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Precision therapy for cancer prevention by targeting carcinogenesis. 以致癌为目标的癌症预防精准疗法。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-14 DOI: 10.1002/mc.23798
Guoguo Jin, Kangdong Liu, Zhiping Guo, Zigang Dong

Cancer represents a major global public health burden, with new cases estimated to increase from 14 million in 2012 to 24 million by 2035. Primary prevention is an effective strategy to reduce the costs associated with cancer burden. For example, measures to ban tobacco consumption have dramatically decreased lung cancer incidence and vaccination against human papillomavirus can prevent cervical cancer development. Unfortunately, the etiological factors of many cancer types are not completely clear or are difficult to actively control; therefore, the primary prevention of such cancers is not practical. In this review, we update the progress on precision therapy by targeting the whole carcinogenesis process, especially for three high-risk groups: (1) those with chronic inflammation, (2) those with inherited germline mutations, and (3) those with precancerous lesions like polyps, gastritis, actinic keratosis or dysplasia. We believe that attenuating chronic inflammation, treating precancerous lesions, and removing high-risk tissues harboring germline mutations are precision methods for cancer prevention.

癌症是全球公共卫生的一大负担,据估计,新发病例将从 2012 年的 1400 万增加到 2035 年的 2400 万。初级预防是降低癌症负担相关成本的有效策略。例如,禁止吸烟的措施大大降低了肺癌的发病率,接种人类乳头瘤病毒疫苗可以预防宫颈癌的发生。遗憾的是,许多癌症类型的致病因素尚未完全明确或难以主动控制,因此,对这类癌症进行一级预防并不现实。在这篇综述中,我们将介绍针对整个致癌过程的精准治疗的最新进展,尤其是针对以下三类高危人群的精准治疗:(1)慢性炎症患者;(2)遗传性基因突变患者;(3)息肉、胃炎、光化性角化病或发育不良等癌前病变患者。我们认为,减轻慢性炎症、治疗癌前病变和清除携带种系突变的高危组织是预防癌症的精确方法。
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引用次数: 0
ITGB3-enriched extracellular vesicles mediate the formation of osteoclastic pre-metastatic niche to promote lung adenocarcinoma bone metastasis. 富含ITGB3的细胞外囊泡介导破骨细胞转移前骨龛的形成,促进肺腺癌骨转移。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-13 DOI: 10.1002/mc.23803
Rong Qiu, Yan Deng, Yue Lu, Xingyu Liu, Qin Huang, Yuzhen Du

The regulatory mechanisms underlying bone metastasis in lung adenocarcinoma (LUAD) are not yet fully understood despite the frequent occurrence of bone involvement. This study aimed to examine the involvement and mechanism of integrin subunit beta 3 (ITGB3) in the process of LUAD bone metastasis. Our findings indicate that ITGB3 facilitates the migration and invasion of LUAD cells in vitro and metastasis to the bone in vivo. Furthermore, ITGB3 stimulates osteoclast production and activation, thereby expediting osteolytic lesion progression. Extracellular vesicles (EVs) isolated from the conditioned medium (CM) of LUAD cells overexpressing ITGB3 determined that ITGB3 facilitates osteoclastogenesis and enhances osteoclast activity by utilizing EVs-mediated transport to RAW264.7 cells. Our in vivo findings demonstrated that ITGB3-EVs augmented the population of osteoclasts, thereby establishing an osteoclastic pre-metastatic niche (PMN) conducive to the colonization and subsequent growth of LUAD cells in the bone. ITGB3 is enriched in serum EVs of patients diagnosed with LUAD bone metastasis, potentially facilitating osteoclast differentiation and activation in vitro. Our research illustrates that ITGB3-EVs derived from LUAD cells facilitate osteoclast differentiation and activation by modulating the phosphorylation level of p38 MAPK. This process ultimately leads to the generation of osteolytic PMN and accelerates the progression of bone metastasis.

尽管肺腺癌(LUAD)经常发生骨转移,但其骨转移的调控机制尚未完全明了。本研究旨在探讨整合素亚基 beta 3(ITGB3)在肺腺癌骨转移过程中的参与和机制。我们的研究结果表明,ITGB3 在体外促进 LUAD 细胞的迁移和侵袭,在体内促进向骨转移。此外,ITGB3 还能刺激破骨细胞的生成和活化,从而加速溶骨病变的发展。从过表达 ITGB3 的 LUAD 细胞的条件培养基(CM)中分离出的胞外囊泡(EVs)确定,ITGB3 通过利用 EVs 介导的向 RAW264.7 细胞的转运,促进了破骨细胞的生成并增强了破骨细胞的活性。我们的体内研究结果表明,ITGB3-EVs 增加了破骨细胞的数量,从而建立了一个有利于 LUAD 细胞在骨中定植和随后生长的破骨细胞转移前生态位(PMN)。ITGB3在确诊为LUAD骨转移患者的血清EV中富集,有可能促进破骨细胞在体外的分化和活化。我们的研究表明,从 LUAD 细胞中提取的 ITGB3-EV 可通过调节 p38 MAPK 的磷酸化水平促进破骨细胞的分化和活化。这一过程最终导致溶骨性 PMN 的生成,并加速骨转移的进展。
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引用次数: 0
Pyroptosis-related gene GSDMC indicates poor prognosis and promotes tumor progression by activating the AKT/mTOR pathway in lung squamous cell carcinoma. 肺鳞状细胞癌中的热蛋白沉积相关基因 GSDMC 可通过激活 AKT/mTOR 通路预示不良预后并促进肿瘤进展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-13 DOI: 10.1002/mc.23805
Yi Zhang, Yuzhi Wang, Jiamiao Weng, Jianlin Chen, Yue Zheng, Yu Xia, Zhixin Huang, Lilan Zhao, Xiongfeng Chen, Haijun Tang, Yi Huang

Lung squamous cell carcinoma (LUSC) is one of the most common malignant tumors of the respiratory. Pyroptosis plays an essential role in cancer, but there is limited research investigating pyroptosis in LUSC. In this study, pyroptosis-related genes were observed to have extensive multiomics alterations in LUSC through analysis of the TCGA database. Utilizing machine learning for selection and verifying expression levels, GSDMC was chosen as the critical gene for further experiments. Our research found that GSDMC is overexpressed in LUSC tissues and cells, and is associated with poor prognosis. Knockdown of GSDMC in LUSC inhibits cell proliferation, invasion, metastasis, chemotherapeutic sensitivity, and reduced tumor formation in nude mice, accompanied by downregulation of proliferative and EMT-related protein expression. However, these effects were counteracted in cells where GSDMC is overexpressed. Mechanistically, the oncogenic role of GSDMC is primarily achieved through the activation of the AKT/mTOR pathway, and this effect can be significantly reversed by rapamycin. Finally, SMAD4's interaction with the promoter region of GSDMC results in the suppression of GSDMC expression. In summary, our study through bioinformatics and experimental approaches not only proves that SMAD4 regulates the protumorigenic role of GSDMC through transcriptional targeting, but also indicates the possibility of developing the SMAD4/GSDMC/AKT/mTOR signaling axis as a potential biomarker and treatment target for LUSC.

肺鳞状细胞癌(LUSC)是呼吸系统最常见的恶性肿瘤之一。热蛋白沉积在癌症中起着至关重要的作用,但对肺鳞癌中热蛋白沉积的研究却很有限。在这项研究中,通过对TCGA数据库的分析,观察到在LUSC中与化脓相关的基因有广泛的多组学改变。利用机器学习选择和验证表达水平,GSDMC被选为进一步实验的关键基因。我们的研究发现,GSDMC在LUSC组织和细胞中过表达,并与不良预后相关。在 LUSC 中敲除 GSDMC 可抑制细胞增殖、侵袭、转移和化疗敏感性,并减少裸鼠肿瘤的形成,同时下调增殖和 EMT 相关蛋白的表达。然而,这些作用在 GSDMC 过表达的细胞中被抵消了。从机理上讲,GSDMC的致癌作用主要是通过激活AKT/mTOR通路实现的,而雷帕霉素可以显著逆转这种效应。最后,SMAD4 与 GSDMC 启动子区域的相互作用导致 GSDMC 的表达受到抑制。总之,我们通过生物信息学和实验方法进行的研究不仅证明了SMAD4通过转录靶向调控GSDMC的原癌作用,还表明了将SMAD4/GSDMC/AKT/mTOR信号轴作为LUSC潜在生物标志物和治疗靶点的可能性。
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引用次数: 0
Combined treatment with Aronia berry extract and oligomeric proanthocyanidins exhibit a synergistic anticancer efficacy through LMNB1-AKT signaling pathways in colorectal cancer. 通过LMNB1-AKT信号通路,络氨酸浆果提取物和低聚原花青素联合治疗结直肠癌具有协同抗癌功效。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI: 10.1002/mc.23800
Yuan Li, Caiming Xu, Wenhao Weng, Ajay Goel

Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.

结直肠癌(CRC)是全球发病率最高、复发率最高的恶性肿瘤之一,目前是癌症相关死亡的第二大原因。与 CRC 相关的高发病率和高死亡率主要归因于当前治疗方法的有效性有限,以及对标准治疗方法出现的化疗抗药性。最近的研究表明,包括阿罗尼亚浆果提取物(ABE)和低聚原花青素(OPC)在内的几种天然产品可为癌症治疗提供安全、经济、多靶点的辅助作用。在此,我们假设 ABE 和 OPCs 的联合治疗可协同调节 CRC 的多种致癌途径,从而增强其抗癌活性。我们首先进行了一系列体外实验,以评估 ABE 和 OPCs 对 CRC 细胞系的协同抗癌作用。结果表明,这两种化合物在抑制细胞活力、抑制集落形成和诱导细胞凋亡(p
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引用次数: 0
A novel high-risk model identified by epithelial-mesenchymal transition predicts prognosis and radioresistance in rectal cancer. 通过上皮-间质转化确定的新型高风险模型可预测直肠癌的预后和放射抗性。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-26 DOI: 10.1002/mc.23797
Feiyu Qin, Zehua Bian, Lingzhen Jiang, Yulin Cao, Junhui Tang, Liang Ming, Yan Qin, Zhaohui Huang, Yuan Yin

Many studies have shown that tumor cells that survive radiotherapy are more likely to metastasize, but the underlying mechanism remains unclear. Here we aimed to identify epithelial-mesenchymal transition (EMT)-related key genes, which associated with prognosis and radiosensitivity in rectal cancer. First, we obtained differentially expressed genes by analyzing the RNA expression profiles of rectal cancer retrieved from The Cancer Genome Atlas database, EMT-related genes, and radiotherapy-related databases, respectively. Then, Lasso and Cox regression analyses were used to establish an EMT-related prognosis model (EMTPM) based on the identified independent protective factor Fibulin5 (FBLN5) and independent risk gene EHMT2. The high-EMTPM group exhibited significantly poorer prognosis. Then, we evaluated the signature in an external clinical validation cohort. Through in vivo experiments, we further demonstrated that EMTPM effectively distinguishes radioresistant from radiosensitive patients with rectal cancer. Moreover, individuals in the high-EMTPM group showed increased expression of immune checkpoints compared to their counterparts. Finally, pan-cancer analysis of the EMTPM model also indicated its potential for predicting the prognosis of lung squamous cell carcinoma and breast cancer patients undergoing radiotherapy. In summary, we established a novel predictive model for rectal cancer prognosis and radioresistance based on FBLN5 and EHMT2 expressions, and suggested that immune microenvironment may be involved in the process of radioresistance. This predictive model could be used to select management strategies for rectal cancer.

许多研究表明,放疗后存活的肿瘤细胞更容易转移,但其潜在机制仍不清楚。在此,我们旨在找出与直肠癌预后和放疗敏感性相关的上皮-间质转化(EMT)相关关键基因。首先,我们分别从癌症基因组图谱数据库、EMT相关基因和放疗相关数据库中检索直肠癌的RNA表达谱,分析其差异表达基因。然后,根据已确定的独立保护因子Fibulin5(FBLN5)和独立风险基因EHMT2,使用Lasso和Cox回归分析建立了EMT相关预后模型(EMTPM)。高EMTPM组的预后明显较差。然后,我们在外部临床验证队列中对该特征进行了评估。通过体内实验,我们进一步证明了 EMTPM 能有效区分放射耐药和放射敏感的直肠癌患者。此外,与同类患者相比,高EMTPM组患者的免疫检查点表达量有所增加。最后,对 EMTPM 模型进行的泛癌症分析还表明,该模型具有预测接受放疗的肺鳞癌和乳腺癌患者预后的潜力。总之,我们根据 FBLN5 和 EHMT2 的表达建立了一个新的直肠癌预后和放射抗性预测模型,并认为免疫微环境可能参与了放射抗性的过程。这一预测模型可用于选择直肠癌的治疗策略。
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引用次数: 0
M2 macrophage exosome-derived Apoc1 promotes ferroptosis resistance in osteosarcoma by inhibiting ACSF2 deubiquitination. M2巨噬细胞外泌体衍生的Apoc1通过抑制ACSF2的去泛素化促进骨肉瘤的抗铁蛋白沉积。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-23 DOI: 10.1002/mc.23796
Ping Yin, Min Tang, Guosheng Zhao

Osteosarcoma (OS) is the most common primary malignant tumor of bone. The aim of this study was to investigate the regulatory mechanisms of M2 macrophage exosomes (M2-Exos) in ferroptosis in OS. A mouse model was established to investigate the in vivo role of M2-Exos. We investigated their effects on ferroptosis in OS using erastin, a ferroptosis activator, and deferoxamine mesylate, an iron chelator. In vitro, we investigated whether the Apoc1/Acyl-CoA Synthetase Family Member 2 (ACSF2) axis mediates these effects, using shApoc1 and shACSF2. The mechanisms whereby Apoc1 regulates ACSF2 were examined using cyclohexanone, a protein synthesis inhibitor, and MG132, a proteasomal inhibitor. M2-Exos reversed the inhibitory effects of erastin on OS cells, thus enhancing their viability, migration, invasion, proliferation, and reducing ferroptosis. Apoc1 was highly expressed in M2-Exos, and interfering with this expression reversed the effects of M2-Exos on OS cells. ACSF2 mediated the effects of M2-Exos-derived Apoc1. Apoc1 interacted with ACSF2, which, in turn, interacted with USP40. Apoc1 overexpression increased ACSF2 ubiquitination, promoting its degradation, whereas USP40 overexpression inhibited ACSF2 ubiquitination and promoted its expression. Apoc1 overexpression inhibited ACSF2 binding to USP40. M2-Exos-derived Apoc1 promoted ferroptosis resistance by inhibiting USP40 binding to ACSF2 and promoting ACSF2 ubiquitination and degradation, thus enhancing OS development.

骨肉瘤(Osteosarcoma,OS)是最常见的原发性骨恶性肿瘤。本研究的目的是探讨M2巨噬细胞外泌体(M2-Exos)在骨肉瘤铁凋亡中的调控机制。我们建立了一个小鼠模型来研究M2-Exos在体内的作用。我们使用铁跃迁激活剂依拉斯汀和铁螯合剂甲磺酸去铁胺研究了它们对 OS 中铁跃迁的影响。在体外,我们利用 shApoc1 和 shACSF2 研究了 Apoc1/酰基辅酶合成酶家族成员 2(ACSF2)轴是否介导了这些效应。我们使用蛋白质合成抑制剂环己酮和蛋白酶体抑制剂 MG132 考察了 Apoc1 调节 ACSF2 的机制。M2-Exos逆转了麦拉宁对OS细胞的抑制作用,从而增强了它们的活力、迁移、侵袭和增殖,并减少了铁突变。Apoc1 在 M2-Exos 中高表达,干扰其表达可逆转 M2-Exos 对 OS 细胞的影响。ACSF2介导了M2-Exos衍生的Apoc1的作用。Apoc1 与 ACSF2 相互作用,而 ACSF2 又与 USP40 相互作用。Apoc1 的过表达增加了 ACSF2 的泛素化,促进了其降解,而 USP40 的过表达抑制了 ACSF2 的泛素化,促进了其表达。Apoc1 的过表达抑制了 ACSF2 与 USP40 的结合。来源于M2-Exos的Apoc1通过抑制USP40与ACSF2的结合,促进ACSF2泛素化和降解,从而增强OS的发育,从而提高铁变态反应的抵抗力。
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引用次数: 0
Quercetin inhibits endothelial & hepatocellular carcinoma cell crosstalk via reducing extracellular vesicle-mediated VEGFR2 mRNA transfer. 槲皮素通过减少细胞外囊泡介导的 VEGFR2 mRNA 转移,抑制内皮细胞和肝细胞癌细胞的串联。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-22 DOI: 10.1002/mc.23807
Wei Xiong, Bo Zheng, Di Liu, Mo Pu, Shijie Zhou, Ying Deng

This study aims to investigate the regulatory effects of quercetin extracellular vesicles (EVs)-mediated expression of vascular endothelial growth factor receptor 2 (VEGFR2) in hepatocellular carcinoma (HCC)-derived circulating tumor cells (CTCs) and the underlying mechanisms. CTCs were isolated from patients with pathologically diagnosed HCC, with VEGFR2 expression visualized by fluorescence in situ hybridization (FISH). The human HCC cell line Huh-7 and SK-HEP-1 were used for in vitro studies to assess EVs uptake, VEGFR2 mRNA transfer, invasion, migration, cancer stem cell (CSC) properties, and VEGF secretion. Results showed that VEGFR2 mRNA was commonly expressed in HCC-CTCs, with a higher incidence in biphenotypic CTCs. Its expression was limited in HCC cell lines, but present in certain liver cells. In vitro experiments confirmed that VEGFR2 mRNA could be transferred to HCC cells via EVs from primary tumor endothelial cells (PTECs), which was impaired by quercetin treatment. Quercetin significantly reduced VEGFR2 mRNA and protein expression in HCC cells, weakened their invasive and metastatic capacities, and diminished VEGFR2-mediated CSC properties. In vivo, quercetin reduced VEGF secretion, impaired angiogenesis, slowed tumor growth, and decreased the number and proportion of VEGFR2-positive CTCs. In summary, VEGFR2 mRNA is present in HCC-CTCs, potentially sourced from PTECs-derived EVs. Quercetin effectively inhibits VEGFR2 expression, impacting HCC cell invasion, metastasis, and CSC characteristics. Besides, it reduces VEGFR2-positive CTCs in vivo. These effects support its therapeutic potential in HCC treatment by targeting the angiogenesis and tumor dissemination pathway.

本研究旨在探讨槲皮素细胞外囊泡(EVs)介导的血管内皮生长因子受体2(VEGFR2)在肝细胞癌(HCC)产生的循环肿瘤细胞(CTCs)中的表达调控作用及其内在机制。CTCs 从病理诊断为 HCC 的患者中分离出来,通过荧光原位杂交(FISH)检测 VEGFR2 的表达。人类 HCC 细胞系 Huh-7 和 SK-HEP-1 被用于体外研究,以评估 EVs 吸收、VEGFR2 mRNA 转移、侵袭、迁移、癌症干细胞(CSC)特性和 VEGF 分泌。结果表明,VEGFR2 mRNA 在 HCC-CTCs 中普遍表达,在双型 CTCs 中表达率更高。它在 HCC 细胞系中的表达有限,但在某些肝细胞中存在。体外实验证实,VEGFR2 mRNA可通过原发性肿瘤内皮细胞(PTECs)的EVs转移到HCC细胞中,而槲皮素处理可抑制这种转移。槲皮素能明显降低HCC细胞中VEGFR2 mRNA和蛋白的表达,削弱其侵袭和转移能力,并降低VEGFR2介导的CSC特性。在体内,槲皮素可减少血管内皮生长因子的分泌,阻碍血管生成,减缓肿瘤生长,并减少 VEGFR2 阳性 CTC 的数量和比例。总之,HCC-CTCs 中存在 VEGFR2 mRNA,其来源可能是 PTECs 衍生的 EVs。槲皮素能有效抑制 VEGFR2 的表达,从而影响 HCC 细胞的侵袭、转移和 CSC 特性。此外,它还能减少体内 VEGFR2 阳性的 CTC。这些作用支持了槲皮素通过靶向血管生成和肿瘤扩散途径治疗 HCC 的潜力。
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引用次数: 0
m6A modification of VEGFA mRNA by RBM15/YTHDF2/IGF2BP3 contributes to angiogenesis of hepatocellular carcinoma. RBM15/YTHDF2/IGF2BP3 对 VEGFA mRNA 的 m6A 修饰有助于肝细胞癌的血管生成。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-02 DOI: 10.1002/mc.23802
Xiaoxin Xu, Shuxiang Wu, Yi Zhang, Weijie Fan, Xinjian Lin, Kunqi Chen, Xu Lin

Vascular endothelial growth factor A (VEGFA) plays a critical role as a potent angiogenesis factor and is highly expressed in hepatocellular carcinoma (HCC). Although the expression of VEGFA has been strongly linked to the aggressive nature of HCC, the specific posttranscriptional modifications that might contribute to VEGFA expression and HCC angiogenesis are not yet well understood. In this study, we aimed to investigate the epitranscriptome regulation of VEGFA in HCC. A comprehensive analysis integrating MeRIP-seq, RNA-seq, and crosslinking-immunprecipitation-seq data revealed that VEGFA was hypermethylated in HCC and identified the potential m6A regulators of VEGFA including a m6A methyltransferase complex component RBM15 and the two readers, YTHDF2 and IGF2BP3. Through rigorous cell and molecular biology experiments, RBM15 was validated as a key component of methyltransferase complex responsible for m6A methylation of VEGFA, which was subsequently recognized and stabilized by IGF2BP3 and YTHDF2, leading to enhanced VEGFA expression and VEGFA-related functions such as human umbilical vascular endothelial cells (HUVEC) migration and tube formation. In the HCC xenograft model, knockdown of RBM15, IGF2BP3, or YTHDF2 resulted in reduced expression of VEGFA, accompanied by significant inhibition of tumor growth closely associated with VEGFA expression and angiogenesis. Furthermore, our analysis of HCC clinical samples identified positive correlations between the expression levels of VEGFA and the regulators RBM15, IGF2BP3, and YTHDF2. Collectively, these findings offer novel insights into the posttranscriptional modulation of VEGFA and provide potential avenues for alternative approaches to antiangiogenesis therapy targeting VEGFA.

血管内皮生长因子 A(VEGFA)作为一种强效血管生成因子发挥着至关重要的作用,并在肝细胞癌(HCC)中高度表达。虽然血管内皮生长因子 A 的表达与 HCC 的侵袭性密切相关,但可能导致血管内皮生长因子 A 表达和 HCC 血管生成的特定转录后修饰还不十分清楚。在本研究中,我们旨在研究 VEGFA 在 HCC 中的表转录组调控。通过整合 MeRIP-seq、RNA-seq 和交联免疫沉淀-seq 数据进行综合分析,发现 HCC 中 VEGFA 存在高甲基化,并确定了 VEGFA 的潜在 m6A 调控因子,包括 m6A 甲基转移酶复合物成分 RBM15 以及两个读取因子 YTHDF2 和 IGF2BP3。通过严格的细胞和分子生物学实验,RBM15 被证实是负责 VEGFA m6A 甲基化的甲基转移酶复合物的关键成分,随后它被 IGF2BP3 和 YTHDF2 识别并稳定,从而增强了 VEGFA 的表达和 VEGFA 相关功能,如人脐血管内皮细胞(HUVEC)的迁移和管形成。在 HCC 异种移植模型中,敲除 RBM15、IGF2BP3 或 YTHDF2 可降低 VEGFA 的表达,同时显著抑制与 VEGFA 表达和血管生成密切相关的肿瘤生长。此外,我们对 HCC 临床样本的分析发现,VEGFA 的表达水平与调控因子 RBM15、IGF2BP3 和 YTHDF2 之间存在正相关。总之,这些发现为 VEGFA 的转录后调控提供了新的见解,并为针对 VEGFA 的抗血管生成疗法提供了潜在的替代方法。
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引用次数: 0
Delta-Like Homolog 2 Facilitates Malignancy of Hepatocellular Carcinoma via Activating EGFR/PKM2 Signaling Pathway. Delta-Like同源物2通过激活表皮生长因子受体/PKM2信号通路促进肝细胞癌恶变
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1002/mc.23836
Xiangye Liu, Tingting Li, Yuting Wang, Xiaoge Gao, Feitong Wang, Yang Chen, Kaisheng Wang, Weiming Luo, Fanyun Kong, Yanbo Kou, Hongjuan You, Delong Kong, Qing Zhang, Renxian Tang

Delta-like homolog 2 (DLK2) plays a crucial role in adipogenesis, chondrogenic differentiation, and the progression of certain cancers. However, the key roles of DLK2 underlying the progression of hepatocellular carcinoma (HCC) remain ambiguous. In the current study, we demonstrate that DLK2 is upregulated in HCC, significantly correlated with clinicopathological variables and serves as an independent diagnostic marker. Functional assays reveal that DLK2 facilitates malignant progression of HCC in vitro and in vivo models. Mechanistically, DLK2 binds to EGFR resulting in its auto-phosphorylation, which activates NK-κB pathway leading to P65-dependent transcriptional upregulation of PKM2. Furthermore, that elevates both enzyme-dependent and -independent activities of PKM2 contributing to cancer proliferation and metastasis. In summary, our findings demonstrate a novel pro-tumoral role and mechanism of DLK2 in the regulation of HCC malignant progression, suggesting its potential as a clinical diagnostic marker and therapeutic target.

德尔塔样同源物 2(Delta-like homolog 2,DLK2)在脂肪生成、软骨分化和某些癌症的进展中起着至关重要的作用。然而,DLK2 在肝细胞癌(HCC)进展中的关键作用仍不明确。在本研究中,我们发现 DLK2 在 HCC 中上调,与临床病理变量显著相关,是一种独立的诊断标志物。功能测试显示,DLK2 在体外和体内模型中促进了 HCC 的恶性进展。从机理上讲,DLK2 与表皮生长因子受体结合,导致表皮生长因子受体自身磷酸化,从而激活 NK-κB 通路,导致 P65 依赖性 PKM2 转录上调。此外,这还会提高 PKM2 的酶依赖性和非依赖性活性,导致癌症增殖和转移。总之,我们的研究结果证明了 DLK2 在调控 HCC 恶性进展中的一种新的促肿瘤作用和机制,表明它有可能成为一种临床诊断标志物和治疗靶点。
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引用次数: 0
FGFR2 in the Development and Progression of Cutaneous Squamous Cell Cancer. 表皮生长因子受体 2(FGFR2)在皮肤鳞状细胞癌的发生和发展中的作用
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1002/mc.23835
Ethan M Kallenberger, Alok Khandelwal, Priyatosh Nath, Shaun A Nguyen, John DiGiovanni, Cherie-Ann Nathan

Cutaneous squamous cell carcinoma (cSCC) is an increasingly common malignancy of the skin and the leading cause of death from skin cancer in adults over the age of 85. Fibroblast growth factor receptor 2 (FGFR2) has been identified as an important effector of signaling pathways that lead to the growth and development of cSCC. In recent years, there have been numerous studies evaluating the role FGFR2 plays in multiple cancers, its contribution to resistance to anticancer therapy, and new drugs that may be used to inhibit FGFR2. This review will provide an overview of our current understanding of FGFR2 and potential mechanisms in which we can target FGFR2 in cSCC. The goals of this review are the following: (1) to highlight our current knowledge of the role of FGFR2 in healthy skin and contrast this with its role in the development of cancer; (2) to further explain the specific molecular mechanisms that FGFR2 uses to promote tumorigenesis; (3) to describe how FGFR2 contributes to more invasive disease; (4) to describe its immunosuppressive effects in skin; and (5) to evaluate its effect on current anticancer therapy and discuss therapies on the horizon to target FGFR2 related malignancy.

皮肤鳞状细胞癌(cSCC)是一种越来越常见的皮肤恶性肿瘤,也是 85 岁以上成年人死于皮肤癌的主要原因。成纤维细胞生长因子受体 2 (FGFR2) 已被确定为导致 cSCC 生长和发展的信号通路的重要作用因子。近年来,已有大量研究评估了 FGFR2 在多种癌症中的作用、它对抗癌治疗耐药性的贡献以及可用于抑制 FGFR2 的新药。本综述将概述我们目前对表皮生长因子受体 2 的了解,以及在 cSCC 中靶向表皮生长因子受体 2 的潜在机制。本综述的目标如下:(1) 强调我们目前对 FGFR2 在健康皮肤中作用的了解,并将其与在癌症发展中的作用进行对比;(2) 进一步解释 FGFR2 促进肿瘤发生的特定分子机制;(3) 描述 FGFR2 如何导致更具侵袭性的疾病;(4) 描述其在皮肤中的免疫抑制作用;(5) 评估其对当前抗癌疗法的影响,并讨论即将推出的针对 FGFR2 相关恶性肿瘤的疗法。
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Molecular Carcinogenesis
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