Epigenetic Regulation in Chromium-Induced Carcinogenesis: History
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Contributor:
Lei Zhao
,
Ranakul Islam
,
Yifang Wang
,
Xiujuan Zhang
,
Ling-Zhi Liu

Chromium (Cr)is a naturally occurring heavy metal widely distributed in soil, rocks, and living organisms. Cr primarily exists in two stable valence states: trivalent chromium [Cr(III)] or Cr(VI). Cr(VI) exposure can cause a series of adverse effects on the respiratory system (including asthma, bronchitis, and respiratory tract irritation), skin (including contact dermatitis, skin burns, blisters, and skin ulcers), gastrointestinal (GI) tract (including gastric ulcers and gastritis), and kidneys (acute tubular necrosis and renal failure).

  • heavy metal
  • epigenetics
  • DNA methylation
  • histone modification

1. DNA Methylation

As a major type of epigenetic modification, DNA methylation has been intensely studied in the context of Cr(Ⅵ) exposure [1]. Fundamental alterations in DNA methylation status have been discovered in the blood and lung cancer tissues of Cr(VI)-exposed workers and in Cr(VI)-exposed and transformed lung epithelial cells [2]. Here, the most recent understanding regarding the roles of DNA methylation in Cr(VI)-induced tumorigenesis and angiogenesis was summarized.
Because DNA damage represents one of the major genotoxic effects of Cr(VI), some studies have investigated the role of DNA methylation in Cr(VI)-caused DNA damage and dysfunction of the DNA repair system. Cr(VI) exposure has been shown to cause increased DNA damage and down-regulated expression of p16INK4a (a negative regulator of the cell cycle) in 16HBE cells. The CpG1, CpG31, and CpG32 of p16INK4a were hypermethylated and the methylation levels of these sites were negatively correlated with p16INK4a expression and cell survival rate but positively correlated with DNA damage level, suggesting that increased methylation of p16INK4a may contribute to Cr(VI)-induced cancer by lowering p16INK4a expression and causing accumulation of DNA damage [3]. Furthermore, reduced expression of p16INK4a and aberrantly up-regulated methylation of p16INK4a promoter were also discovered in human workers with lung cancer and long-term (≥15 years) exposure to Cr(VI), suggesting that the hypermethylation of p16INK4a is involved in the Cr(VI) carcinogenesis [4]. In another study, the methylation was increased for the CpG sites in DNA repair genes, including O6-methylguanine-DNA-methyltransferase (MGMT), 8-oxoguanine DNA glycosylase (HOGG1), RAD51 recombinase (RAD51), X-ray repair cross-complementing 1 (XRCC1), and ERCC excision repair 3 (ERCC3). The mRNA levels of these genes were decreased in Cr(VI)-exposed 16HBE cells; the methylation levels of these genes were negatively correlated with corresponding mRNA levels [5]. In a cross-sectional study of 87 workers exposed to Cr and 30 subjects without Cr exposure, DNA damage was accumulated in Cr(VI)-exposed workers, and hypermethylation of the CpG sites of DNA repair genes, including MGMT, HOGG1, and RAD51, was also observed in these workers [5]. These studies indicate that DNA hypermethylation may suppress the DNA repair system, leading to accumulated genetic damage and finally contributing to Cr(VI) carcinogenesis.
Lung cancers of Cr(VI)-exposed workers have a higher frequency of replication error (RER) (defined by the presence of microsatellite instability (MSI)) than lung cancers of patients not exposed to Cr(VI) [6][7]. MSI is often caused by the loss of DNA mismatch repair (MMR) genes, such as MutL homolog 1 (MLH1) [8]. In the Cr(VI)-exposed lung cancers, the MLH1 level was repressed and the down-regulated MLH1 expression was correlated with the degree of MSI [7][9]. Increased methylation of MLH1 promoter was observed in Cr(VI)-exposed lung cancers, which was associated with repressed MLH1 expression [7][9][10]. Notably, the direct effect of MLH1 methylation on MLH1 protein expression was not investigated by these studies. The overall methylation status was also significantly higher in Cr(VI) lung cancers than non-Cr(VI) lung cancers [10]. Additionally, increased promoter methylation and decreased expression of p16 and APC were also observed in Cr(VI)-exposed lung cancers [10]. These results suggest that DNA hypermethylation-mediated down-regulation of MLH1 expression may contribute to Cr(VI)-induced carcinogenesis by impairing the DNA repair system. The roles of aberrant DNA methylation/demethylation in Cr(VI)-induced carcinogenesis and cancer progression are summarized in Table 1.
Table 1. Roles of altered DNA methylation in Cr(VI) exposure-induced carcinogenesis.
Cells or Tissues Compound Route Exposure Time Change (s) Role Mechanism
16HBE cells [3] Dichromate (Cr2O72−) Culture medium 24 h Hypermethylation at CpG1, CpG31, and CpG32 of p16INK4a promoter Pro-oncogenic Hypermethylation of the promoter caused lowered p16INK4a expression and accumulation of DNA damage.
Human lung cancer [4] Chromate Inhalation >15 y
16HBE/human lung cancer [5] Potassium dichromate (K2Cr2O7) Culture medium/ inhalation 24 h Hypermethylation of MGMT, HOGG1, RAD51, XRCC1, and ERCC3 Pro-oncogenic Decreased the expression of these DNA repair genes, leading to suppressed DNA repair system and resultant accumulation of genetic damages.
Human lung cancer [7][9] Chromate Inhalation N/A Hypermethylation of MLH1 promoter Pro-oncogenic Inhibit the expression of MLH1, a DNA mismatch repair gene, causing increased microsatellite instability of the genome.
Human lung cancer [10] Chromate Inhalation N/A Global DNA hypermethylation Hypermethylation of p16 and APC promoters Pro-oncogenic Globally increased genomic methylation; increased promoter methylation caused decreased expression of p16 and APC, two tumor suppressors, contributing to Cr(VI) carcinogenesis.
Cr(VI): hexavalent chromium; MGMT: O6-methylguanine-DNA-methyltransferase; HOGG1: 8-oxoguanine DNA glycosylase; RAD51: RAD51 recombinase; XRCC1: X-ray repair cross-complementing 1; ERCC3: ERCC excision repair 3; MLH1: MutL homolog 1; APC: adenomatous polyposis coli.

2. Histone Modification

2.1. Histone Methylation

Histone modification is another common type of epigenetic modification involved in the formation and development of cancers [11]. Cr(VI) exposure has been shown to cause extensive alterations in histone modifications. For example, Cr(VI) exposure caused globally increased levels of H3K9me2/3 and H3K4me2/3 but decreased levels of H3K27me3 and H3R2me2 in A549 human lung cancer cells [12][13]. Cr(VI) also caused gene-specific histone modifications that resulted in altered gene expression. For example, Cr(VI) exposure induced increased H3K9me2 in the promoter of MLH1, likely through up-regulating G9a (also known as euchromatic histone-lysine N-methyltransferase, 2), a histone methyltransferase that specifically methylates H3K9, causing repressed MLH1 expression [12]. The altered global and gene-specific histone modifications and the resultant gene expression changes, such as inhibition of tumor suppressor MLH1, have been shown to contribute to Cr(VI) carcinogenesis in a growing number of studies.
Chronic low-dose Cr(VI) exposure has been shown to induce cell transformation and acquisition of cancer stem cell (CSC)-like properties in BEAS-2B and 16HBE cells. Cr(VI)-transformed cells had increased levels of H3K9me2 and H3K27me3, two repressive methylation marks, and greatly increased levels of histone-lysing methyltransferases (HMTs) for H3K9 (GLP, G9a, SUV39H1 histone lysine methyltransferase (SUV39H1)) or H3K27 (enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)) [14]. Additionally, SUV39H1 and EZH2 were also up-regulated in the lung cancer of Cr(VI)-exposed workers [14]. The up-regulated HMTs played a causal role in elevated levels of H3K9me2 and H3K27me3, and were indispensable in Cr(VI)-induced cell transformation and in maintaining the cancerous and CSC-like property of Cr(VI)-transformed cells. Furthermore, increased HMTs also contributed to Cr(VI)-exposure-caused DNA damage, as knockdown of HMTs attenuated Cr(VI)-induced DNA damage. Collectively, these results indicate that dysregulated histone modification machinery contributes to Cr(VI)-induced genotoxic effects, carcinogenesis, and cancer progression [14].
Hedgehog (Hh) signaling plays a key role in embryogenesis and stem cell functions; dysregulation of the Hh pathway has been reported in various human cancers. The expression of the hedgehog-interacting protein (HHIP), a downstream target and a negative regulator of Hh signaling, was down-regulated in Cr(VI)-transformed BEAS-2B cells and primary lung cancers [15]. The down-regulation of HHIP contributed to Cr(VI)-induced malignant transformation by activating the Hh signaling, as the forced expression of HHIP inactivated Hh signaling and inhibited cell proliferation and anchorage-independent growth in Cr(VI)-transformed cells [15]. Mechanistically, the suppressed HHIP expression was attributed to multiple epigenetic modifications of its promoter region, including DNA hypermethylation, reduced levels of H3K9ac and H3K4me3, two active histone marks, and enriched H3K27me3, a repressive histone mark [15].

2.2. Histone Acetylation

Histone acetylation is another major type of histone modification. C-X-C motif chemokine ligand 5 (CXCL5) is an inflammatory factor involved in multiple processes relevant to tumor formation and progression [16]. CXCL5 level was dramatically up-regulated in the peripheral blood monocytes (PBMCs) and plasma from workers with occupational exposure to Cr(VI) and the lung tissues of mice intranasally exposed to Cr(VI) and Cr(VI)-transformed BEAS-2B cells [17]. Functionally, CXCL5 promoted Cr(VI)-induced cell transformation and played an important role in maintaining cancer phenotypes of Cr(VI)-transformed BEAS-2B cells. CXCL5 also prompted Cr(VI)-induced epithelial-mesenchymal transition (EMT) by up-regulating zinc finger E-box binding homeobox 1 (ZEB1) [17]. Two mechanisms have been proposed to account for the up-regulated CXCL5: Cr(VI) exposure activated c-Myc, which specifically binds to the CXCL5 promoter and recruited p300 to form a transcription complex; the c-Myc/p300 complex then enhanced the histone H3 acetylation and eventually promoted CXCL5 transcription. Hypomethylation of CXCL5 promoter due to Cr(VI)-induced DNA methyltransferase 1 (DNMT1) down-regulation also contributed to CXCL5 induction [17]. These findings indicate that epigenetic machinery contributes to Cr(VI)-induced carcinogenesis and cancer progression through epigenetically up-regulating CXCL5. The level of nuclear protein 1 (NUPR1) was significantly up-regulated in Cr(VI)-exposed BEAS-2B cells due to epigenetic mechanisms, such as hypomethylation and increased H3K9 and H3K14 acetylation levels of its promoter [18]. Elevated NUPR1, in turn, led to reduced global and promoter-specific H4K16ac (such as for tripartite motif containing 42 (TRIM42) and inhibitors of apoptosis (IAP)) by inhibiting the transcription of males absent on the first (MOF), a histone acetyltransferase that specifically acetylates H4K16 [19]. Functionally, up-regulated NUPR1 promoted Cr(VI)-induced transformation of BEAS-2B cells, consistent with previous reports that NUPR1 promoted the development and metastasis of lung, pancreatic, and breast cancers [20][21][22]. Notably, NUPR1 expression was not increased in transformed BEAS-2B cells, suggesting that it may only be required for initiation of cell transformation; however, reduced MOF and H4K16ac were observed in both Cr(VI)-exposed and transformed cells, indicating that they were required for both initiation and maintenance of cell transformation [18]. These results support the notion that Cr(VI)-induced NUPR1 contributes to Cr(VI)-induced carcinogenesis by altering the histone modification marks and subsequent gene expression perturbations [18]. c-Myc is a master regulator of cell metabolism; dysregulated metabolism plays an important role in cancer development [23]. Clementino et al. have found that c-Myc mediated aberrant histone acetylation contributes to Cr(VI)-induced carcinogenesis by promoting glycolytic shift [24]. Cr(VI)-transformed BEAS-2B cells showed glycolytic shift mediated by up-regulated c-Myc. The glycolytic shift, in turn, led to increased acetyl coenzyme A (acetyl-CoA) levels and several histone acetylation marks, including H3K9ac, H3K27ac, and acetyl-histone 4 (Ac-H4) and 2B (Ac-H2B). The up-regulated acetylation of H3 at the promoter of ATP citrate lyase (ACLY) promoted the transcription of ACLY, a key enzyme for producing acetyl-CoA; up-regulated ACLY, in turn, increased c-Myc expression, acetyl-CoA level, and histone acetylation, forming a positive feedback loop that drives a metabolic shift in Cr(VI)-transformed cells [24]. The glycolytic shift and resultant glycolysis played critical roles in maintaining the malignant phenotypes of Cr(VI)-transformed cells, because the reverse of the glycolytic shift by glucose depletion significantly inhibited the growth, CSC-like property, and tumorigenicity of the transformed cells [24]. SET nuclear proto-oncogene (SET), a major regulator of histone modifications, was increased in Cr(VI)-exposed and Cr(VI)-transformed 16HBE cells [25]. Increased SET promoted proliferation and cell cycle progression and inhibited apoptosis of transformed 16HBE cells. Mechanistic studies indicated that increased SET mediated the reduction in H3K18ac and H3K27ac at the tumor protein P53 binding protein 1 (53BP1) promoter, resulting in decreased expression of 53BP1 in Cr(VI)-exposed and Cr(VI)-transformed 16HBE cells [25][26]. The 53BP1 protein binds to the central domain of TP53 and plays an important role in DNA damage repair [27]; inhibition of 53BP1 may cause DNA damage accumulation and inhibition of apoptosis, therefore promoting tumorigenesis and cancer progression [28]. Additionally, Cr(VI) also caused global decreases in H3K18ac and H3K27ac, which might have broad effects on gene expression. These results demonstrate the involvement of SET-mediated histone hypoacetylation in Cr(VI)-induced lung carcinogenesis. The roles of histone modifications in Cr(VI)-induced carcinogenesis and cancer progression are summarized in Table 2.
Table 2. Roles of histone modifications in Cr(VI) exposure-induced carcinogenesis.
Cells or Tissues Compound Route Exposure Time Modification (s) Role Mechanism
BEAS-2B/16HBE cells [14] K2Cr2O7 Culture medium 20 w/40 w Increased global H3K9me2 and H3K27me3 Pro-oncogenic Cr(VI) led to up-regulated global H3K9me2 and H3K27me3 by increasing the levels of HMTs. The aberrant histone methylation contributed to Cr(VI)-induced genotoxicity and carcinogenesis.
Human lung cancer [10] Chromate Inhalation NA Globally increased H3K9me2/3 and H3K4me2/3, but decreased H3K27me3
and H3R2me2
Increased H3K9me2 in MLH1 promoter		 Pro-oncogenic Cr(VI) induced globally increased H3K9me2/3 and H3K4me2/3, but decreased H3K27me3 and H3R2me2. Cr(VI) also caused increased H3K9me2 in MLH1 promoter, likely via up-regulating G9a and SUV39H1, causing repressed expression of MLH1, a tumor suppressor.
A549 [12] K2CrO4 Culture medium 1 h–24 h
A549 [13] K2CrO4 Culture medium 24 h
BEAS-2B [15] K2CrO4 Culture medium 6 months Reduced H3K9ac and H3K4me3, but enriched H3K27me3 in the promoter of HHIP Pro-oncogenic Cr(VI) caused reduced levels of H3K9ac and H3K4me3 but enriched H3K27me3 in the promoter of HHIP, leading to decreased expression of HHIP. Decreased HHIP activated the hedgehog signaling, which contributed to Cr(VI) carcinogenesis.
BEAS-2B [17] K2Cr2O7 Culture medium 6 months Enhanced histone H3 acetylation in the promoter of CXCL5 Pro-oncogenic Cr(VI) activated the c-Myc/p300 complex, which was specifically bound to the CXCL5 promoter and enhanced H3 acetylation and eventually promoted CXCL5 transcription. Up-regulated CXCL5 contributed to Cr(VI) carcinogenesis.
BEAS-2B [18] K2CrO4 Culture medium 24 h/1–2 w Increased H3K9ac and H3K14ac of NUPR1 promoter Pro-oncogenic Cr(VI) caused increased H3K9ac and H3K14ac of NUPR1 promoter and elevated NUPR1 expression, which in turn promoted Cr(VI)-induced transformation of BEAS-2B cells.
BEAS-2B cells [24] K2Cr2O7 Culture medium 20 w Increased H3K9ac and H3K27ac at the promoter of ACLY Pro-oncogenic Cr(VI) led to a glycolytic shift, which led to increased H3K9ac, H3K27ac, and H2B and H4 acetylation. The up-regulated H3ac at the ACLY promoter promoted ACLY transcription; up-regulated ACLY in turn increased the glycolytic shift and histone acetylation, forming a positive feedback loop. The glycolytic shift played a critical role in maintaining the malignant phenotypes of Cr(VI)-transformed cells.
16HBE [25][26] K2CrO4 Culture medium 15 w Global and 53BP1 promoter-specific decreases in H3K18ac and H3K27ac Pro-oncogenic Cr(VI) caused increased SET, resulting in global and 53BP1 promoter-specific reduction in H3K18ac and H3K27ac. The promoter histone hypoacetylation resulted in decreased expression of 53BP1, which contributed to Cr(VI) carcinogenesis by causing DNA damage accumulation and inhibition of apoptosis.
Cr(VI): hexavalent chromium; HMTs: histone-lysing methyltransferases; MLH1: MutL homolog 1; HHIP: hedgehog-interacting protein; CXCL5: C-X-C motif chemokine ligand 5; NUPR1: nuclear protein 1; ACLY: ATP citrate lyase; SET: SET nuclear proto-oncogene; 53BP1: P53 binding protein 1.

3. Non-Coding RNA

3.1. miRNA

The dysregulation of miRNA expression has recently been shown to have important roles in Cr(VI)-induced cell transformation, carcinogenesis, and angiogenesis. 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 [29]. 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. The down-regulated miR27a/b promoted Cr(VI)-induced tumorigenesis and angiogenesis through up-regulating NF-E2-related factor-2 (Nrf2) [30], a transcription factor that has been known to promote cell proliferation, colony formation, migration, and angiogenesis in various cancers [31]. These results indicate that miR-27a and miR-27b act as tumor suppressors and the miR-27a/b/Nrf2 signaling plays a pivotal role in Cr(VI)-induced carcinogenesis and angiogenesis.
An oncogenic miRNA, miR-21, was up-regulated in Cr(VI)-treated BEAS-2B cells, and elevated miR-21 promoted Cr(VI)-induced transformation of BEAS-2B cells. Mechanistically, Cr(VI) induced interleukin-6 (IL-6) expression, which in turn promoted the signal transducer and activator of transcription 3 (STAT3) phosphorylation, and activated STAT3 bound to the miR-21 promoter to promote its transcription. Up-regulated miR-21 directly down-regulated programmed cell death 4 (PDCD4), a tumor suppressor [32][33]; inhibition of PDCD4 suppressed downstream E-cadherin expression and promoted β-catenin/TCF-dependent transcription of c-Myc and plasminogen activator, urokinase receptor (uPAR). The c-Myc oncogene plays a critical role in the process of carcinogenesis [34], and uPAR is involved in cancer progression [35]. These results suggest that activation of the miR-21/PDCD4 signaling contributes to Cr(VI)-induced lung carcinogenesis through regulating important downstream factors, such as E-cadherin, c-Myc, and uPAR [32]. Additionally, up-regulated miR-21 and suppressed PDCD4 were also observed in the lung tissues of mice intranasally exposed to Cr(VI), multiple lung cancer cell lines (H2030, H460, H23, and A549), and human lung adenocarcinoma tissues, suggesting that the miR-21/PDCD4 pathway is involved in lung cancer caused by both Cr(VI) and non-Cr(VI) factors [32]. Furthermore, quercetin, an antioxidant flavonoid widely present in fruits and vegetables, inhibited Cr(VI)-induced activation of miR-21/PDCD4 cascade in BEAS-2B cells by decreasing ROS generation; quercetin therefore inhibited Cr(VI)-induced malignant transformation and suppressed the growth of xenograft tumor of Cr(VI)-transformed cells, suggesting a preventive and therapeutic role of quercetin in Cr(VI)-caused lung cancer [33]. On the contrary, Cr(VI) caused the down-regulation of miR-21 in L02 hepatocytes, and the subsequent increase in PDCD4 contributed to Cr(VI)-induced apoptosis and inhibited proliferation of L02 cells, suggesting that the inhibited miR-21/PDCD4 signaling contributes to Cr(VI)-induced hepatotoxicity [36].
Expression of miR-143, a tumor-suppressive miRNA [37], was decreased in BEAS-2B cells exposed to Cr(VI), Cr(VI)-transformed BEAS-2B cells, and the plasma of Cr(VI)-exposed workers [38][39]. Suppressed miR-143 promoted the growth and tumor angiogenesis of Cr(VI)-transformed BEAS-2B cells in vitro and in vivo [38][39]. Mechanistically, ectopic miR-143 overexpression directly targeted both insulin-like growth factor-1 receptor (IGF-IR) and insulin receptor substrate-1 (IRS1), suppressed the activation of downstream ERK signaling, and inhibited the EKR pathway, lowering the expression of IL-8, a major angiogenesis activator in Cr(VI)-induced angiogenesis [38]. miR-143 could also inhibit the expression of IL-6, hypoxia-inducible factor-1 subunit alpha (HIF-1α), p70S6K1, and NF-κB p65, causing reduced expression of IL-8 and vascular endothelial growth factor (VEGF) [38][39]. Collectively, these results indicate that down-regulation of miR-143 contributes to Cr(VI)-induced carcinogenesis and angiogenesis through activation of multiple signaling pathways, including IGF-IR/IRS1/ERK, mTOR/p70S6K1, HIF-1α/VEGF, and NF-κB p65 pathways [38][39]. Moreover, the miR-143 level was also significantly lower in A549 and H2195 lung cancer cells than in BEAS-2B cells, suggesting a broad role of miR-143 in lung cancer [38].
Cr(VI) exposure has been shown to cause DNA damage and subsequent activation of DNA repair genes. In a cohort study, plasma miR-3940-5p level was significantly down-regulated in workers exposed to Cr(VI) and negatively associated with blood Cr level. However, the low miR-3940-5p level was associated with high expression of XRCC2 (a DNA repair gene targeted by miR-3940-5p) in peripheral lymphocytes [40]. Furthermore, miR-3940-5p was inhibited in Cr(VI)-treated 16HBE cells; down-regulated miR-3940-5p then enhanced homologous recombination after double-strand breaks (DSBs) caused by Cr(VI) exposure [41]. These studies suggest that repression of miR-3940-5p plays a protective role in Cr(VI)-induced cell transformation by mitigating the accumulation of DNA damage. Exposure of human B lymphoblast HMy2.CIR cells to Cr(VI) caused global miRNA expression changes. Functional analysis of altered miRNAs indicated that down-regulation of miR-148a-3p and miR-21-5p might contribute to Cr (VI)-induced cell apoptosis, and up-regulated miR-221-3p might result in increased cell apoptosis and accumulation of DSBs and total DNA damage [42]. c-Myc, a proto-oncogene, played a critical role in maintaining the CSC-like property and tumorigenicity of Cr(VI)-transformed BEAS-2B cells; it also promoted Cr(VI)-induced transformation and acquisition of CSC-like properties in BEAS-2B cells. Mechanistic studies indicated that chronic Cr(VI) exposure increased c-Myc expression by down-regulating the level of miR-494, suggesting that inhibited miR-494/c-Myc cascade contributes to chronic Cr(VI) exposure-induced initiation and progression of lung cancer [43]. The roles of miRNAs in Cr(VI)-induced carcinogenesis and cancer progression are summarized in Table 3.
Table 3. Roles of altered miRNA in Cr(VI) exposure-induced carcinogenesis.
Cells or Tissues Compound Route Exposure Time miRNA Alteration Role Target (s) Mechanism
BEAS-2B/BALB/cJ mice [30] Na2Cr2O7/
zinc chromate		 Culture medium/intranasal instillation 6 months /12 w miR-27a miR-27b Down Tumor suppressor NRF2 MiR-27a/b were down-regulated in response to ROS production upon Cr(VI) exposure; down-regulated miR27a/b promoted Cr(VI)-induced tumorigenesis and angiogenesis by up-regulating NRF2.
BEAS-2B [32][33] K2Cr2O7 Culture medium 24 h/
6 months		 miR-21 Up Oncogenic PDCD4 Cr(VI) promoted miR-21 transcription by activating STAT3. Up-regulated miR-21 directly targeted PDCD4, a tumor suppressor. Inhibition of PDCD4 contributed to Cr(VI)-induced cancer by suppressing the expression of E-cadherin, c-Myc, and uPAR.
L02 hepatocytes [36] NA Culture medium 24 h miR-21 Down Pro-apoptotic PDCD4 Cr(VI) caused a decrease in miR-21 and a subsequent increase in PDCD4, contributing to Cr(VI)-induced apoptosis and decreased proliferation of liver cells.
BEAS-2B [38][39] Na2Cr2O7 Culture medium 6 months miR-143 Down Tumor suppressor IGF-IR
IRS1		 Cr(VI) lowered miR-143 expression; decreased miR-143 promoted Cr(VI)-induced tumor growth and angiogenesis by activating IGF-IR/IRS1/ERK, mTOR/p70S6K1, HIF-1α/VEGF, and NF-κB p65 pathways.
Human lung cancer [40] Na2Cr2O7 Inhalation 3.0–10.0 years miR-3940-5p Down Oncogenic NA Cr(VI) led to decreased miR-3940-5p; the lowered miR-3940-5p then enhanced the HR of DSBs to mitigate the accumulation of DNA damage, playing a protective role in Cr(VI)-caused cell transformation.
16HBE [41] Na2CrO4 Culture medium 24 h
BEAS-2B [43] K2Cr2O7 Culture medium 20 w miR-494 Down Tumor suppressor c-Myc Cr(VI) caused down-regulation of miR-494, which in turn led to increased c-Myc, contributing to Cr(VI)-induced transformation and acquisition of CSC-like properties in BEAS-2B cells.
Cr(VI): hexavalent chromium; ROS: reactive oxygen species; Nrf2: NF-E2-related factor-2; PDCD4: programmed cell death 4; uPAR: plasminogen activator, urokinase receptor; IGF-IR: insulin-like growth factor-1 receptor; IRS1: insulin receptor substrate-1; HR: homologous recombination; DSBs: double-strand breaks; CSC: cancer stem cells.

3.2. lncRNA

Fewer studies have been performed to investigate the role of lncRNAs in Cr(VI)-induced cancers. Hu et al. characterized the differentially expressed lncRNAs in 16HBE cells exposed to Cr(VI) for 24 h. They found 1868 significantly up-regulated and 2203 significantly down-regulated lncRNAs. Further bioinformatics analysis suggested that the differentially expressed lncRNAs formed a complex regulation network and were associated with immune response, cell cycle, DNA damage, repair, etc. However, whether these dysregulated lncRNAs contributed to Cr(VI)-induced carcinogenesis is currently unknown [44].

This entry is adapted from the peer-reviewed paper 10.3390/cancers14235768

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