新鲜和老化的纳米氧化锌的长期暴露通过上调Claudin-2来促进肝细胞癌恶性肿瘤
Long-Term Exposure of Fresh and Aged Nano Zinc Oxide Promotes Hepatocellular Carcinoma Malignancy by Up-Regulating Claudin-2
影响因子:6.50000
分区:医学2区 / 药学2区 纳米科技3区
发表日期:2024
作者:
Na Yu, Mingqin Su, Juan Wang, Yakun Liu, Jingya Yang, Jingyi Zhang, Meimei Wang
摘要
肿瘤的发育和进展是一个长期且复杂的过程，该过程受固有（例如基因突变）和外在（例如环境污染）因子的组合的组合。作为解毒器官，肝脏在人类暴露和对包括纳米材料（NMS）在内的各种环境污染物的反应中起着重要作用。肝细胞癌（HCC）是最常见的恶性肿瘤之一，仍然对人类健康构成严重威胁。 NMS是否促进肝癌的进展仍然难以捉摸，并评估长期暴露于纳米颗粒（NP）仍然是一个挑战。 In this study, we focused on the promotional effects of nano zinc oxide (nZnO) on the malignant progression of human HCC cells HepG2, especially aged nZnO that has undergone physicochemical transformation.In in vitro experiments, we performed colony forming efficiency, soft agar colony formation, and cell migration/invasion assays on HepG2 cells that had been exposed to a low dose of NZNO（1.5μg/ml）持续3或4个月。在体内实验中，我们皮下接种了已长期暴露于NZNO的HEPG2细胞4个月，进入BALB/C无壁nude小鼠并观察到肿瘤的形成。施用ZnCl2来确定锌离子的作用。智剂量暴露于NZNO中，显着加剧了HCC细胞的恶性进展，而年龄的NZNO可能会加剧恶性进展的严重程度。此外，通过转录组测序分析和体外细胞救援实验，我们证明了NZNO诱导的HCC恶性进展的机制可以与Claudin-2（CLDN2）的激活有关通过上调CLDN2，肝细胞癌恶性肿瘤。这项工作对癌症患者的含义可能是深远的，因为使用各种纳米药物和无意中的环境转化的NMS可能会在不知不觉中加速其癌症的进展。
Abstract
Tumor development and progression is a long and complex process influenced by a combination of intrinsic (eg, gene mutation) and extrinsic (eg, environmental pollution) factors. As a detoxification organ, the liver plays an important role in human exposure and response to various environmental pollutants including nanomaterials (NMs). Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and remains a serious threat to human health. Whether NMs promote liver cancer progression remains elusive and assessing long-term exposure to subtoxic doses of nanoparticles (NPs) remains a challenge. In this study, we focused on the promotional effects of nano zinc oxide (nZnO) on the malignant progression of human HCC cells HepG2, especially aged nZnO that has undergone physicochemical transformation.In in vitro experiments, we performed colony forming efficiency, soft agar colony formation, and cell migration/invasion assays on HepG2 cells that had been exposed to a low dose of nZnO (1.5 μg/mL) for 3 or 4 months. In in vivo experiments, we subcutaneously inoculated HepG2 cells that had undergone long-term exposure to nZnO for 4 months into BALB/c athymic nude mice and observed tumor formation. ZnCl2 was administered to determine the role of zinc ions.Chronic low-dose exposure to nZnO significantly intensified the malignant progression of HCC cells, whereas aged nZnO may exacerbate the severity of malignant progression. Furthermore, through transcriptome sequencing analysis and in vitro cellular rescue experiments, we demonstrated that the mechanism of nZnO-induced malignant progression of HCC could be linked to the activation of Claudin-2 (CLDN2), one of the components of cellular tight junctions, and the dysregulation of its downstream signaling pathways.Long-term exposure of fresh and aged nZnO promotes hepatocellular carcinoma malignancy by up-regulating CLDN2. The implications of this work can be profound for cancer patients, as the use of various nanoproducts and unintentional exposure to environmentally transformed NMs may unknowingly hasten the progression of their cancers.