Table 2 Toxicologically relevant metals-induced EMT marker alterations

Promotes EMT

AS

• HBE cells

• 2.5 μM of NaAsO₂ for 16 weeks

–

AS decreases the level of E-cadherin; increases the level of vimentin and ZEB1/ZEB2

[21]

• HBE cells

• 1.0 μM NaAsO₂ for 15 weeks

AS activates HIF-2α-dependent transcriptional activity

AS decreases the level of E-cadherin; increases the level of vimentin, ZEB1/ZEB2, and twist

[22]

• HBE cells

• 1.0 μM NaAsO₂

AS induces up-regulation of

miR-21

AS upregulates the expression of twist

[23]

• HaCaT cells

• 1.0 μM NaAsO₂

AS activates NF-κB signal pathway

AS decreases the level of E-cadherin; increases the level of vimentin and SNAI1

[24]

• HaCaT cells

• 1.0 μM NaAsO₂

AS enhances miR-21 levels by IL-6 activation of the STAT3 signal pathway

AS decreases the level of E-cadherin; increases the level of vimentin

[25]

• HaCaT cells

• 1.0 μM NaAsO₂ for 0, 10, 20, 30, or 40 passages

–

AS induces down-regulation of E-cadherin and up-regulation of vimentin, ZEB1, twist, and SNAI1

[26]

• HaCaT cells

• 1.0 μM NaAsO₂ for 0, 10, 20, 30, or 40 passages

AS increases miR-21 and decreases PTEN levels, which then activates AKT signaling

AS decreases the level of E-cadherin; increases the level of vimentin

[27]

• HBE cells

• 1.0 μM NaAsO₂ for 0, 10, 20, or 30 passages

AS induces secretion of IL-6 and activates STAT3 signaling, which upregulates miR-21

AS decreases the level of E-cadherin; increases the level of N-cadherin and vimentin

[28]

• HBE cells

• 2.5 μM of NaAsO₂ for 16 weeks

–

AS decreases the level of E-cadherin; increases the level of vimentin

[29]

• BEAS-2B cells

• Chronic treatment: 0.25 µM NaAsO₂ for 16 weeks; acute treatment: 2.5 µM for 48 h

AS induces EMT likely via activation the MEK/ERK1/2 signaling

AS decreases the expression of E-cadherin; increases the expression of vimentin, ZEB1, and SNAI1

[30]

• BEAS-2B cells

• Chronic treatment: 0.25 μM As₂O₃ for 10 and 20 weeks; acute treatment: 5 μM As₂O₃ for 0, 6, 12, and 24 h

–

AS decreases the expression of E-cadherin; increases the expression of vimentin, ZEB1, MMP-3, MMP-9, and β-catenin

[31]

• L-02 cells

• 2.0 μM NaAsO₂ for 0−30 passages

–

AS decreases the expression of E-cadherin; increases the expression of N-cadherin and α-SMA

[33]

• L-02 cells

• 2.0 μM NaAsO₂ for 0−30 passages

–

AS decreases the expression of E-cadherin; increases the expression of SNAI1and vimentin

[34]

• HPL-1D cells

• 2 µM NaAsO₂ for 38 weeks

AS increases the expressions of KRAS, ERK1/2, p-ERK, and AKT1

AS decreases the expression of E-cadherin; increases the expression of vimentin and MMP2

[35]

• SV-HUC-1 cells

• 0.5 μM NaAsO₂ for 40 weeks

AS increases the expression of HER2, which induces EMT via MAPK, AKT, and Src/STAT3 signaling pathways

AS decreases the expression of E-cadherin; increases the expression of vimentin and SNAI1

[36]

• HK-2 cells

• 100 pg/mL and 10 ng/ mL NaAsO₂ for 72 h for acute treatment, 2 months for chronic treatment

–

AS increases the expression of N-cadherin and vimentin

[38]

• Caco2 and HCT116 cells

• 1 and 0.1 µM of NaAsO₂ for short-term (36 h) and long-term (20 days) treatment

–

AS decreases the expression of E-cadherin; increases the expression of N-cadherin, FIB1, and vimentin

[39]

• NHEK/SVTERT3‑5 cells

• 0.05, 0.1, and 0.25 µM of ATO for short-term treatment (72 h) and chronic exposure (6 months)

–

AS decreases the expression of keratin-14, ZO-1, and E-cadherin; increases the expression of TCF8/ZEB1 and SNAI2

[40]

• HeLa cells

• 0.5 µM NaAsO₂ for about 45 days

–

AS decreases the expression of β-catenin, claudin-1, claudin-3, and ZO-1; increases the expression of SNAI1, SNAI2, and vimentin

[41]

Cd

• Female ApoE knockout mice

• 100 mg/L of CdCl₂ drinking water for 12 weeks

Cd induces transcriptional activation of the Wnt pathway

Cd increases the expression of collagen I, fibronectin and twist

[61]

• Caki-1, 786-O, and 769-P cells

• 0.1 and 0.5 μM CdCl₂ for 24 h

Cd activates the cAMP/PKA-COX2 signaling

Cd decreases the expression of E-cadherin, increases the expressions of N-cadherin and vimentin

[59]

• A549 and BEAS-2B cells

• 10 or 20 μM CdCl₂ for 9−15 weeks

Cd activates Notch1 signaling, which then activates HIF-1α and IGF-1R/AKT/ERK/S6K1 signaling pathways

Cd decreases the expression of E-cadherin; increases the expression of N-cadherin and vimentin

[60]

• BEAS-2B and BEP2D cells

• 0, 2.5, 5, and 10 μM CdCl₂ for 72 h

Cd downregulates miR-30 family miRNAs

Cd decreases the expression of E-cadherin and increases the expressions of ZEB1 and vimentin

[55]

• BEAS-2B cells

• 5−10 μM of CdCl₂ for 48 h

–

Cd decreases the expression of E-cadherin, EPCAM, and KRT7; increases the expression of N-cadherin, integrin β1/β3, vimentin, and S100A11

[53]

• MCF10A and hTERT-HPNE cells

• MCF10A: 2.5 µM CdCl₂ for 40 weeks; hTERT-HPNE: 1 µM CdCl₂ for 30 weeks

–

Cd decreases the expression of E-cadherin and increases the expressions of N-cadherin and vimentin

[56]

• MCF10A, MDA-MB-231, HCC 1937 and HCC 38 cells

• 1 or 3 μM CdCl₂ for 4 weeks

–

Cd decreases the expression of E-cadherin and claudin-1 and increases the expressions of N-cadherin and vimentin

[57]

• Triple-negative MDA-MB-231 cells

• 1−3 μM CdCl₂ for short-term treatment (24 h) and long-term treatment (8 weeks)

–

Cd decreases the expression of E-cadherin; increases the expression of N-cadherin, twist, and SNAI2

[58]

Co

• MiaPaCa2 cells

• 0.08 mM CoCl₂ for 24 h

Co induces the expression of HIF-1α, activates Notch1 signal

Co decreases the expression of E-cadherin; increases the expression of N-cadherin and SNAI1

[66]

• MCF7 and MDA-MB-231cells

• 200 µmol/L CoCl₂ for 24, 48, and 72 h

–

Co decreases the expression of E-cadherin; increases the expression of vimentin, MMP2, and MMP9

[70]

• MCF7 and MDA-MB-231cells

• 300 or 450 µM CoCl₂ for 72 h

–

Co decreases the expression of E-cadherin; increases the expression of N-cadherin and vimentin

[71]

• TE-1 and EC-1 cells

• 100 µmol/L CoCl₂ for 12 or 24 h

Co activates STAT3 and upregulates the expression of HIF-1α

Co decreases the expression of E-cadherin; increases the expression of N-cadherin and vimentin

[67]

• HepG2 cells

• 200 µmol/L CoCl₂ for 12 or 24 h

Co increased HIF-1α and COX-2 expression

Co decreases the expression of E-cadherin; increases the expression of SNAI1and vimentin

[68]

• A549 and PC9 cells

• 100 µmol/L CoCl₂ for 24−48 h

Co increases Netrin-1 expression and activates the PI3K/AKT pathway

Co decreases the expression of E-cadherin; increases the expression of vimentin

[69]

• M139 and M214 cells

• 100 μM CoCl₂ for 16 or 36 h

–

Co decreases the expression of E-cadherin; increases the expression of N-cadherin

[73]

• LO2 cells

•100 μM CoCl₂ for 24 or 72 h

Co activates TGF-β/Smad signaling

Co decreases the expression of E-cadherin; increases the expression of α-SMA, vimentin, N-cadherin, fibronectin, and SNAI1

[74]

• SRA01/04 cells

• 150 μM CoCl₂

Co induces the expression of HIF-1α and Notch1

Co decreases the expression of E-cadherin; increases the expression of SNAI1

[75]

Cr

• 121 prostate tumor serum samples; six-week-old immunodeficient (BALB/c nude) male mice; PC3 cells

• Mice: given water containing K₂CrO₄ (5 μg/mL) for 14 days; cells: 0.4 µM K₂CrO₄ for 48 h

–

Cr (VI) decreases the expression of E-cadherin; increases the expression of N-cadherin and SNAI1

[80]

• BEAS-2B, CrTF1, CrTF2, and A549 cells

• 0.5 μM K₂Cr₂O₇ for 3–10 weeks

–

Cr (VI) decreases the expression of E-cadherin; increases the expression of vimentin

[81]

• HK-2 cells

• 0−2 μM K₂Cr₂O₇ for 1−72 h

–

Cr (VI) increases the expression of paxillin, vimentin, and α-SMA

[82]

Ni

• Eight-week-old female immunodeficient nude mice; BEAS-2B and A549 cells

• Mice: 0, 20 or 100 mg NiCl₂/kg/day by oral gavage for 60 days; cells: 0, 0.25, 0.5 mM and 0, 0.5, 1 mM NiCl₂ respectively for 48 h;

Ni increases miR-4417 expression

Ni decreases the expression of E-cadherin; increases the expression of fibronectin

[86]

• BEAS-2B cells

• Chronic treatment:100 μM NiCl₂ for 6 weeks; acute treatment: 500 μM NiCl₂ for 72 h

Ni suppresses the expression of ZEB1’s repressors miR-200/205

Ni decreases the expression of E-cadherin and claudin 1; increases the expression of fibronectin1 and ZEB1

[87]

Cu

• 240 ICR mice

• Mice: 10, 20, or 40 mg CuSO₄/kg by intragastric administration

Cu activates TGF-β1/Smad pathway and MAPKs pathways

Cu decreases the expression of E-cadherin; increases the expression of twist and vimentin

[93]

Inhibits EMT

AS

• Immortalized epicardial cells

• 1.34 μM As₄S₄ or 0.134 μM MMA (III) for 24 h or 48 h

AS and MMA (III) block Smad2/3, Erk1/2, and Erk5 phosphorylation

AS increases the expression of E-cadherin; decreases TGFβ2, TβRIII, SNAI1, and MMP2

[47]

• Mca-Rh7777 cells

• 2 μM ATO for 24 or 48 h

–

ATO increases the expression of E-cadherin; decreases E-cadherin, vimentin, and twist

[44]

• SW1353, OUMS-27, and HCS-2/8 cells

• 1.5 μM ATO for 48 h

ATO upregulates the expression of miR-125b

ATO increases the expression of E-cadherin; decreases the expression of N-cadherin, vimentin, and SNAI2

[45]

• SMMC-7721, Huh7, MHCC97H, HCCLM3, and L02 cells

• 2 μM ATO

–

ATO increases the expression of E-cadherin; decreases the expression of N-cadherin and vimentin

[46]

• AGS cells

• 5 or 10 μM ATO for 48 h

ATO induces SHP-1 expression and attenuates p-JAK2/ p-STAT3

ATO increases the expression of E-cadherin; decreases the expression of SNAI1

[43]

• Immortalized murine epicardial cells

• 1.34 − 6.7 μM NaAsO₂ for 18 h

AS blocks the canonical TGFβ signaling

AS decreases the expression of TGFβ2, TBRIII, SNAI1, and Has2

[48]

Cd

• Adult mammary stem cells

• 0.25 and 2.5 μM CdCl₂ for 7–10 days

–

Cd decreases the expression of ZEB1, vimentin, and TGFBI

[62]

Cu

• 7−8-week-old male BALB/c nude mice; Hep3B and HepG2 cells

• Mice: 9.6 mg/kg Copper (II) D-gluconate by injection into the right flank twice a week for 29 days; cells: 0.1 μM Cu

Cu down-regulates NF-κB and TGF-β signaling

Cu decreases the expression of MMP2 and SNAI2; increases the expression of E-cadherin

[96]