Particulate hexavalent chromium alters microRNAs in human lung cells that target key carcinogenic pathways

Speer, Rachel M.; Meaza, Idoia; Toyoda, Jennifer H; Lu, Yuan; Xu, Qian; Walter, Ronald B.; Kong, Maiying; Lü, Haiyan; Kouokam, J. Calvin; Wise, John Pierce

doi:10.1016/j.taap.2022.115890

Cited by 9 publications

(2 citation statements)

References 54 publications

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“…Another possible cause of Cr(VI)-induced protein and mRNA loss is microRNA disruption. MicroRNA sequencing showed Cr(VI) caused global miRNA dysregulation, including up- and downregulation of multiple miRNAs involved in several cancer pathways [ 111 ]; however, securin was not specifically targeted by any of the altered miRNAs (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Hexavalent Chromium Targets Securin to Drive Numerical Chromosome Instability in Human Lung Cells

Toyoda,

Martino,

Speer

et al. 2023

IJMS

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Hexavalent chromium [Cr(VI)] is a known human lung carcinogen with widespread exposure in environmental and occupational settings. Despite well-known cancer risks, the molecular mechanisms of Cr(VI)-induced carcinogenesis are not well understood, but a major driver of Cr(VI) carcinogenesis is chromosome instability. Previously, we reported Cr(VI) induced numerical chromosome instability, premature centriole disengagement, centrosome amplification, premature centromere division, and spindle assembly checkpoint bypass. A key regulator of these events is securin, which acts by regulating the cleavage ability of separase. Thus, in this study we investigated securin disruption by Cr(VI) exposure. We exposed human lung cells to a particulate Cr(VI) compound, zinc chromate, for acute (24 h) and prolonged (120 h) time points. We found prolonged Cr(VI) exposure caused marked decrease in securin levels and function. After prolonged exposure at the highest concentration, securin protein levels were decreased to 15.3% of control cells, while securin mRNA quantification was 7.9% relative to control cells. Additionally, loss of securin function led to increased separase activity manifested as enhanced cleavage of separase substrates; separase, kendrin, and SCC1. These data show securin is targeted by prolonged Cr(VI) exposure in human lung cells. Thus, a new mechanistic model for Cr(VI)-induced carcinogenesis emerges with centrosome and centromere disruption as key components of numerical chromosome instability, a key driver in Cr(VI) carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Hexavalent Chromium Targets Securin to Drive Numerical Chromosome Instability in Human Lung Cells

Toyoda,

Martino,

Speer

et al. 2023

IJMS

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“…Speer et al reported that acute or prolonged exposure to Cr(VI) led to altered global miRNA expression in the human bronchial fibroblast WTHBF-6 cell line. In silico pathway analysis revealed these altered miRNAs were enriched in pathways involved in carcinogenesis [ 74 ]. Two redox-sensitive miRNAs, miR-27a and miR-27b, were down-regulated in response to ROS production in BEAS-2B cells chronically exposed to Cr(VI), in Cr(VI)-transformed BEAS-2B cells, and in the lung tissues of mouse intranasally exposed to Cr(VI) for 12 weeks.…”

Section: Chromium (Cr)mentioning

confidence: 99%

Epigenetic Regulation in Chromium-, Nickel- and Cadmium-Induced Carcinogenesis

Zhao

Islam

Wang

et al. 2022

Cancers

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Environmental and occupational exposure to heavy metals, such as hexavalent chromium, nickel, and cadmium, are major health concerns worldwide. Some heavy metals are well-documented human carcinogens. Multiple mechanisms, including DNA damage, dysregulated gene expression, and aberrant cancer-related signaling, have been shown to contribute to metal-induced carcinogenesis. However, the molecular mechanisms accounting for heavy metal-induced carcinogenesis and angiogenesis are still not fully understood. In recent years, an increasing number of studies have indicated that in addition to genotoxicity and genetic mutations, epigenetic mechanisms play critical roles in metal-induced cancers. Epigenetics refers to the reversible modification of genomes without changing DNA sequences; epigenetic modifications generally involve DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs. Epigenetic regulation is essential for maintaining normal gene expression patterns; the disruption of epigenetic modifications may lead to altered cellular function and even malignant transformation. Therefore, aberrant epigenetic modifications are widely involved in metal-induced cancer formation, development, and angiogenesis. Notably, the role of epigenetic mechanisms in heavy metal-induced carcinogenesis and angiogenesis remains largely unknown, and further studies are urgently required. In this review, we highlight the current advances in understanding the roles of epigenetic mechanisms in heavy metal-induced carcinogenesis, cancer progression, and angiogenesis.

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Prolonged Particulate Hexavalent Chromium Exposure Induces DNA Double-Strand Breaks and Inhibits Homologous Recombination Repair in Primary Rodent Lung Cells

Wise,

Lu,

Meaza

et al. 2024

Biol Trace Elem Res

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Particulate hexavalent chromium alters microRNAs in human lung cells that target key carcinogenic pathways

Cited by 9 publications

References 54 publications

Hexavalent Chromium Targets Securin to Drive Numerical Chromosome Instability in Human Lung Cells

Hexavalent Chromium Targets Securin to Drive Numerical Chromosome Instability in Human Lung Cells

Epigenetic Regulation in Chromium-, Nickel- and Cadmium-Induced Carcinogenesis

Prolonged Particulate Hexavalent Chromium Exposure Induces DNA Double-Strand Breaks and Inhibits Homologous Recombination Repair in Primary Rodent Lung Cells

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