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miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma

Luo, Meiying, Wu, Longfei, Zhang, Kexin, Wang, Hong, Zhang, Tian, Gutierrez, Lucas, O’Connell, Douglas, Zhang, Peng, Li, Yu, Gao, Tongtong, Ren, Wenyan, Yang, Yongfei·2018·Cell Death & Differentiation
DOI 10.1038/s41418-017-0053-8PMC PMC6113319
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Fig. 1 miR-137 negatively regulates ferroptosis in melanoma. a The A375 and G-361 human melanoma cells were treated with erastin (2.5–40 µM) or RSL3 (0.1–10 µM) with or without a cell death inhibitor (ferrostatin-1, 1 µM; ZVAD-FMK, 10 µM; necrosulfonamide, 0.5 µM) for 24 h. Cell death was assayed using a CCK-8 kit. Data shown represent mean ± SD from three independent experiments. ****p < 0.0001. b Overexpression of miR-137 suppressed erastin- and RSL3-induced cell death in human melanoma cells. Indicated cells were treated with erastin (2.5–40 µM) or RSL3 (0.1–10 µM) for 24 h. Cell death was assayed using a CCK-8 kit. Data shown represent mean ± SD from three independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001. c Inhibition of endogenous miR-137 enhanced erastin- and RSL3-induced cell death in human melanoma cells. Indicated cells were treated with erastin (2.5–40 µM) or RSL3 (0.1–10 µM) for 24 h. Cell death was assayed using a CCK-8 kit. Data shown represent mean ± SD from three independent experiments. *p < 0.05; **p < 0.01. d Quantitative RT-PCR showing the relative expression levels of miR-137 in b. Data are mean ± SD from three independent experiments. ***p < 0.001. e Quantitative RT-PCR showing the relative expression levels of miR-137 in d. Data are mean ± SD from three independent experiments. ***p < 0.001
Fig. 1 miR-137 negatively regulates ferroptosis in melanoma. a The A375 and G-361 human melanoma cells were treated with erastin (2.5–40 µM) or RSL3 (0.1–10 µM) with or without a cell death inhibitor (ferrostatin-1, 1 µM; ZVAD-FMK, 10 µM; necrosulfonamide, 0.5 µM) for 24 h. Cell death was assayed using a CCK-8 kit. Data shown represent mean ± SD from three independent experiments. ****p < 0.0001. b Overexpression of miR-137 suppressed erastin- and RSL3-induced cell death in human melanoma cells. Indicated cells were treated with erastin (2.5–40 µM) or RSL3 (0.1–10 µM) for 24 h. Cell death was assayed using a CCK-8 kit. Data shown represent mean ± SD from three independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001. c Inhibition of endogenous miR-137 enhanced erastin- and RSL3-induced cell death in human melanoma cells. Indicated cells were treated with erastin (2.5–40 µM) or RSL3 (0.1–10 µM) for 24 h. Cell death was assayed using a CCK-8 kit. Data shown represent mean ± SD from three independent experiments. *p < 0.05; **p < 0.01. d Quantitative RT-PCR showing the relative expression levels of miR-137 in b. Data are mean ± SD from three independent experiments. ***p < 0.001. e Quantitative RT-PCR showing the relative expression levels of miR-137 in d. Data are mean ± SD from three independent experiments. ***p < 0.001CC BY-NC-SA · PubMed Central
Fig. 2 miR-137 regulates the lipid metabolism of melanoma cells. a miR-137 overexpression significantly suppressed the erastin- and RSL3-induced lipid formation. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. The lipid formation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. **p < 0.01. b miR-137 antagomirs significantly increased the erastin- and RSL3-induced lipid formation. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. The lipid formation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. **p < 0.01. c Overexpression of miR-137 significantly suppressed erastin- and RSL3-induced lipid ROS level as assessed by flow cytometry using C11-BODIPY. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. d Cells transfected with miR-137 antagomirs showed increased lipid ROS level as assessed by BODIPY-C11 staining. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. e, f The expression levels of miR-137 influences the Fe2+ accumulation in erastin or RSL3-treated A375 and G-361 cells. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h and the intracellular Fe2+ was assayed. Data shown represent mean ± SD from three independent experiments. *p < 0.05
Fig. 2 miR-137 regulates the lipid metabolism of melanoma cells. a miR-137 overexpression significantly suppressed the erastin- and RSL3-induced lipid formation. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. The lipid formation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. **p < 0.01. b miR-137 antagomirs significantly increased the erastin- and RSL3-induced lipid formation. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. The lipid formation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. **p < 0.01. c Overexpression of miR-137 significantly suppressed erastin- and RSL3-induced lipid ROS level as assessed by flow cytometry using C11-BODIPY. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. d Cells transfected with miR-137 antagomirs showed increased lipid ROS level as assessed by BODIPY-C11 staining. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. e, f The expression levels of miR-137 influences the Fe2+ accumulation in erastin or RSL3-treated A375 and G-361 cells. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h and the intracellular Fe2+ was assayed. Data shown represent mean ± SD from three independent experiments. *p < 0.05CC BY-NC-SA · PubMed Central
Fig. 3 Glutaminolysis mediates miR-137-induced ferroptosis inhibition. a Schematic overview of the glutaminolysis pathway in ferroptosis. Glutamine (Gln) is transferred into cell cytoplasm by importers SLC1A5/SLC38A1, and subsequently converted to glutamate (Glu) by glutaminase GLS2 in mitochondria. The aspartate transaminase GOT1 ultimately converts Glu to a-ketoglutarate (a-KG), which contributes to ROS accumulation by an unknown mechanism. The small-molecule inhibitors are indicated in red: L-Gln transporter inhibitor GPNA; GLS inhibitor Compound 968; Pan-transaminases inhibitor AOA. b Pharmacological inhibition of multiple components in the glutaminolysis pathway abrogated anti-miR-137-mediated ferroptosis cell death and lipid accumulation. Cells transfected with control or miR-137 antagomirs were treated with erastin (5 µM) and GPNA (5 mM)/compound 968 (20 µM)/AOA (0.5 mM) for 24 h. The cell viability was assayed using a CCK-8 kit and the lipid accumulation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. n.s. nonsignificant; **p < 0.01. c Knockdown of Gln importers or metabolic enzymes blocked anti-miR-137-mediated ferroptosis cell death and lipid accumulation. Cells stably expressing control shRNA or indicated shRNA targeting metabolic enzymes were transfected with control or miR-137 antagomir, and then treated with erastin (5 µM) for 24 h. The cell viability was assayed using a CCK-8 kit and the lipid accumulation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. **p < 0.01. d The knockdown efficiency of three shRNA constructs targeting SLC1A5, GLS2 and GOT1 were detected by western blot. e The knockdown efficiency of shRNA construct targeting SLC38A1 was measured by real-time RT-PCR. Data shown represent mean ± SD from three independent experiments. ***p < 0.001.
Fig. 3 Glutaminolysis mediates miR-137-induced ferroptosis inhibition. a Schematic overview of the glutaminolysis pathway in ferroptosis. Glutamine (Gln) is transferred into cell cytoplasm by importers SLC1A5/SLC38A1, and subsequently converted to glutamate (Glu) by glutaminase GLS2 in mitochondria. The aspartate transaminase GOT1 ultimately converts Glu to a-ketoglutarate (a-KG), which contributes to ROS accumulation by an unknown mechanism. The small-molecule inhibitors are indicated in red: L-Gln transporter inhibitor GPNA; GLS inhibitor Compound 968; Pan-transaminases inhibitor AOA. b Pharmacological inhibition of multiple components in the glutaminolysis pathway abrogated anti-miR-137-mediated ferroptosis cell death and lipid accumulation. Cells transfected with control or miR-137 antagomirs were treated with erastin (5 µM) and GPNA (5 mM)/compound 968 (20 µM)/AOA (0.5 mM) for 24 h. The cell viability was assayed using a CCK-8 kit and the lipid accumulation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. n.s. nonsignificant; **p < 0.01. c Knockdown of Gln importers or metabolic enzymes blocked anti-miR-137-mediated ferroptosis cell death and lipid accumulation. Cells stably expressing control shRNA or indicated shRNA targeting metabolic enzymes were transfected with control or miR-137 antagomir, and then treated with erastin (5 µM) for 24 h. The cell viability was assayed using a CCK-8 kit and the lipid accumulation was measured by MDA assay. Data shown represent mean ± SD from three independent experiments. **p < 0.01. d The knockdown efficiency of three shRNA constructs targeting SLC1A5, GLS2 and GOT1 were detected by western blot. e The knockdown efficiency of shRNA construct targeting SLC38A1 was measured by real-time RT-PCR. Data shown represent mean ± SD from three independent experiments. ***p < 0.001.CC BY-NC-SA · PubMed Central
Fig. 4 miR-137 directly targets SLC1A5 in melanoma cells. a Sequence alignment of miR-137 and the 3′-UTR of SLC1A5 or SLC38A1. The seed sequence of miR-137 and the binding sites in 3′-UTR are indicated in red. The 3′-UTR mutants containing mismatched nucleotides are shown at the bottom. The binding site of SLC1A5 is highly conserved in several species (left), but the binding site of SLC38A1 is not conserved between different species (right). b miR-137 overexpression inhibited the expression of 3′-UTR-luciferase reporter of SLC1A5 in A375 and G-361 cells, but the mutant construct was immune to miR-137. Data are mean ± SD from three independent experiments. ***p < 0.001; n.s. not significant. c miR-137 overexpression has no effect on the expression of 3′-UTR-luciferase reporter of SLC38A1 in A375 and G-361 cells. d miR-137 regulates the mRNA level of SLC1A5 in A375 and G-361 cells. The mRNA levels were measured by quantitative RT-PCR, data are mean ± SD from three independent experiments. **p < 0.01. e The protein levels of SLC1A5 were modulated by miR-137 in A375 and G-361 cells. Cells transfected with indicated constructs or antagomirs were collected, and the protein level of SLC1A5 was detected by western blot. Actin was used as a loading control. f Quantitative analysis of the experiments in (e). Data are mean ± SD from three independent experiments. **p < 0.01, ***p < 0.001. g miR-137 overexpression significantly suppressed the [3H]-l-glutamine uptake in A375 and G-361 cells. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. Data shown represent mean ± SD from three independent experiments. ***p < 0.001. h Inhibition of endogenous miR-137 showed increased [3H]-L-glutamine uptake in A375 and G-361 cells. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. Data shown represent mean ± SD from three independent experiments. **p < 0.01
Fig. 4 miR-137 directly targets SLC1A5 in melanoma cells. a Sequence alignment of miR-137 and the 3′-UTR of SLC1A5 or SLC38A1. The seed sequence of miR-137 and the binding sites in 3′-UTR are indicated in red. The 3′-UTR mutants containing mismatched nucleotides are shown at the bottom. The binding site of SLC1A5 is highly conserved in several species (left), but the binding site of SLC38A1 is not conserved between different species (right). b miR-137 overexpression inhibited the expression of 3′-UTR-luciferase reporter of SLC1A5 in A375 and G-361 cells, but the mutant construct was immune to miR-137. Data are mean ± SD from three independent experiments. ***p < 0.001; n.s. not significant. c miR-137 overexpression has no effect on the expression of 3′-UTR-luciferase reporter of SLC38A1 in A375 and G-361 cells. d miR-137 regulates the mRNA level of SLC1A5 in A375 and G-361 cells. The mRNA levels were measured by quantitative RT-PCR, data are mean ± SD from three independent experiments. **p < 0.01. e The protein levels of SLC1A5 were modulated by miR-137 in A375 and G-361 cells. Cells transfected with indicated constructs or antagomirs were collected, and the protein level of SLC1A5 was detected by western blot. Actin was used as a loading control. f Quantitative analysis of the experiments in (e). Data are mean ± SD from three independent experiments. **p < 0.01, ***p < 0.001. g miR-137 overexpression significantly suppressed the [3H]-l-glutamine uptake in A375 and G-361 cells. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. Data shown represent mean ± SD from three independent experiments. ***p < 0.001. h Inhibition of endogenous miR-137 showed increased [3H]-L-glutamine uptake in A375 and G-361 cells. Indicated cells were treated with erastin (5 µM in A375, 10 µM in G-361) or RSL3 (0.1 µM in A375, 0.5 µM in G-361) for 24 h. Data shown represent mean ± SD from three independent experiments. **p < 0.01CC BY-NC-SA · PubMed Central
Fig. 5 Overexpression of SLC1A5 rescued miR-137-mediated ferroptosis inhibition. a, b, c Cell viability a, intracellular MDA levels b, and [3H]-L-glutamine uptake c of indicated cells were measured. A375 cells were transfected with indicated constructs and treated with erastin (5 µM) or RSL3 (0.1 µM). The concentration of GPNA is 5 mM. Data are mean ± SD from three independent experiments. **p < 0.01, ***p < 0.001, ****p < 0.0001. d Lipid ROS levels of indicated cells were measured by flow cytometry using C11-BODIPY. A375 cells were transfected with indicated constructs and treated with erastin (5 µM) or RSL3 (0.1 µM). e Immunoblot analysis of SLC1A5 in A375 cells following indicated transfections and treatments. Actin was used as a loading control. f, g, h Cell viability f, intracellular MDA levels g and [3H]-l-glutamine uptake h of indicated cells were measured. G-361 cells were transfected with indicated constructs and treated with erastin (10 µM) or RSL3 (0.5 µM). The concentration of GPNA is 5 mM. Data are mean ± SD from three independent experiments. **p < 0.01, ***p < 0.001, ****p < 0.0001. i Lipid ROS levels of indicated cells were measured by flow cytometry using C11-BODIPY. G-361 cells were transfected with indicated constructs and treated with erastin (10 µM) or RSL3 (0.5 µM). j Immunoblot analysis of SLC1A5 in G-361 cells following indicated transfections and treatments. Actin was used as a loading control
Fig. 5 Overexpression of SLC1A5 rescued miR-137-mediated ferroptosis inhibition. a, b, c Cell viability a, intracellular MDA levels b, and [3H]-L-glutamine uptake c of indicated cells were measured. A375 cells were transfected with indicated constructs and treated with erastin (5 µM) or RSL3 (0.1 µM). The concentration of GPNA is 5 mM. Data are mean ± SD from three independent experiments. **p < 0.01, ***p < 0.001, ****p < 0.0001. d Lipid ROS levels of indicated cells were measured by flow cytometry using C11-BODIPY. A375 cells were transfected with indicated constructs and treated with erastin (5 µM) or RSL3 (0.1 µM). e Immunoblot analysis of SLC1A5 in A375 cells following indicated transfections and treatments. Actin was used as a loading control. f, g, h Cell viability f, intracellular MDA levels g and [3H]-l-glutamine uptake h of indicated cells were measured. G-361 cells were transfected with indicated constructs and treated with erastin (10 µM) or RSL3 (0.5 µM). The concentration of GPNA is 5 mM. Data are mean ± SD from three independent experiments. **p < 0.01, ***p < 0.001, ****p < 0.0001. i Lipid ROS levels of indicated cells were measured by flow cytometry using C11-BODIPY. G-361 cells were transfected with indicated constructs and treated with erastin (10 µM) or RSL3 (0.5 µM). j Immunoblot analysis of SLC1A5 in G-361 cells following indicated transfections and treatments. Actin was used as a loading controlCC BY-NC-SA · PubMed Central
Fig. 6 miR-137-mediated ferroptosis inhibition was rescued by a-KG but not glutamine. a L-Gln induces cell death in erastin or RSL3-treated A375 cells in a dose-dependent manner. Overexpression of miR-137 blocked the cell death-inducing activity of L-Gln. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h, and the cell viability was assayed using a CCK-8 kit. The concentrations of L-Gln were 0.02, 0.1 and 0.5 mM. Data are mean ± SD from three independent experiments. n.s. not significant; *p < 0.05. b The intercellular MDA levels of erastin or RSL3-treated A375 cells were induced by L-Gln in a dose-dependent manner, which were blocked by the overexpression of miR-137. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h. The concentrations of L-Gln were 0.02, 0.1 and 0.5 mM. Data are mean ± SD from three independent experiments. *p < 0.05. c a-KG induces cell death in both control and miR-137-overexpressing A375 cells in a dose-dependent manner. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h. The concentrations of a-KG were 0.5, 1 and 2 mM. Data are mean ± SD from three independent experiments. **p < 0.01. d The intercellular MDA levels in both control and miR-137-overexpressing A375 cells were induced by a-KG in a dose-dependent manner. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h. The concentrations of a-KG were 0.5, 1 and 2 mM. Data are mean ± SD from three independent experiments. **p < 0.01
Fig. 6 miR-137-mediated ferroptosis inhibition was rescued by a-KG but not glutamine. a L-Gln induces cell death in erastin or RSL3-treated A375 cells in a dose-dependent manner. Overexpression of miR-137 blocked the cell death-inducing activity of L-Gln. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h, and the cell viability was assayed using a CCK-8 kit. The concentrations of L-Gln were 0.02, 0.1 and 0.5 mM. Data are mean ± SD from three independent experiments. n.s. not significant; *p < 0.05. b The intercellular MDA levels of erastin or RSL3-treated A375 cells were induced by L-Gln in a dose-dependent manner, which were blocked by the overexpression of miR-137. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h. The concentrations of L-Gln were 0.02, 0.1 and 0.5 mM. Data are mean ± SD from three independent experiments. *p < 0.05. c a-KG induces cell death in both control and miR-137-overexpressing A375 cells in a dose-dependent manner. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h. The concentrations of a-KG were 0.5, 1 and 2 mM. Data are mean ± SD from three independent experiments. **p < 0.01. d The intercellular MDA levels in both control and miR-137-overexpressing A375 cells were induced by a-KG in a dose-dependent manner. Indicated cells were treated with erastin (5 µM) or RSL3 (0.1 µM) for 24 h. The concentrations of a-KG were 0.5, 1 and 2 mM. Data are mean ± SD from three independent experiments. **p < 0.01CC BY-NC-SA · PubMed Central
Fig. 7 Inhibition of miR-137 enhances the ferroptosis activity in vivo. a Colony formation assay of the indicated A375 cell lines. Cells were treated with erastin (5 µM) for 24 h, and were grown without erastin for 14 days. For each cell line, all dishes were fixed, stained, and photographed at the same time. Data are mean ± SD from three independent experiments. **p < 0.01. b Quantitative RT-PCR showing the relative expression levels of SLC1A5 in indicated A375 cells in a. Data are mean ± SD from three independent experiments. **p < 0.01. c Colony formation assay of the indicated G-361 cell lines. Cells were treated with erastin (10 µM) for 24 h, and were grown without erastin for 14 days. For each cell line, all dishes were fixed, stained, and photographed at the same time. Data are mean ± SD from three independent experiments. **p < 0.01. d Quantitative RT-PCR showing the relative expression levels of SLC1A5 in indicated G-361 cells in c. Data are mean ± SD from three independent experiments. **p < 0.01. e, f Suppression of miR-137 enhances erastin-induced ferroptosis in vivo. C57BL/6 mice were injected subcutaneously with indicated A375 cells e or G-361 cells f (1 × 106 cells per mouse) and treated with erastin (15 mg/kg intraperitoneally, twice every other day) when the tumor volume reached 50 mm3. Tumor volume was calculated every 4 days. Data represent mean ± SD (n = 5–6 mice per group). Significance was determined by one-sided Mann–Whitney U-test, *p < 0.05. g Schematic depicting miR-137-mediated ferroptosis in melanoma cells. miR-137 suppresses erastin-induced ferroptosis by directly targeting Gln importer SLC1A5
Fig. 7 Inhibition of miR-137 enhances the ferroptosis activity in vivo. a Colony formation assay of the indicated A375 cell lines. Cells were treated with erastin (5 µM) for 24 h, and were grown without erastin for 14 days. For each cell line, all dishes were fixed, stained, and photographed at the same time. Data are mean ± SD from three independent experiments. **p < 0.01. b Quantitative RT-PCR showing the relative expression levels of SLC1A5 in indicated A375 cells in a. Data are mean ± SD from three independent experiments. **p < 0.01. c Colony formation assay of the indicated G-361 cell lines. Cells were treated with erastin (10 µM) for 24 h, and were grown without erastin for 14 days. For each cell line, all dishes were fixed, stained, and photographed at the same time. Data are mean ± SD from three independent experiments. **p < 0.01. d Quantitative RT-PCR showing the relative expression levels of SLC1A5 in indicated G-361 cells in c. Data are mean ± SD from three independent experiments. **p < 0.01. e, f Suppression of miR-137 enhances erastin-induced ferroptosis in vivo. C57BL/6 mice were injected subcutaneously with indicated A375 cells e or G-361 cells f (1 × 106 cells per mouse) and treated with erastin (15 mg/kg intraperitoneally, twice every other day) when the tumor volume reached 50 mm3. Tumor volume was calculated every 4 days. Data represent mean ± SD (n = 5–6 mice per group). Significance was determined by one-sided Mann–Whitney U-test, *p < 0.05. g Schematic depicting miR-137-mediated ferroptosis in melanoma cells. miR-137 suppresses erastin-induced ferroptosis by directly targeting Gln importer SLC1A5CC BY-NC-SA · PubMed Central

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Metadata

Authors
Luo, M., Wu, L., Zhang, K., Wang, H., Zhang, T., Gutierrez, L., O’Connell, D., Zhang, P., Li, Y., Gao, T., Ren, W., & Yang, Y.
ORCID
Yang, Yongfei
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2018-01-18
Volume
25
Issue
8
Pages
1457-1472
ISSN
  • 1350-9047
  • 1476-5403
DOI
10.1038/s41418-017-0053-8
PMC
PMC6113319
Cited by
408
References
17
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0 (tdm)

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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