Crystalline silica particles are fibrogenic agents and established carcinogens, but the mechanisms for disease initiation and progression are not well understood. Previous studies demonstrate that the tumor suppressor gene, programmed cell death 4 (PDCD4), and its upstream regulator, microRNA 21 (miR-21), may be oncogenes for novel cancer prevention or anticancer therapies.
Methods:
This study examined the alterations of miR-21-PDCD4 signaling in mouse epidermal JB6 cells after exposure to freshly fractured silica particles.
Results:
The results demonstrate that exposure to crystalline silica caused PDCD4 inhibition in JB6 cells and a significant increase in miR-21 expression. Inhibition of phosphorylated extracellular signal-regulated kinases (ERKs) or phosphorylated p38 with U0126 or SB 203580 reversed silica-induced PDCD4 inhibition. Reactive oxygen species (ROS) scavengers and N-acetyl-l-cysteine also reversed the inhibitory effect of silica on PDCD4 expression. Human lung epithelial BEAS-2B or JB6 cells chronically exposed to low-dose silica resulted in neoplastic transformation as assayed by soft agar.
Discussion:
These findings demonstrate that freshly fractured silica particles may induce miR-21 expression and PDCD4 inhibition, which may be mediated through ROS and ERK pathways. Unraveling the complex mechanisms associated with these events may provide insights into the initiation and progression of silica-induced carcinogenesis.
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References
1.
CraigheadJE. Diseases associated with exposure to silica and nonfibrous silicate minerals. Arch Pathol Lab Med, 1988; 112:673–720.
2.
DingM, ShiX, LuY, et al.Induction of activator protein-1 through reactive oxygen species by crystalline silica in JB6 cells. J Biol Chem, 2001; 276(12):9108–9114.
3.
McDonaldJC. Silica and lung cancer. In: Silica and Silica-Induced Lung Diseases. (V. CastranovaVV, and WallaceW. eds.) CRC Press: Boca Baton, FL, 1996, pp.383–406.
4.
ReiserKM, LastJA. Silicosis and fibrogenesis: Fact and artifact. Toxicology, 1979; 13(1):51–72.
5.
CastranovaV, VallyathanV. Silicosis and coal workers’ pneumoconiosis. Environ Health Perspect, 2000; 108(Suppl 4):675–684.
6.
DingM, ChenF, ShiX, et al.Diseases caused by silica: Mechanisms of injury and disease development. Int Immunopharmacol, 2002; 2(2–3):173–182.
7.
ZiskindM, JonesRN, WeillH. Silicosis. Am Rev Respir Dis, 1976; 113(5):643–665.
8.
DingM, ShiX, DongZ, et al.Freshly fractured crystalline silica induces activator protein-1 activation through ERKs and p38 MAPK. J Biol Chem, 1999; 274(43):30611–30616.
9.
JohnsonN, SmithD, SebringR, et al.Silica‐induced alveolar cell tumors in rats. Am J Ind Med, 1987; 11(1):93–107.
10.
MuhleH, KittelB, ErnstH, et al.Neoplastic lung lesions in rat after chronic exposure to crystalline silica. Scand J Work Environ Health, 1995; 21(Suppl 2):27–29.
11.
MuhleH, TakenakaS, MohrU, et al.Lung tumor induction upon long‐term low‐level inhalation of crystalline silica. Am J Ind Med, 1989; 15(3):343–346.
12.
WehnerAP, DagleGE, ClarkML, et al.Lung changes in rats following inhalation exposure to volcanic ash for two years. Environ Res, 1986; 40(2):499–517.
13.
International Agency for Research on Cancer. Review of human carcinogens. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Publications; 2012;Vol. 100.
14.
AngelP, KarinM. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta, 1991; 1072(2–3):129–157.
15.
CastranovaV. Signaling pathways controlling the production of inflammatory mediators in response to crystalline silica exposure: Role of reactive oxygen/nitrogen species. Free Radic Biol Med, 2004; 37(7):916–925.
16.
HuangR, ChenH, LiangJ, et al.Dual role of reactive oxygen species and their application in cancer therapy. J Cancer, 2021; 12(18):5543–5561.
17.
YangH-S, KniesJL, StarkC, et al.Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Oncogene, 2003; 22(24):3712–3720.
18.
CmarikJL, MinH, HegamyerG, et al.Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Proc Natl Acad Sci U S A, 1999; 96(24):14037–14042.
19.
Lankat‐ButtgereitB, GökeR. The tumour suppressor Pdcd4: Recent advances in the elucidation of function and regulation. Biol Cell, 2009; 101(6):309–317.
20.
YangH-S, JansenAP, NairR, et al.A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-κB or ODC transactivation. Oncogene, 2001; 20(6):669–676.
21.
HilliardA, HilliardB, ZhengS-J, et al.Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. J Immunol, 2006; 177(11):8095–8102.
22.
SchmidT, JansenAP, BakerAR, et al.Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion. Cancer Res, 2008; 68(5):1254–1260.
23.
AsanganiIA, RasheedSA, NikolovaD, et al.MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene, 2008; 27(15):2128–2136.
24.
FrankelLB, ChristoffersenNR, JacobsenA, et al.Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem, 2008; 283(2):1026–1033.
25.
HouL, BowmanL, MeighanTG, et al.Induction of miR-21-PDCD4 signaling by UVB in JB6 cells involves ROS-mediated MAPK pathways. Exp Toxicol Pathol, 2013; 65(7–8):1145–1148.
26.
HouL, BowmanL, MeighanTG, et al.Induction of miR-21-PDCD4 signaling by tungsten carbide-cobalt nanoparticles in JB6 cells involves ROS-mediated MAPK pathways. J Environ Pathol Toxicol Oncol, 2013; 32(1):41–51.
27.
DalalN, ShiX, VallyathanV. Role of free radicals in the mechanisms of hemolysis and lipid peroxidation by silica: Comparative ESR and cytotoxicity studies. J Toxicol Environ Health, 1990; 29(3):307–316.
28.
MagayeR, ZhouQ, BowmanL, et al.Metallic nickel nanoparticles may exhibit higher carcinogenic potential than fine particles in JB6 cells. PLoS One, 2014; 9(4):e92418.
29.
FengR, LuY, BowmanLL, et al.Inhibition of activator protein-1, NF-κB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid. J Biol Chem, 2005; 280(30):27888–27895.
30.
DingM, HuangC, LuY, et al.Involvement of protein kinase C in crystalline silica-induced activation of the MAP kinase and AP-1 pathway. Am J Physiol Lung Cell Mol Physiol, 2006; 290(2):L291–L297.
31.
AllgayerH. Pdcd4, a colon cancer prognostic that is regulated by a microRNA. Crit Rev Oncol Hematol, 2010; 73(3):185–191.
32.
WagnerMM, WagnerJ. Lymphomas in the Wistar rat after intrapleural inoculation of silica. J Natl Cancer Inst, 1972; 49(1):81–91.
33.
SaffiottiU, WilliamsA, DanielL, et al.Carcinogenesis by crystalline silica: animal, cellular, and molecular studies. Silica and Silica-induced Lung Diseases. CRC Press: Boca Raton, FL, 1996, pp.345–381.
34.
DanielLN, MaoY, WilliamsAO, et al.Direct interaction between crystalline silica and DNA—a proposed model for silica carcinogenesis. Scand J Work Environ Health, 1995; 21(Suppl 2):22–26.
35.
BernsteinLR, Ben-AriET, SimekSL, et al.Gene regulation and genetic susceptibility to neoplastic transformation: AP-1 and p80 expression in JB6 cells. Environ Health Perspect, 1991; 93:111–119.
DharA, YoungMR, ColburnNH. The role of AP-1, NF-κB and ROS/NOS in skin carcinogenesis: The JB6 model is predictive. Mol Cell Biochem, 2002; 234–235(1–2):185–193.
38.
NakamuraY, GindhartTD, WintersteinD, et al.Early superoxide dismutase-sensitive event promotes neoplastic transformation in mouse epidermal JB6 cells. Carcinogenesis, 1988; 9(2):203–207.
39.
AchanzarWE, BrambilaEM, DiwanBA, et al.Inorganic arsenite-induced malignant transformation of human prostate epithelial cells. J Natl Cancer Inst, 2002; 94(24):1888–1891.
40.
TokarEJ, QuW, LiuJ, et al.Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst, 2010; 102(9):638–649.
41.
DongZ, BirrerMJ, WattsRG, et al.Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc Natl Acad Sci U S A, 1994; 91(2):609–613.
42.
DongZ, HuangC, BrownRE, et al.Inhibition of activator protein 1 activity and neoplastic transformation by aspirin. J Biol Chem, 1997; 272(15):9962–9970.
43.
HuangC, MaW-Y, HanenbergerD, et al.Inhibition of ultraviolet B-induced activator protein-1 (AP-1) activity by aspirin in AP-1-luciferase transgenic mice. J Biol Chem, 1997; 272(42):26325–26331.
44.
HalliwellB. Oxidative stress and cancer: Have we moved forward? Biochem J, 2007; 401(1):1–11.
45.
CrosbyL, HyderK, DeAngeloA, et al.Morphologic analysis correlates with gene expression changes in cultured F344 rat mesothelial cells. Toxicol Appl Pharmacol, 2000; 169(3):205–221.
46.
ChengY, LiuX, ZhangS, et al.MicroRNA-21 protects against the H2O2-induced injury on cardiac myocytes via its target gene PDCD4. J Mol Cell Cardiol, 2009; 47(1):5–14.
47.
LinY, LiuX, ChengY, et al.Involvement of MicroRNAs in hydrogen peroxide-mediated gene regulation and cellular injury response in vascular smooth muscle cells. J Biol Chem, 2009; 284(12):7903–7913.
48.
DavidsonLA, WangN, ShahMS, et al.n-3 Polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis, 2009; 30(12):2077–2084.
49.
MelkamuT, ZhangX, TanJ, et al.Alteration of microRNA expression in vinyl carbamate-induced mouse lung tumors and modulation by the chemopreventive agent indole-3-carbinol. Carcinogenesis, 2010; 31(2):252–258.
50.
ShenY-L, JiangY-G, GreenleeAR, et al.MicroRNA expression profiles and miR-10a target in anti-benzo [a] pyrene-7, 8-diol-9, 10-epoxide-transformed human 16HBE cells. Biomed Environ Sci, 2009; 22(1):14–21.
51.
GarzonR, CalinGA, CroceCM. MicroRNAs in cancer. Annu Rev Med, 2009; 60:167–179.
52.
KrichevskyAM, GabrielyG. miR‐21: A small multi‐faceted RNA. J Cell Mol Med, 2009; 13(1):39–53.
53.
YuT, WangX-y, GongR-G, et al.The expression profile of microRNAs in a model of 7, 12-dimethyl-benz [a] anthrance-induced oral carcinogenesis in Syrian hamster. J Exp Clin Cancer Res, 2009; 28(1):1–10.
54.
JansenAP, CamalierCE, ColburnNH. Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res, 2005; 65(14):6034–6041.
55.
ArnoldRS, ShiJ, MuradE, et al.Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1. Proc Natl Acad Sci U S A, 2001; 98(10):5550–5555.
56.
KalscheuerS, ZhangX, ZengY, et al.Differential expression of microRNAs in early-stage neoplastic transformation in the lungs of F344 rats chronically treated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis, 2008; 29(12):2394–2399.
57.
KumamotoK, SpillareEA, FujitaK, et al.Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res, 2008; 68(9):3193–3203.
58.
PogribnyIP, TryndyakVP, BoykoA, et al.Induction of microRNAome deregulation in rat liver by long-term tamoxifen exposure. Mutat Res, 2007; 619(1–2):30–37.
59.
HaganJ, CroceC. MicroRNAs in carcinogenesis. Cytogenet Genome Res, 2007; 118(2–4):252–259.
60.
InoueK-I, TakanoH, YanagisawaR, et al.Effects of airway exposure to nanoparticles on lung inflammation induced by bacterial endotoxin in mice. Environ Health Perspect, 2006; 114(9):1325–1330.
