MEG3 in Carcinogenesis of Heavy Metals: Comparison
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Maternally expressed gene 3 (MEG3), a long non-coding RNAs (lncRNA)cRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Most heavy metals are toxic and carcinogenic to humans. Heavy metals are widely utilized in various industrial and agricultural products, such as paints, batteries, pigments, electronic waste, and insecticides/pesticides. Contaminated heavy metals in the environment flow into soil, lake, river, and ocean through rain and groundwater, where the metals accumulate via the circulating bio-system, resulting in high concentrations in humans. Chromium (Cr(VI)), arsenic (As), nickel (Ni), and cadmium (Cd) are listed as Group 1 human carcinogens by the International Agency for Research on Cancer (IARC). Studies have indicated that exposure to these metals disrupts cellular signaling pathways, such as damaged repair processes, reduced gene expression of tumor suppressors, and aberrant metabolism, leading to carcinogenesis.

  • metals
  • MEG3
  • long non-coding RNA
  • carcinogenesis

1. Maternally Expressed Gene 3 in Hexavalent Chromium Carcinogenesis

Hexavalent chromium (Cr(VI)) compounds are widely utilized in multiple industrial activities such as wood preservation, tanning, paint production, chemical production, and electroplating. The contamination of soils and groundwater caused by the use of Cr(VI) in these industrial and agricultural practices has brought worldwide concerns about the adverse health effects on humans. The Environmental Protection Agency (EPA) and IARC have classified Cr(VI) as a confirmed human carcinogen for lung cancer. It has been reported that the chronic exposure of human bronchial epithelial cells to low doses of Cr(VI) caused malignant cell transformation [1]. These transformed cells displayed rapid cell growth [2], resistance to apoptosis [3], increased angiogenesis [4], and tumor growth in xenograft animals [5].
The mechanisms of Cr(VI)-induced carcinogenesis have been extensively studied. However, the role of long non-coding RNA, such as maternally expressed gene 3 (MEG3), in Cr(VI) carcinogenesis has not been well investigated. The results from Arraystar microarray and bioinformatic analysis showed that the short-term exposure of human bronchial epithelial 16HBE cells to Cr(VI) caused 1,868 long non-coding RNAs (lncRNAs) upregulation and 2,203 lncRNAs downregulation [6]. MEG3 was not listed in the top 10 downregulated genes [6]. TheOur recent study has observed that the MEG3 expression level was reduced in BEAS-2B cells exposed to Cr(VI) and that MEG3 was lost in Cr(VI)-transformed cells [7]. The ectopic expression of MEG3 decreased the migration and invasion of Cr(VI)-transformed cells [7]. While miR145-5p was upregulated in Cr(VI)-transformed cells, the ectopic expression of MEG3 decreased miR-145-5p levels and NEDD9 protein levels [7]. The levels of miR-145-3p were increased in the plasma of workers occupationally exposed to Cr(VI) compared to those without exposure [8]. β-catenin was activated in Cr(VI)-transformed cells, the overexpression of MEG3 decreased the activation of β-catenin [7]. Further study has found that MEG3 was bound to miR-145 and the mutation of MEG3 at the binding site for miR-145 was unable to alter NEDD9 expression or decrease the invasion and migration of Cr(VI)-transformed cells [7]. Interestingly, the knockdown of MEG3 in normal BEAS-2B cells promoted migration and invasion [7]. The study indicated that in Cr(VI)-transformed cells, the loss of MEG3 increased developmentally downregulated protein 9 (NEDD9) expression, resulting in the activation of β-catenin and the further upregulation of EMT, promoting migration and invasion [7].

2. Maternally Expressed Gene 3 in Arsenic Carcinogenesis

Arsenic compounds are widely used as pesticides, fungicides, herbicides, wood preservatives, and paints. The contamination of drinking water due to agricultural activities is the major exposure route for humans to arsenic compounds. Inorganic forms of arsenite and arsenate compounds have been classified as confirmed human carcinogens of the bladder, lung, and skin by EPA and IARC.
The mechanisms of arsenic carcinogenesis have been the most studied among all heavy metals that have been classified as human carcinogens, including Cr(VI), nickel, and cadmium. However, very few studies on MEG3 in arsenic carcinogenesis are available. It has been reported that paternal non-occupational exposure to environmental arsenic elevated DNA methylation levels of MEG3 in the sperm of 353 male subjects [9]. The results from a case-control study revealed that MEG3 levels in peripheral blood lymphocytes were positively correlated with the levels of inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in the urine of workers exposed to arsenic [10]. It has also been reported that MEG3 levels in peripheral blood were reduced in workers exposed to arsenic occupationally, while the arsenic concentrations were increased in the urine [11].

3. Maternally Expressed Gene 3 in Nickel Carcinogenesis

Nickel compounds were classified as Group 1 human carcinogens by IARC in 1990 [12]. The carcinogenic effects of nickel include oxidative stress, DNA damage, inflammation, and epigenetic and genetic changes [13]. Hypoxia-inducible factor-1 (HIF-1), a transcription factor, plays an important role in the regulation of angiogenesis [14]. HIF-1α, a regulatory subunit of HIF-1, is responsible for the transcriptional function of HIF-1. TheOur previous study has found that nickel activated the hypoxia-inducible pathway, which is important in the nickel-induced carcinogenic process [15]. It has also been reported that nickel exposure caused HIF-1α protein accumulation, leading to malignant cell transformation [16].
Although the mechanisms of nickel carcinogenesis have been well investigated, the role of lncRNA in nickel-induced carcinogenesis has yet to be extensively studied. It has been reported that the exposure of the cells to nickel caused the downregulation of MEG3, leading to malignant cell transformation [17]. While the knockdown of MEG3 facilitated the malignant cell transformation by nickel, the overexpression of MEG3 reduced the malignant cell transformation induced by chronic exposure to nickel in BEAS-2B cells [17]. Lung squamous cell carcinomas are the major type of lung cancer induced by occupational exposure to nickel [18]. MEG3 was downregulated in the tumor tissues from human lung squamous cell carcinoma compared to those from adjacent normal lung tissues [17]. Chronic exposure of the cells to nickel downregulated MEG3, causing the transcriptional inhibition of the c-Jun-mediated PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and the upregulation of HIF-1α protein, leading to malignant cell transformation [17]. Further study suggested that the downregulation of MEG3 was due to the hypermethylation of the promoter through elevated DNA methyltransferase 3 beta (DNMT3b) induced by nickel. The reduced interaction of MEG3 with c-Jun inhibited PHLPP1 transcription, resulting in the upregulation of HIF-1α protein through the activation of the Akt/p70S6k/S6 pathway [17].
MEG3 was downregulated in the pulmonary fibrosis tissues of rats induced by nickel oxide nanoparticles (NiO NPs) [19]. Autophagy proteins Beclin 1 and LC3B were both downregulated and p62 was upregulated in the lung fibrosis tissues [19]. The overexpression of MEG3 was able to restore levels of Beclin1 and LC3B reduced by NiO NPs in A549 cells [19]. The Hedgehog pathway plays an important role in cell proliferation. The overexpression of MEG3 inhibited the Hedgehog pathway activated by NiO NPs exposure [19]. While the exposure of NiO NPs to rats activated the p38 MAPK and induced inflammatory responses, the overexpression of MEG3 suppressed the p38 MAPK, resulting in reduced levels of inflammatory cytokines, including IL-6, IL-8, and TNF-α [20].

4. Maternally Expressed Gene 3 in Cadmium Carcinogenesis

Adverse health effect caused by exposure to cadmium (Cd) compounds is a major public health concern. Cd(II) is the common Cd oxidation state. Studies have demonstrated that Cd(II) exposure causes lung cancer and cancers of other organs [21][22][23][24][25][26][27][28][29]. IARC has classified Cd(II) as a human Group 1 carcinogen [22].
Although the mechanism of Cd(II)-induced carcinogenesis remains largely unknown, recent studies have indicated that MEG3 plays a key role in malignant cell transformation induced by Cd(II) exposure [30]. Chronic exposure of BEAS-2B cells to a low dose of Cd(II) induced malignant cell transformations and generated cancer stem cell (CSC)-like cells [30]. MEG3 level was markedly reduced in Cd(II)-transformed cells. The p21 level was reduced and the levels of Rb phosphorylation and Bcl-xL protein were increased in those Cd(II)-transformed cells [30]. The overexpression of MEG3 elevated the p21 level and decreased levels of both Rb phosphorylation and Bcl-xL, resulting in reduced apoptosis resistance of Cd(II)-transformed cells [30].
One function of the MEG3-DMR is to maintain activity in the MEG3-IG region. The hypermethylation of MEG3-DMR induced by Cd(II) altered the expression of various genes in this imprinted domain [31]. The results from a study of 287 pairs of infants–mothers showed significantly increased levels of prenatal Cd and MEG3-DMR hypermethylation in cord blood, and the associations were strongest in those born to African American women compared with those born to White women or Hispanic women, indicating that prenatal Cd exposure is associated with the aberrant methylation of the MEG3-DMR at birth [31]. Thus, it is speculated that the reductions in MEG3 transcripts by Cd cause the loss of MEG3 tumor suppression function, resulting in increased susceptibility to cancer.
The role of MEG3 in metal-induced carcinogenesis is summarized in Table 1.
Table 1. The role of MEG3 in metal-induced carcinogenesis. Exposure to chromium (Cr(VI)), arsenic (As), nickel (Ni), or cadmium (Cd) downregulated MEG3, disrupting multiple cellular signaling pathways, leading to malignant cell transformation, inflammation, and enhanced migration and invasion. BEAS-2B: human bronchial epithelial cells. BLF: bronchoalveolar lavage fluid.
Metals MEG3 Levels Tissues or Cells Target Genes Hallmarks of Cancer References
Cr(VI) Downregulation BEAS-2B cells NEDD9, β-catenin, and EMT Migration and invasion [7]
As Downregulation Human sperms DNA methylation of MEG3   [9]
Downregulation Human peripheral blood lymphocytes     [10][11]
Ni Downregulation BEAS-2B cells Akt/p70S6k/S6 signaling Cell transformation [17]
Downregulation A549 cells and BLF from rats Inflammatory cytokines and p38 MAPK Inflammation of the lungs [20]
Cd Downregulation BEAS-2B cells p21, Rb, and Bcl-xL Cell transformation [30]
Downregulation Human cord blood Hypermethylation of MEG3   [31]

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