饮用水中的慢性无机砷（iAs）暴露是影响超过2.25亿人的全球问题。皮肤是iAs的主要靶器官。miRNA失调和染色体不稳定性（CIN）被认为是iAs引起癌变的机制。CIN是癌症特征，四倍体细胞可以更好地耐受染色体数量和畸变的增加，从而有助于CIN的演化。miR-186在iAs诱导的鳞状细胞癌相对于iAs诱导的角化过度表达。生物信息学分析表明，miR-186靶向重要的细胞周期调节因子mRNA，包括有丝分裂检查点丝氨酸/苏氨酸激酶B（BUB1）和细胞分裂周期27（CDC27）。我们假设miR-186过表达通过靶向有丝分裂调节因子导致CIN的诱导，从而导致iAs诱导的角质细胞转化。 Ker-CT 细胞是一个接近二倍体的人角质细胞系，被转染具有miR-186过表达或乱序控制慢病毒的克隆。经过puromycin筛选后，获得了稳定的克隆。用0或100 nM iAs维持慢病毒表达乱序控制miRNA或miR-186的克隆4周。未暴露的乱序控制克隆被视为口头匹配对照组。慢性暴露于iAs后，miR-186的表达在miR-186克隆中增加。miR-186过表达显著降低CDC27的水平，与iAs的暴露无关。iAs暴露下的miR-186克隆中四倍体或非整倍体细胞的百分比增加。非整倍体可能起源于四倍体中间体。miR-186抑制CDC27可能会导致有丝分裂检查点复合物组装和维持细胞周期阻滞的能力受损，从而导致染色体错位。因此，过表达miR-186并长期暴露于iAs的细胞可能具有不正确的染色体分离和CIN。这些数据表明，iAs引起 miRNA的失调介导了四倍体，非整倍体和染色体不稳定性，从而导致iAs诱导的癌变。版权所有©2023作者。由Elsevier Inc.保留所有权利。

Chronic inorganic arsenic (iAs) exposure in drinking water is a global issue affecting >225 million people. Skin is a major target organ for iAs. miRNA dysregulation and chromosomal instability (CIN) are proposed mechanisms of iAs-induced carcinogenesis. CIN is a cancer hallmark and tetraploid cells can better tolerate increase in chromosome number and aberration, contributing to the evolution of CIN. miR-186 is overexpressed in iAs-induced squamous cell carcinoma relative to iAs-induced hyperkeratosis. Bioinformatic analysis indicated that miR-186 targets mRNAs of important cell cycle regulators including mitotic checkpoint serine/threonine kinase B (BUB1) and cell division cycle 27 (CDC27). We hypothesized that miR-186 overexpression contributes to iAs-induced transformation of keratinocytes by targeting mitotic regulators leading to induction of CIN. Ker-CT cells, a near diploid human keratinocyte cell line, were transduced with miR-186 overexpressing or scrambled control lentivirus. Stable clones were isolated after puromycin selection. Clones transduced with lentivirus expressing either a scrambled control miRNA or miR-186 were maintained with 0 or 100 nM iAs for 4 weeks. Unexposed scrambled control clones were considered as passage matched controls. Chronic iAs exposure increased miR-186 expression in miR-186 clones. miR-186 overexpression significantly reduced CDC27 levels irrespective of iAs exposure. The percentage of tetraploid or aneuploid cells was increased in iAs exposed miR-186 clones. Aneuploidy can arise from a tetraploid intermediate. Suppression of CDC27 by miR-186 may lead to impairment of mitotic checkpoint complex formation and its ability to maintain cell cycle arrest leading to chromosome misalignment. As a result, cells overexpressing miR-186 and chronically exposed to iAs may have incorrect chromosome segregation and CIN. These data suggest that dysregulation of miRNA by iAs mediates tetraploidy, aneuploidy and chromosomal instability contributing to iAs-induced carcinogenesis.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.