型。此外,还研究了PDA/MSN@CTS的体内光热效应,以及它与光热疗法(PTT)的联合效应。研究人员成功合成了均匀稳定的PDA/MSN@CTS,并在肿瘤环境和近红外照射下进行了高效释放。随着近红外激光条件的增加,PDA/MSN@CTS的体内细胞毒性、细胞凋亡率、活性氧清除能力以及对AGS细胞迁移和侵袭的抑制能力均显著增强。体内评估显示,PDA/MSN@CTS具有良好的血液相容性和生物安全性,同时还具有强大的肿瘤组织靶向性。将纳米颗粒与 PTT 结合可促进 PDA/MSN@CTS 的抗GC 作用。与游离药物相比,PDA/MSN@CTS 对癌细胞具有更高的选择性,在体外和体内均表现出有效的抗癌活性和生物相容性。此外,我们的纳米材料还具有优异的光热特性,在近红外条件下,PDA/MSN@CTS 可发挥协同治疗作用。
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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 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub 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
Case report & review: Bilateral NIFTP harboring concomitant HRAS and KRAS mutation: Report of an unusual case and literature review. 病例报告与综述:同时携带 HRAS 和 KRAS 突变的双侧 NIFTP:罕见病例报告与文献综述。
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-04 DOI: 10.1002/mc.23813
Marianna Rita Brogna, Francesca Collina, Maria Grazia Chiofalo, Debora De Bartolo, Angela Montone, Maria Rosaria Schiano, Michele Del Sesto, Nubia Pizza, Gerardo Ferrara

Diagnosis and treatment of thyroid disease are affected by the wide range of thyroid cancer subtypes and their varying degrees of aggressiveness. To better describe the indolent nature of thyroid neoplasms previously classified as noninvasive follicular variant of papillary thyroid carcinoma (NI-FVPTC), the Endocrine Pathology Society working group has recently coined the term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP). The purpose of this nomenclature change is to avoid patients the distress of cancer diagnosis and to decrease the overtreatment of thyroid nodules with a RAS-LIKE molecular profile similar to follicular adenoma. Consequently, the reclassification has a significant impact on thyroid nodule clinical care as well as histopathologic and cytopathologic diagnosis. This paper will focus on a unique case of Bilateral NIFTP harboring concomitant HRAS and KRAS mutation; we will also review the background, molecular features, and clinical implications of NIFTP as well as the factors behind the nomenclature update. It also seemed helpful to emphasize the impact of NIFTP on clinical practice to avoid overtreating nodules that could be safely managed with lobectomy alone. Actually, despite the diagnosis is postsurgery, a comprehensive preoperative evaluation may raise a suspicion of NIFTP and suggest a more careful plan for treatment. Here, we present a unique case of bilateral NIFTP after total thyroidectomy; subsequent molecular analysis revealed that the patient's right nodule harbored an isolated p.(Q61K) HRAS mutation, while the left a p.(Q61K) KRAS mutation. To the best of our knowledge, this is the first case report of this nature. The existence of simultaneous mutations highlights the occurrence of intratumoral heterogeneity (ITH) also in the context of FVPTC, which requires comprehensive investigation. The available information shows that NIFTP, identified in accordance with stringent inclusion and exclusion criteria, exhibits a very latent clinical behavior even in the face of conservative lobectomy, lacking of radioactive iodine therapy. However, it cannot be regarded as a benign lesion because there is a small but significant incidence of adverse events, such as lymph nodes and distant metastases. Currently, NIFTP can only be suspected before surgery: several efforts could be explored to identify key molecular, cytological, and ultrasonographic traits that may be helpful in raising the possibility of NIFTP in the preoperative context. Additionally, our discovery of simultaneous mutations within the same lesion strengthens the evidence of ITH even in FVPTC. Although the extent and biological impact of this phenomenon in NIFTP are still debated, a deeper understanding is essential to ensure appropriate clinical management.

甲状腺癌亚型种类繁多,侵袭性程度各异,这影响了甲状腺疾病的诊断和治疗。为了更好地描述以前被归类为甲状腺乳头状癌非侵袭性滤泡变异型(NI-FVPTC)的甲状腺肿瘤的惰性,内分泌病理学协会工作组最近创造了 "具有乳头状核特征的非侵袭性滤泡甲状腺肿瘤"(NIFTP)一词。这一术语变化的目的是避免患者因被诊断为癌症而苦恼,并减少对具有类似滤泡腺瘤的 RAS-LIKE 分子特征的甲状腺结节的过度治疗。因此,重新分类对甲状腺结节的临床治疗以及组织病理学和细胞病理学诊断都有重大影响。本文将重点讨论一例独特的同时携带 HRAS 和 KRAS 突变的双侧 NIFTP;我们还将回顾 NIFTP 的背景、分子特征和临床意义,以及术语更新背后的因素。此外,强调 NIFTP 对临床实践的影响似乎也很有帮助,可避免过度治疗仅通过肺叶切除术就能安全处理的结节。事实上,尽管诊断是在手术后进行的,但全面的术前评估可能会引起对 NIFTP 的怀疑,并建议采取更谨慎的治疗方案。在此,我们介绍了一例独特的甲状腺全切除术后双侧 NIFTP 病例;随后的分子分析显示,患者右侧结节携带孤立的 p.(Q61K) HRAS 突变,而左侧结节携带 p.(Q61K) KRAS 突变。据我们所知,这是首例此类病例报告。同时存在突变突显了 FVPTC 也存在瘤内异质性 (ITH),需要进行全面调查。现有资料表明,根据严格的纳入和排除标准确定的 NIFTP,即使在保守的肺叶切除术和缺乏放射性碘治疗的情况下,也会表现出非常潜伏的临床表现。然而,由于淋巴结和远处转移等不良事件的发生率虽小但却很高,因此不能将其视为良性病变。目前,NIFTP 只能在手术前进行怀疑:可以通过多种努力来确定关键的分子、细胞学和超声特征,这些特征可能有助于在术前提高 NIFTP 的可能性。此外,我们在同一病灶中同时发现了突变,这也加强了 ITH 甚至在 FVPTC 中存在的证据。尽管对这种现象在 NIFTP 中的程度和生物学影响仍有争议,但深入了解这种现象对确保适当的临床管理至关重要。
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引用次数: 0
ADAR1 Promotes Invasion and Migration and Inhibits Ferroptosis via the FAK/AKT Pathway in Colorectal Cancer. ADAR1 通过 FAK/AKT 通路促进结直肠癌的侵袭和迁移并抑制铁凋亡
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-06 DOI: 10.1002/mc.23818
Dongsheng He, Chao Niu, Rilan Bai, Naifei Chen, Jiuwei Cui

The role of adenosine deaminase acting on RNA1 (ADAR1) in colorectal cancer (CRC) is poorly understood. This study investigated the roles and underlying molecular mechanisms of ADAR1 and its isoforms, explored the correlations between ADAR1 expression and the immune microenvironment and anticancer drug sensitivity, and examined the potential synergy of using ADAR1 expression and clinical parameters to determine the prognosis of CRC patients. CRC samples showed significant upregulation of ADAR1, and high ADAR1 expression was correlated with poor prognosis. Silencing ADAR1 inhibited the proliferation, invasion, and migration of CRC cells and induced ferroptosis by suppressing FAK/AKT activation, and the results of rescue assays were consistent with these mechanisms. Both ADAR1-p110 and ADAR1-p150 were demonstrated to regulate the FAK/AKT pathway, with ADAR1-p110 playing a particularly substantial role. In evaluating the prognosis of CRC patients, combining ADAR1 expression with clinical parameters produced a substantial synergistic effect. The in vivo tumorigenesis of CRC was significantly inhibited by silencing ADAR1. Furthermore, ADAR1 expression was positively correlated with tumor mutational burden (TMB) and microsatellite status (p < 0.05), indicating that ADAR1 plays a complex role in CRC immunotherapy. In conclusion, ADAR1 plays oncogenic roles in CRC both in vitro and in vivo, potentially by inhibiting ferroptosis via downregulation of the FAK/AKT pathway. Thus, ADAR1 serves as a potential prognostic biomarker and a promising target for CRC therapy.

人们对作用于RNA1的腺苷脱氨酶(ADAR1)在结直肠癌(CRC)中的作用知之甚少。本研究探讨了ADAR1及其同工型的作用和潜在分子机制,探索了ADAR1表达与免疫微环境和抗癌药物敏感性之间的相关性,并研究了利用ADAR1表达和临床参数判断CRC患者预后的潜在协同作用。CRC样本显示ADAR1明显上调,ADAR1高表达与预后不良相关。沉默ADAR1可抑制CRC细胞的增殖、侵袭和迁移,并通过抑制FAK/AKT活化诱导铁变态反应。ADAR1-p110和ADAR1-p150都被证明能调节FAK/AKT通路,其中ADAR1-p110的作用尤为重要。在评估 CRC 患者的预后时,将 ADAR1 表达与临床参数相结合会产生很大的协同效应。沉默 ADAR1 能显著抑制 CRC 的体内肿瘤发生。此外,ADAR1的表达与肿瘤突变负荷(TMB)和微卫星状态呈正相关(p
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引用次数: 0
SIRT1 promotes doxorubicin-induced breast cancer drug resistance and tumor angiogenesis via regulating GSH-mediated redox homeostasis. SIRT1 通过调节 GSH 介导的氧化还原平衡,促进多柔比星诱导的乳腺癌耐药性和肿瘤血管生成。
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-13 DOI: 10.1002/mc.23809
Shashikanta Sahoo, Sunita Kumari, Sriravali Pulipaka, Yogesh Chandra, Srigiridhar Kotamraju

Sirtuin 1 (SIRT1), a member of histone deacetylase III family, plays a pivotal role in mediating chemoresistance in several cancers, including breast cancer. However, the molecular mechanism by which the deregulated SIRT1 promotes doxorubicin (Dox) resistance is still elusive. Here, we showed that the cell proliferation rates and invasive properties of MDA-MB-231 breast cancer cells were increased from low- to high-Dox-resistant cells. In agreement, severe combined immunodeficiency disease (SCID) mice bearing labeled MDA-MB-231high Dox-Res cells showed significantly higher tumor growth, angiogenesis, and metastatic ability than parental MDA-MB-231 cells. Interestingly, the levels of SIRT1 and glutathione (GSH) were positively correlated with the degree of Dox-resistance. Dox-induced SIRT1 promoted NRF2 nuclear translocation with an accompanying increase in the antioxidant response element promotor activity and GSH levels. In contrast, inhibition of SIRT1 by EX527 greatly reversed these events. More so, Dox-resistance-induced pro-proliferative, proangiogenic, and invasive effects were obviated with depletion of either SIRT1 or GSH. Together, Dox-induced SIRT1 promotes dysregulation of redox homeostasis leading to breast cancer chemoresistance, tumor aggressiveness, angiogenesis, and metastasis.

Sirtuin 1(SIRT1)是组蛋白去乙酰化酶 III 家族的成员,在多种癌症(包括乳腺癌)的化疗耐药性中起着关键作用。然而,SIRT1 的失调促进多柔比星(Dox)耐药性的分子机制仍未确定。在这里,我们发现从低Dox耐药细胞到高Dox耐药细胞,MDA-MB-231乳腺癌细胞的增殖率和侵袭性都有所增加。与此相一致的是,携带标记了高Dox-Res细胞的MDA-MB-231重症联合免疫缺陷病(SCID)小鼠的肿瘤生长、血管生成和转移能力明显高于亲代MDA-MB-231细胞。有趣的是,SIRT1 和谷胱甘肽(GSH)的水平与 Dox 抗性程度呈正相关。Dox诱导的SIRT1促进了NRF2的核转位,并伴随着抗氧化反应元件启动子活性和GSH水平的增加。与此相反,EX527 对 SIRT1 的抑制大大逆转了这些事件。此外,通过消耗 SIRT1 或 GSH,还可消除 Dox 抗性诱导的促增殖、促血管生成和侵袭效应。总之,Dox 诱导的 SIRT1 促进了氧化还原平衡失调,从而导致乳腺癌化疗耐药性、肿瘤侵袭性、血管生成和转移。
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引用次数: 0
Oscillatory hypoxia induced gene expression predicts low survival in human breast cancer patients. 振荡性缺氧诱导的基因表达可预测人类乳腺癌患者的低存活率。
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-16 DOI: 10.1002/mc.23810
Yasir Suhail, Yamin Liu, Wenqiang Du, Junaid Afzal, Xihua Qiu, Amina Atiq, Paola Vera-Licona, Eran Agmon, Kshitiz

Hypoxia is one of the key factors in the tumor microenvironment regulating nearly all steps in the metastatic cascade in many cancers, including in breast cancer. The hypoxic regions can however be dynamic with the availability of oxygen fluctuating or oscillating. The canonical response to hypoxia is relayed by transcription factor Hypoxia-Inducible Factor 1 (HIF-1), which is stabilized in hypoxia and acts as the master regulator of a large number of downstream genes. However, HIF-1 transcriptional activity can also fluctuate either due to unstable hypoxia, or by lactate mediated noncanonical degradation of HIF-1. Our understanding of how oscillatory hypoxia or HIF-1 activity specifically influences cancer malignancy is very limited. Here, using MDA-MB-231 cells as a model of triple negative breast cancer characterized by severe hypoxia, we measured the gene expression changes induced specifically by oscillatory hypoxia. We found that oscillatory hypoxia can specifically regulate gene expression differently, and at times opposite to stable hypoxia. Using the Cancer Genome Atlas RNAseq data of human cancer samples, we show that the oscillatory specific gene expression signature in MDA-MB-231 is enriched in most human cancers, and prognosticates low survival in breast cancer patients. In particular, we found that oscillatory hypoxia, unlike stable hypoxia, induces unfolded protein folding response in cells resulting in gene expression predicting reduced survival.

缺氧是肿瘤微环境中的关键因素之一,几乎调节着许多癌症(包括乳腺癌)转移级联的所有步骤。然而,缺氧区域可能是动态的,氧气的供应会波动或摆动。对缺氧的典型反应由转录因子缺氧诱导因子 1(HIF-1)传递,该因子在缺氧环境中稳定,是大量下游基因的主调节因子。然而,HIF-1 的转录活性也会因不稳定的缺氧或乳酸介导的 HIF-1 非规范降解而波动。我们对振荡性缺氧或 HIF-1 活性如何具体影响癌症恶性程度的了解非常有限。在这里,我们使用 MDA-MB-231 细胞作为以严重缺氧为特征的三阴性乳腺癌模型,测量了振荡性缺氧特别诱导的基因表达变化。我们发现,振荡性缺氧能以不同的方式特异性调控基因表达,有时甚至与稳定型缺氧相反。利用癌症基因组图谱(Cancer Genome Atlas)中人类癌症样本的 RNAseq 数据,我们发现 MDA-MB-231 中的振荡特异性基因表达特征在大多数人类癌症中都有富集,并预示着乳腺癌患者的低生存率。我们特别发现,与稳定低氧不同,振荡低氧会诱导细胞中的未折叠蛋白折叠反应,导致预测生存率降低的基因表达。
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引用次数: 0
Inhibition of XPR1-dependent phosphate efflux induces mitochondrial dysfunction: A potential molecular target therapy for hepatocellular carcinoma? 抑制 XPR1 依赖性磷酸盐外流会诱发线粒体功能障碍:肝细胞癌的潜在分子靶向疗法?
IF 4.3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-13 DOI: 10.1002/mc.23812
Zi-Qiang Liao, Yang-Feng Lv, Mei-Diao Kang, Yu-Long Ji, Yue Liu, Le-Ran Wang, Jia-Liang Tang, Zhi-Qiang Deng, Yun Yi, Qun Tang

Xenotropic and polytropic retrovirus receptor 1 (XPR1) is the only known transporter associated with Pi efflux in mammals, and its impact on tumor progression is gradually being revealed. However, the role of XPR1 in hepatocellular carcinoma (HCC) is unknown. A bioinformatics screen for the phosphate exporter XPR1 was performed in HCC patients. The expression of XPR1 in clinical specimens was analyzed using quantitative real-time PCR, Western blot analysis, and immunohistochemical assays. Knockdown of the phosphate exporter XPR1 was performed by shRNA transfection to investigate the cellular phenotype and phosphate-related cytotoxicity of the Huh7 and HLF cell lines. In vivo tests were conducted to investigate the tumorigenicity of HCC cells xenografted into immunocompromised mice after silencing XPR1. Compared with that in paracancerous tissue, XPR1 expression in HCC tissues was markedly upregulated. High XPR1 expression significantly correlated with poor patient survival. Silencing of XPR1 leads to decreased proliferation, migration, invasion, and colony formation in HCC cells. Mechanistically, knockdown of XPR1 causes an increase in intracellular phosphate levels; mitochondrial dysfunction characterized by reduced mitochondrial membrane potential and adenosine triphosphate levels; increased reactive oxygen species levels; abnormal mitochondrial morphology; and downregulation of key mitochondrial fusion, fission, and inner membrane genes. This ultimately results in mitochondria-dependent apoptosis. These findings reveal the prognostic value of XPR1 in HCC progression and, more importantly, suggest that XPR1 might be a potential therapeutic target.

各向异性和多向性逆转录病毒受体 1(XPR1)是哺乳动物中唯一已知的与π外流相关的转运体,其对肿瘤进展的影响正逐渐被揭示。然而,XPR1 在肝细胞癌(HCC)中的作用尚不清楚。研究人员在 HCC 患者中进行了磷酸盐转运体 XPR1 的生物信息学筛选。利用实时定量 PCR、Western 印迹分析和免疫组化检测分析了 XPR1 在临床标本中的表达。通过 shRNA 转染敲除磷酸盐输出因子 XPR1,研究了 Huh7 和 HLF 细胞系的细胞表型和磷酸盐相关的细胞毒性。通过体内试验研究了沉默 XPR1 后 HCC 细胞异种移植到免疫缺陷小鼠体内的致瘤性。与癌旁组织相比,XPR1在HCC组织中的表达明显上调。XPR1 的高表达与患者的生存率明显相关。沉默 XPR1 会导致 HCC 细胞的增殖、迁移、侵袭和集落形成减少。从机理上讲,敲除 XPR1 会导致细胞内磷酸盐水平升高;线粒体功能障碍,表现为线粒体膜电位和三磷酸腺苷水平降低;活性氧水平升高;线粒体形态异常;以及线粒体融合、裂变和内膜关键基因下调。这最终导致线粒体依赖性凋亡。这些发现揭示了 XPR1 在 HCC 进展中的预后价值,更重要的是,这些发现表明 XPR1 可能是一个潜在的治疗靶点。
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Molecular Carcinogenesis
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