长时间暴露于新鲜和老化纳米氧化锌促进肝细胞癌恶性进展的机制：上调Claudin-2

Long-Term Exposure of Fresh and Aged Nano Zinc Oxide Promotes Hepatocellular Carcinoma Malignancy by Up-Regulating Claudin-2

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International Journal of Nanomedicine

影响因子:6.5

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

DOI: 10.2147/IJN.S478279

摘要

肿瘤的发生与发展是一个漫长且复杂的过程，受内在因素（如基因突变）和外在因素（如环境污染）共同影响。作为一个解毒器官，肝脏在人体暴露于各种环境污染物（包括纳米材料，NMs）中的反应中扮演着重要角色。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。关于NMs是否促进肝癌进程以及亚毒性剂量纳米颗粒（NPs）的长期暴露评估仍然具有挑战性。在本研究中，我们重点研究了纳米氧化锌（nZnO）对人HCC细胞HepG2恶性进展的促发作用，特别是经过物理化学转变的老化nZnO。在体外实验中，我们对暴露于低剂量（1.5 μg/mL）nZnO达3或4个月的HepG2细胞进行了克隆形成效率、软琼脂克隆形成和细胞迁移/侵袭等实验。在体内实验中，将经过长时间暴露（4个月）的HepG2细胞皮下注射入BALB/c裸鼠，观察肿瘤形成情况。通过给予ZnCl2以研究锌离子的作用。长期低剂量暴露nZnO显著增强了HCC细胞的恶性进展，而老化nZnO可能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HCC恶性进展的机制可能与激活细胞紧密连接成分之一的Claudin-2（CLDN2）及其下游信号通路的失调有关。长时间暴露于新鲜和老化的nZnO通过上调CLDN2促进肝细胞癌的恶性程度。本研究的意义在于，为癌症患者提供了重要启示：各种纳米产品的使用及其在环境中非意图性暴露，可能无形中加快其癌症的进展。

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.