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Immune dynamics shaping pre-metastatic and metastatic niches in liver metastases: from molecular mechanisms to therapeutic strategies 形成肝转移瘤转移前和转移壁龛的免疫动态:从分子机制到治疗策略
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-14 DOI: 10.1186/s12943-024-02171-z
Chang Zhu, Jing-Yu Liao, Yi-Yang Liu, Ze-Yu Chen, Rui-Zhi Chang, Xiao-Ping Chen, Bi-Xiang Zhang, Jun-Nan Liang
Liver metastases are commonly detected in the advanced stages of various malignant tumors, representing a significant clinical challenge. Throughout the process of liver metastases formation, immune cells play a pivotal role, particularly in the pre-metastatic and metastatic niches within the liver. Immune cells establish extensive and intricate interactions with tumor cells and other components in the liver, collectively promoting and sustaining the growth of liver metastases. Despite the limited efficacy of existing therapeutic modalities against some advanced liver metastases, novel immune-based treatment approaches are continuously being explored and validated. Building on the systematic elucidation of the immunosuppressive characteristics of liver metastases, we explored the potential of novel immunotherapies applicable to patients with liver metastases from multiple dimensions.
肝转移通常在各种恶性肿瘤的晚期阶段被发现,是一项重大的临床挑战。在肝转移瘤形成的整个过程中,免疫细胞发挥着举足轻重的作用,尤其是在肝脏内的转移前和转移龛中。免疫细胞与肿瘤细胞和肝脏中的其他成分建立广泛而复杂的相互作用,共同促进和维持肝转移灶的生长。尽管现有治疗方法对某些晚期肝转移瘤的疗效有限,但人们仍在不断探索和验证基于免疫的新型治疗方法。在系统阐明肝转移瘤免疫抑制特征的基础上,我们从多个维度探索了适用于肝转移瘤患者的新型免疫疗法的潜力。
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引用次数: 0
Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer 先天性免疫激活与 PD-1/PD-L1 阻断相结合治疗结直肠癌的细胞机制
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1186/s12943-024-02166-w
Qi Xie, Xiaolin Liu, Rengyun Liu, Jingxuan Pan, Jing Liang
PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.
PD-1/PD-L1阻断疗法对黑色素瘤、肾癌、膀胱癌和肺癌显示出非凡的临床疗效;然而,只有少数结直肠癌(CRC)患者能从这些疗法中获益。由于肿瘤微环境的复杂性,PD-1/PD-L1 阻断疗法对 CRC 的疗效受到了限制。PD-1/PD-L1 阻断免疫疗法是基于以 T 细胞为中心的肿瘤免疫观点。然而,T 细胞应答的发生和维持以及长效记忆 T 细胞的形成都依赖于先天性免疫应答。鉴于先天性免疫在抗肿瘤免疫反应中的关键作用,本综述总结了在激活先天性免疫的同时使用 PD-1/PD-L1 阻断的联合疗法,并探讨了其潜在的细胞机制,旨在利用先天性免疫反应为接受 PD-1/PD-L1 阻断疗法的 CRC 患者诱导持久的肿瘤控制。
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引用次数: 0
The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer 在 KRASG12D 驱动的非小细胞肺癌中,PI3K-AKT-mTOR 轴始终是一种治疗依赖因素
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1186/s12943-024-02157-x
W. J. McDaid, L. Wilson, H. Adderley, A. Martinez-Lopez, M. J. Baker, J. Searle, L. Ginn, T. Budden, M. Aldea, A. Marinello, J. V. Aredo, A. Viros, B. Besse, H. A. Wakelee, F. Blackhall, S. Castillo-Lluva, C. R. Lindsay, A. Malliri
KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC. KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.
KRASG12C 和 KRASG12D 抑制剂直接针对非小细胞肺癌(NSCLC)中突变最严重的癌蛋白,是非小细胞肺癌(NSCLC)和一般癌症在转化方面的重大突破。然而,对这些小分子的耐药性凸显了对合理组合伙伴的需求,这就需要对 KRAS 突变异构体下游的信号传导进行深入了解。我们对比了 KrasG12C 和 KrasG12D 基因工程小鼠模型(GEMMs)的肿瘤发生情况。为了证实研究结果并确定突变亚型的特异性依赖性,我们通过 RNA 测序分析了 KrasG12C 和 KrasG12D 启动和适应的同源模型。我们还采用了已确诊的 KRAS 突变 NSCLC 细胞系模型,并通过药理抑制确定了治疗漏洞。我们分析了晚期 KRASG12C 或 KRASG12D 突变 NSCLC 患者生存结果的差异。与 KRASG12C 相比,KRASG12D 在体内表现出更高的效力,表现为更快的肺肿瘤形成和 KRASG12D GEMMs 存活率降低。在同源启动模型中再现的这种增效与 PI3K-AKT-mTOR 信号转导增强有关。然而,在体外和体内肿瘤发生的后期阶段,KRASG12C 的致癌能力和下游通路激活与 KRASG12D 相当,这与患者的临床结果相似。尽管如此,已建立的 KRASG12D NSCLC 模型更依赖于 PI3K-AKT-mTOR 通路,而 KRASG12C 模型则依赖于 MAPK 通路。具体来说,体外和体内抑制 AKT 会增强对 KRASG12D 的抑制作用。我们的数据凸显了一种独特的联合治疗脆弱性,并建议使用直接 KRAS 抑制剂的联合治疗方法的患者选择策略应:i)针对单个 RAS 突变体的具体情况;ii)针对其下游信号转导。
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引用次数: 0
Regulatory T cells in immune checkpoint blockade antitumor therapy 免疫检查点阻断抗肿瘤疗法中的调节性 T 细胞
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-08 DOI: 10.1186/s12943-024-02156-y
An Zhang, Tao Fan, Yixiao Liu, Guanhua Yu, Chunxiang Li, Zheng Jiang
Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group of T lymphocytes with the ability to suppress immune responses and maintain immune homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity and facilitate cancer progression by weakening functions of effector T cells (Teffs). Consequently, targeting Tregs to eliminate them from tumor microenvironments to improve Teffs’ activity could emerge as an effective strategy for cancer immunotherapy. This review outlines the biology of Tregs, detailing their origins, classification, and crucial markers. Our focus lies on the complex role of Tregs in cancer’s development, progression and treatment, particularly on their suppressive role upon antitumor responses via multiple mechanisms. We delve into Tregs’ involvement in immune checkpoint blockade (ICB) therapy, their dual effect on cancer immunotherapy and their potential biomarkers for ICB therapy effectiveness. We also summarize advances in the therapies that adjust Tregs to optimize ICB therapy, which may be crucial for devising innovative cancer treatment strategies.
调节性 T 细胞(Tregs)是人体免疫系统的重要组成部分,是一类异质性 T 淋巴细胞,具有抑制免疫反应和维持免疫平衡的能力。最近的证据表明,调节性 Tregs 可能会削弱效应 T 细胞(Teffs)的功能,从而损害抗肿瘤免疫力并促进癌症进展。因此,以 Tregs 为靶点,将其从肿瘤微环境中清除以提高 Teffs 的活性,可能会成为癌症免疫疗法的一种有效策略。这篇综述概述了 Tregs 的生物学特性,详细介绍了它们的起源、分类和重要标志物。我们的重点是 Tregs 在癌症的发生、发展和治疗中的复杂作用,尤其是它们通过多种机制对抗肿瘤反应的抑制作用。我们将深入探讨 Tregs 在免疫检查点阻断疗法(ICB)中的参与、它们对癌症免疫疗法的双重作用以及 ICB 疗法有效性的潜在生物标志物。我们还总结了调整 Tregs 以优化 ICB 疗法的研究进展,这可能对制定创新的癌症治疗策略至关重要。
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引用次数: 0
Traditional Chinese medicine in treating upper digestive tract cancers 中药治疗上消化道癌症
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-08 DOI: 10.1186/s12943-024-02149-x
Alexis Shiying Huang, Jiaying Wu, Aftab AMIN, Xiu-Qiong Fu, Zhi-Ling Yu
Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized.
上消化道癌症,如口腔癌、喉癌、食管癌和胃癌,占全球癌症病例的 10%,占癌症相关死亡人数的 14.5%。传统的治疗方法通常只能提供有限的生存益处,而且经常出现不良反应和耐药性。中草药在远东地区被广泛用于治疗这些癌症。在这篇叙述性综述中,我们总结了目前关于 138 种中药用于治疗上消化道癌症和癌前病变的临床研究(截至 2024 年 6 月发表)。在癌症治疗方面,共测试了 126 种 CHD,均与传统疗法相结合。每种 CHD 都提高了临床疗效和/或减少了传统疗法的不良反应。五年生存率是评估癌症治疗临床疗效的关键指标。据报道,有四种 CHD 提高了接受传统疗法的患者的五年生存率。这四种化学合成药物是四神解毒片、平消片、扶正固本颗粒和步阳黄五汤。在治疗癌前病变方面,测试了 12 种 CHD:6 种单独使用,6 种与传统疗法联合使用。增生平是其中一种单独使用的 CHD,也是唯一一种已被证实可预防食道癌发展并具有令人信服的证据的 CHD。这篇综述提供了 CHDs 的临床疗效信息,为合理应用 CHDs 治疗上消化道癌症提供了参考。综述的研究存在局限性:大多数试验的样本量较小,且不是多中心试验;只有一项研究调查了所研究的 CHD 的作用机制;没有探讨 CHD 的活性成分。为了促进 CHD 在国际上得到认可,有必要对临床结果、作用机制和活性成分进行严格设计的研究。此外,所研究的 CHD 应标准化。
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引用次数: 0
Variability in non-tumor areas of colorectal cancer patients as revealed by endoscopic intestinal step biopsies 内窥镜肠道阶梯活检显示的结直肠癌患者非肿瘤区域的变异性
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1186/s12943-024-02159-9
Shoko Ikuta, Yutaka Saito, So Takata, Yoichiro Nakatani, Izumi Nagatomo, Satoshi Shiba, Yoshito Takeda, Yasushi Totoki, Sayaka Mizutani, Hironori Sunakawa, Hiroaki Ikematsu, Hiroyuki Takamaru, Atsushi Kumanogoh, Shinichi Yachida
A comprehensive endoscopic small and large intestinal untargeted step biopsy procedure was conducted to compare gene expression between the normal intestinal mucosa of healthy individuals and that of patients with colorectal tumors. From 78 participants (healthy individuals [n = 17], patients with colorectal conventional adenomas [n = 6], patients with Tis–T1 colorectal cancer [n = 41], patients with T2–4 colorectal cancer [n = 14]), biopsies of normal mucosa of the terminal ileum, right-sided colon (cecum and ascending colon), and left-sided colorectum (descending colon, sigmoid colon, and rectum) were obtained using a lower gastrointestinal endoscope. RNA was extracted from all samples, and total transcriptome sequencing was performed. Transcriptome data from 388 samples was analyzed. DNA was also extracted from tumor biopsy tissues and analyzed for whole-exome sequencing. In healthy individuals, gene expression differed significantly among the terminal ileum, right-sided colon, and left-sided colorectum, presumably linked to embryological factors. There were differences in gene expression in the normal mucosa in colorectal cancer patients, compared to healthy controls. Patients with tumors, especially T2–4 colorectal cancer, showed considerable variation in gene expression in non-tumor tissues, even in the terminal ileum distant from the tumor site. Based on endoscopic biopsies, the results imply cancer-predisposing conditions in seemingly normal tissues. The present study points to the importance of small intestine and cancer-predisposing conditions in the colon of colorectal cancer patients, with possible implications for developing novel immunotherapy and other therapeutic modalities.
为了比较健康人的正常肠粘膜与结直肠肿瘤患者的肠粘膜之间的基因表达,我们进行了一次全面的内窥镜小肠和大肠非靶向阶梯活检。使用下消化道内窥镜从 78 名参与者(健康人 [n = 17]、结直肠传统腺瘤患者 [n = 6]、Tis-T1 结直肠癌患者 [n = 41]、T2-4 结直肠癌患者 [n = 14])中获取了回肠末端、右侧结肠(盲肠和升结肠)和左侧结直肠(降结肠、乙状结肠和直肠)正常粘膜的活组织切片。从所有样本中提取 RNA,并进行总转录组测序。分析了 388 个样本的转录组数据。还从肿瘤活检组织中提取了 DNA,并进行了全基因组测序分析。在健康人中,回肠末端、右侧结肠和左侧结直肠的基因表达存在显著差异,这可能与胚胎学因素有关。与健康对照组相比,结直肠癌患者正常粘膜的基因表达存在差异。肿瘤患者,尤其是 T2-4 结直肠癌患者,其非肿瘤组织中的基因表达有相当大的差异,甚至在远离肿瘤部位的回肠末端也是如此。根据内窥镜活检结果,这些结果表明在看似正常的组织中也存在易患癌症的条件。本研究指出了小肠和大肠癌患者结肠中癌症易感条件的重要性,这对开发新型免疫疗法和其他治疗方法可能具有重要意义。
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引用次数: 0
A prospective multi-cohort study identifies and validates a 5-gene peripheral blood signature predictive of immunotherapy response in non-small cell lung cancer 一项前瞻性多队列研究确定并验证了可预测非小细胞肺癌免疫疗法反应的 5 基因外周血特征
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-06 DOI: 10.1186/s12943-024-02160-2
Shaoqiu Chen, Fangfang Liu, Yuanyuan Fu, Chris K. Deng, Jeffrey A. Borgia, Abdul-Ghani Ayman, Masaki Nasu, Mayumi Jijiwa, Hua Yang, Ting Gong, Junlong Wang, Zhougui Ling, Xiaoyan Wang, Hongwei Wang, Qian Chu, Youping Deng
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC. We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS). In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80–0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07–0.58, p = 0.005). Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision.
免疫检查点抑制剂(ICIs)彻底改变了非小细胞肺癌(NSCLC)的治疗格局。由于患者反应的差异性,需要一种基于血液的多队列基因特征来预测 NSCLC 的 ICI 反应。我们对接受 ICIs 治疗的三个独立 NSCLC 患者队列的外周血单核细胞(PBMC)和水衣(BC)样本进行了转录组分析:回顾性队列(PMBCR,n = 59)、回顾性验证队列(BC,n = 44)和前瞻性验证队列(PBMCP,n = 42)。我们确定了可预测 ICI 反应的 5 个基因特征(UQCRB、NDUFA3、CDKN2D、FMNL1-DT 和 APOL3),并在前瞻性 PBMCP 队列中验证了其临床实用性。采用 RECIST 标准对反应进行评估,并对患者的无进展生存期(PFS)和总生存期(OS)进行随访。在前瞻性 PBMCP 队列中,5 基因特征在将患者分层为应答者和非应答者方面表现出很高的准确性(AUC = 0.89,95% CI:0.80-0.99)。预测应答者的 PFS 明显长于预测非应答者(中位:13.8 个月 vs. 4.2 个月,HR = 0.21,95% CI:0.07-0.58,p = 0.005)。我们的研究证实了5基因特征是NSCLC ICI反应的关键生物标志物,从而提高了治疗的精确性。
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引用次数: 0
SARS-CoV-2 nucleocapsid protein interaction with YBX1 displays oncolytic properties through PKM mRNA destabilization SARS-CoV-2核壳蛋白与YBX1的相互作用通过破坏PKM mRNA的稳定性而显示出溶媒特性
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-06 DOI: 10.1186/s12943-024-02153-1
Xin Chen, Baohong Jiang, Yu Gu, Zhaoyang Yue, Ying Liu, Zhiwei Lei, Ge Yang, Minhua Deng, Xuelong Zhang, Zhen Luo, Yongkui Li, Qiwei Zhang, Xuepei Zhang, Jianguo Wu, Chunyu Huang, Pan Pan, Fangjian Zhou, Ning Wang
SARS-CoV-2, a highly contagious coronavirus, is responsible for the global pandemic of COVID-19 in 2019. Currently, it remains uncertain whether SARS-CoV-2 possesses oncogenic or oncolytic potential in influencing tumor progression. Therefore, it is important to evaluate the clinical and functional role of SARS-CoV-2 on tumor progression. Here, we integrated bioinformatic analysis of COVID-19 RNA-seq data from the GEO database and performed functional studies to explore the regulatory role of SARS-CoV-2 in solid tumor progression, including lung, colon, kidney and liver cancer. Our results demonstrate that infection with SARS-CoV-2 is associated with a decreased expression of genes associated with cancer proliferation and metastasis in lung tissues from patients diagnosed with COVID-19. Several cancer proliferation or metastasis related genes were frequently downregulated in SARS-CoV-2 infected intestinal organoids and human colon carcinoma cells. In vivo and in vitro studies revealed that SARS-CoV-2 nucleocapsid (N) protein inhibits colon and kidney tumor growth and metastasis through the N-terminal (NTD) and the C-terminal domain (CTD). The molecular mechanism indicates that the N protein of SARS-CoV-2 interacts with YBX1, resulting in the recruitment of PKM mRNA into stress granules mediated by G3BP1. This process ultimately destabilizes PKM expression and suppresses glycolysis. Our study reveals a new function of SARS-CoV-2 nucleocapsid protein on tumor progression.
SARS-CoV-2 是一种传染性极强的冠状病毒,是 2019 年 COVID-19 全球大流行的罪魁祸首。目前,SARS-CoV-2 在影响肿瘤进展方面是否具有致癌或溶瘤潜能仍不确定。因此,评估SARS-CoV-2对肿瘤进展的临床和功能作用非常重要。在这里,我们整合了 GEO 数据库中 COVID-19 RNA-seq 数据的生物信息学分析,并进行了功能研究,以探索 SARS-CoV-2 在实体瘤(包括肺癌、结肠癌、肾癌和肝癌)进展中的调控作用。我们的研究结果表明,在确诊为 COVID-19 的患者肺组织中,感染 SARS-CoV-2 与癌症增殖和转移相关基因的表达减少有关。在感染了 SARS-CoV-2 的肠器官组织和人类结肠癌细胞中,一些与癌症增殖或转移相关的基因经常下调。体内和体外研究发现,SARS-CoV-2核壳蛋白(N)通过N端(NTD)和C端结构域(CTD)抑制结肠和肾肿瘤的生长和转移。分子机制表明,SARS-CoV-2 的 N 蛋白与 YBX1 相互作用,导致 PKM mRNA 在 G3BP1 的介导下被招募到应激颗粒中。这一过程最终会破坏 PKM 表达的稳定性并抑制糖酵解。我们的研究揭示了SARS-CoV-2核壳蛋白对肿瘤进展的新功能。
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引用次数: 0
Nanoparticles and bone microenvironment: a comprehensive review for malignant bone tumor diagnosis and treatment 纳米颗粒与骨微环境:恶性骨肿瘤诊断与治疗综述
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 DOI: 10.1186/s12943-024-02161-1
Yujing Guan, Wei Zhang, Yuling Mao, Shenglong Li
Malignant bone tumors, which are difficult to treat with current clinical strategies, originate from bone tissues and can be classified into primary and secondary types. Due to the specificity of the bone microenvironment, the results of traditional means of treating bone tumors are often unsatisfactory, so there is an urgent need to develop new treatments for malignant bone tumors. Recently, nanoparticle-based approaches have shown great potential in diagnosis and treatment. Nanoparticles (NPs) have gained significant attention due to their versatility, making them highly suitable for applications in bone tissue engineering, advanced imaging techniques, and targeted drug delivery. For diagnosis, NPs enhance imaging contrast and sensitivity by integrating targeting ligands, which significantly improve the specific recognition and localization of tumor cells for early detection. For treatment, NPs enable targeted drug delivery, increasing drug accumulation at tumor sites while reducing systemic toxicity. In conclusion, understanding bone microenvironment and using the unique properties of NPs holds great promise in improving disease management, enhancing treatment outcomes, and ultimately improving the quality of life for patients with malignant bone tumors. Further research and development will undoubtedly contribute to the advancement of personalized medicine in the field of bone oncology.
恶性骨肿瘤起源于骨组织,可分为原发性和继发性两类,目前的临床策略难以治疗。由于骨微环境的特异性,传统的骨肿瘤治疗手段效果往往不尽如人意,因此,开发新的恶性骨肿瘤治疗方法迫在眉睫。最近,基于纳米粒子的方法在诊断和治疗方面显示出巨大的潜力。纳米粒子(NPs)因其多功能性而备受关注,非常适合应用于骨组织工程、先进成像技术和靶向给药。在诊断方面,纳米粒子通过整合靶向配体提高了成像对比度和灵敏度,从而显著改善了肿瘤细胞的特异性识别和定位,便于早期检测。在治疗方面,纳米粒子可实现靶向给药,增加药物在肿瘤部位的蓄积,同时降低全身毒性。总之,了解骨微环境并利用 NPs 的独特性能,在改善疾病管理、提高治疗效果并最终改善恶性骨肿瘤患者的生活质量方面大有可为。进一步的研究和开发无疑将促进骨肿瘤领域个性化医疗的发展。
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引用次数: 0
Overcoming multi-drug resistance in SCLC: a synergistic approach with venetoclax and hydroxychloroquine targeting the lncRNA LYPLAL1-DT/BCL2/BECN1 pathway. 克服SCLC的多重耐药性:以lncRNA LYPLAL1-DT/BCL2/BECN1通路为靶点的venetoclax和羟氯喹协同方法
IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-31 DOI: 10.1186/s12943-024-02145-1
Shuxin Li, Jianyi Lv, Zhihui Li, Qiuyu Zhang, Jing Lu, Xueyun Huo, Meng Guo, Xin Liu, Changlong Li, Jinghui Wang, Hanping Shi, Li Deng, Zhenwen Chen, Xiaoyan Du

Background: Small cell lung cancer (SCLC) stands as one of the most lethal malignancies, characterized by a grim diagnosis and prognosis. The emergence of multi-drug resistance poses a significant hurdle to effective therapy. Although previous studies have implicated the long noncoding RNA LYPLAL1-DT in the tumorigenesis of SCLC, the precise role of the highly expressed LYPLAL1-DT in SCLC chemoresistance and the underlying mechanism remain inadequately understood.

Methods: cDDP-, VP-16- and PTX-resistant SCLC cells lines were established. The viabilities of SCLC cells were assessed by CCK-8 assay in vitro and xenograft tumor formation assay in vivo. Apoptosis was evaluated by FACS, Western blot and JC-1 fluorescence staining, while autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of LYPLAL1-DT were further investigated by gain- and loss-of-function assays in vitro. Furthermore, the therapeutic efficacy of the combination of venetoclax and HCQ with cDDP, VP-16 or PTX was evaluated by cell line, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice model.

Results: Our findings revealed that LYPLAL1-DT is upregulated in chemoresistant SCLC cell lines. Gain- and loss-of-function assays demonstrated that LYPLAL1-DT impairs sensitivity to cDDP, VP-16, or PTX both in vitro and in vivo. Overexpression of LYPLAL1-DT significantly enhanced autophagy and inhibited apoptosis in SCLC cells. Further analyses, including RIP and RNA pull-down assays, revealed that LYPLAL1-DT promotes the expression of BCL2 by sponging miR-204-5p and is implicated in the assembly of the autophagy-specific complex (BECN1/PtdIns3K complex). Combining venetoclax and HCQ with cDDP, VP-16, or PTX effectively mitigated chemoresistance in SCLC cells and suppressed tumor growth in CDX and PDX models without inducing obvious toxic effects.

Conclusions: Our findings demonstrate that upregulation of LYPLAL1-DT sequesters apoptosis through the LYPLAL1-DT/miR-204-5p/BCL2 axis and promotes autophagy by facilitating the assembly of the BECN1/PtdIns3K complex, thereby mediating multi-drug resistance of SCLC. The triple combination of venetoclax, HCQ, in conjunction with cDDP, VP-16 or PTX overcomes refractory SCLC, shedding light on a potential therapeutic target for combating SCLC chemoresistance.

背景:小细胞肺癌(SCLC小细胞肺癌(SCLC)是致死率最高的恶性肿瘤之一,其诊断和预后均十分严峻。多种药物耐药性的出现是有效治疗的一大障碍。尽管之前的研究表明长非编码 RNA LYPLAL1-DT 与 SCLC 的肿瘤发生有关,但高表达的 LYPLAL1-DT 在 SCLC 化疗耐药中的确切作用及其内在机制仍未得到充分了解。方法:建立了 cDDP-、VP-16- 和 PTX 抗性 SCLC 细胞系,通过 CCK-8 检测体外 SCLC 细胞的存活率和异种移植肿瘤形成检测体内 SCLC 细胞的存活率。细胞凋亡通过 FACS、Western 印迹和 JC-1 荧光染色进行评估,自噬则通过共聚焦显微镜下的自噬通量检测和透射电子显微镜(TEM)下的自噬空泡研究进行探讨。通过体外功能增益和功能缺失实验进一步研究了LYPLAL1-DT的功能作用和机制。此外,我们还通过细胞系、细胞衍生异种移植(CDX)和患者衍生异种移植(PDX)小鼠模型评估了venetoclax和HCQ与cDDP、VP-16或PTX联合治疗的疗效:我们的研究结果表明,LYPLAL1-DT在化疗耐药的SCLC细胞系中上调。功能增益和功能缺失试验表明,LYPLAL1-DT在体外和体内都会降低对cDDP、VP-16或PTX的敏感性。过表达 LYPLAL1-DT 能显著增强 SCLC 细胞的自噬作用并抑制细胞凋亡。进一步的分析(包括 RIP 和 RNA 下拉实验)显示,LYPLAL1-DT 通过疏导 miR-204-5p 促进 BCL2 的表达,并与自噬特异性复合物(BECN1/PtdIns3K 复合物)的组装有关。将venetoclax和HCQ与cDDP、VP-16或PTX联合使用,可有效减轻SCLC细胞的化疗耐药性,并抑制CDX和PDX模型中的肿瘤生长,且不会引起明显的毒性反应:我们的研究结果表明,LYPLAL1-DT的上调可通过LYPLAL1-DT/miR-204-5p/BCL2轴抑制细胞凋亡,并通过促进BECN1/PtdIns3K复合物的组装来促进自噬,从而介导SCLC的多重耐药。venetoclax、HCQ与cDDP、VP-16或PTX的三联疗法克服了难治性SCLC,揭示了对抗SCLC化疗耐药性的潜在治疗靶点。
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Molecular Cancer
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