A let-7/Fas double-negative feedback loop regulates human colon carcinoma cells sensitivity to Fas-related apoptosis

Bone marrow-derived mesenchymal stem cells (MSCs) have been recently used in clinical treatment of inflammatory diseases. Practical strategies improving the immunosuppressive property of MSCs are urgently needed for MSC immunotherapy. In this study, we aimed to develop a microRNA-based strategy to improve MSC immunotherapy. Bioinformatic analysis revealed that let-7a targeted the 3 0 UTR of mRNA of Fas and FasL, both of which are essential for MSCs to induce T cell apoptosis. Knockdown of let-7a by specific inhibitor doubled Fas and Fas ligand (FasL) protein levels in MSCs. Because Fas attracts T cell migration and FasL induces T cell apoptosis, knockdown of let-7a significantly promoted MSC-induced T cell migration and apoptosis in vitro and in vivo. Importantly, MSCs knocked down of let-7a were more efficient to reduce the mortality, prevent the weight loss, suppress the inflammation reaction, and alleviate the tissue lesion of experimental colitis and graftversus-host disease (GVHD) mouse models. In conclusion, knockdown of let-7a significantly improved the therapeutic effect of MSC cytotherapy on inflammatory bowel diseases and GVHD. With high safety and convenience, knockdown of let-7a is a potential strategy to improve MSC therapy for inflammatory diseases in clinic.

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“…Moreover, let-7a has been identified to target Fas mRNA in cancer cells and immune cells. 29,30 So we chose let-7a as the candidate.…”

Section: Knockdown Of Let-7a Enhances Fas and Fasl Protein Levels In mentioning

confidence: 99%

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

Liao

Shao

et al. 2017

Molecular Therapy

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“…Similar results were displayed on HT-29 cells using different stimuli (Liu et al, 2002;Shao et al, 2001). It may be due to a decrease in Fas receptor of human colon epithelial cells during the transition from normal epithelium to adenocarcinoma (Geng et al, 2011), leading to impaired responses to Fas-induced apoptosis in most colon cancer cells (Zang et al, 2008). Moreover, Bid (a downstream molecule of active caspase 8) was cleaved into tBid, and translocation of tBid to the mitochondria was observed (Fig.…”

Section: Induction Of Caspase-dependent Extrinsic and Intrinsic Apoptsupporting

confidence: 82%

A novel natural tautomeric pair of garcinielliptone FC suppressed nuclear factor κB and induced apoptosis in human colorectal cancer cells

Won

Lin

Yen

et al. 2016

Journal of Functional Foods

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“…Fas is a death receptor on the cell surface of a wide variety of cell types, and mediates rapid apoptosis. Although Fas is constitutively expressed in a variety of cell types, the role of Fas has also been evoked recently in apoptosis of various cell types in response to certain stimuli; [32][33][34] ultraviolet irradiation, viral infection, and chemotherapeutic agents effectively increase Fas transcription and, in turn, upregulation of Fas is involved in apoptotic cell death. 35 We also provide further evidence that nanosized TiO .…”

Section: P25-70mentioning

confidence: 99%

Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation

Yoo¹,

Yoon²,

Kwon³

et al. 2012

IJN

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Background: Titanium dioxide (TiO 2 ) has been widely used in many areas, including biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some TiO 2 particles have a considerable cytotoxic effect in normal human cells. However, the molecular basis for the cytotoxicity of TiO 2 has yet to be defined. Methods and results:In this study, we demonstrated that combined treatment with TiO 2 nanoparticles sized less than 100 nm and ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-dependent upregulation of Fas and conformational activation of Bax in normal human cells. Treatment with P25 TiO 2 nanoparticles with a hydrodynamic size distribution centered around 70 nm ) together with ultraviolet A irradiation-induced caspase-dependent apoptotic cell death, accompanied by transcriptional upregulation of the death receptor, Fas, and conformational activation of Bax. In line with these results, knockdown of either Fas or Bax with specific siRNA significantly inhibited TiO 2 -induced apoptotic cell death. Moreover, inhibition of reactive oxygen species with an antioxidant, N-acetyl-L-cysteine, clearly suppressed upregulation of Fas, conformational activation of Bax, and subsequent apoptotic cell death in response to combination treatment using TiO 2 P25-70 and ultraviolet A irradiation. Conclusion:These results indicate that sub-100 nm sized TiO 2 treatment under ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-mediated upregulation of the death receptor, Fas, and activation of the preapoptotic protein, Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.

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A let-7/Fas double-negative feedback loop regulates human colon carcinoma cells sensitivity to Fas-related apoptosis

Cited by 36 publications

References 29 publications

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

A novel natural tautomeric pair of garcinielliptone FC suppressed nuclear factor κB and induced apoptosis in human colorectal cancer cells

Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation

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