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Prolonged cadmium exposure alters benign uterine fibroid cell behavior, extracellular matrix components, and TGFB signaling
Author(s) -
Yan Yitang,
Liu Jingli,
Lawrence Arianna,
Dykstra Michael J.,
Fannin Rick,
Gerrish Kevin,
Tucker Charles J.,
Scappini Erica,
Dixon Darlene
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100354r
Subject(s) - extracellular matrix , cancer research , uterine leiomyoma , downregulation and upregulation , mmp2 , mmp1 , cell growth , biology , microbiology and biotechnology , chemistry , leiomyoma , pathology , medicine , gene expression , gene , biochemistry
The heavy metal Cadmium (Cd), a widespread environmental contaminant, poses serious hazards to human health and is considered a metallohormone and carcinogen. In women with uterine fibroids, there is a significant association between blood Cd levels and increased fibroid tumor size. The aim of this study was to determine if benign human uterine leiomyoma (fibroid) cells could be malignantly transformed in vitro by continuous Cd exposure and, if so, explore a molecular mechanism by which this could occur. We found when fibroid cells were exposed to 10 µM CdCl 2 for 8 weeks, a robust and fast‐growing Cd‐Resistant Leiomyoma (CR‐LM) cell culture was established. The CR‐LM cells formed viable colonies in soft agar and had increased cytoplasmic glycogen aggregates, enhanced cell motility, a higher percentage of cells in G2/M phase, and increased expression of the proliferation marker Ki‐67. NanoString analysis showed downregulation of genes encoding for extracellular matrix (ECM) components, such as collagens, fibronectins, laminins, and SLRP family proteins, whereas genes involved in ECM degradation (MMP1, MMP3, and MMP10) were significantly upregulated. A volcano plot showed that the top differentially genes favored cancer progression. Functional analysis by ingenuity pathway analysis predicted a significant inhibition of TGFB1 signaling, leading to enhanced proliferation and attenuated fibrosis. Prolonged Cd exposure altered phenotypic characteristics and dysregulated genes in fibroid cells predicative of progression towards a cancer phenotype. Therefore, continuous Cd exposure alters the benign characteristics of fibroid cells in vitro , and Cd exposure could possibly pose a health hazard for women with uterine fibroids.