IFN‑γ induces apoptosis in human melanocytes by activating the JAK1/STAT1 signaling pathway

Su, Qianya; Wang, Fei; Dong, Zhengbang; Chen, Mei; Cao, Rong

doi:10.3892/mmr.2020.11403

Cited by 18 publications

(16 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The JAK/STAT1 pathway is involved in almost the entire immune regulation process, including immune surveillance and immune escape. STAT1 promotes cell apoptosis, inhibits cell growth and differentiation and plays an important role in inhibiting tumorigenesis and tumor development by regulating the interferon (IFN) system [ 40 ]. STAT1-dependent IDO overexpression blocked the activation of T cells, which was related to an increase in PD-L1 expression in high-level triple-negative breast cancer (TNBC) cells [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

To explore immune synergistic function of Quercetin in inhibiting breast cancer cells

et al. 2021

View full text Add to dashboard Cite

Background The precancerous disease of breast cancer is an inevitable stage in the tumorigenesis and development of breast neoplasms. Quercetin (Que) has shown great potential in breast cancer treatment by inhibiting cell proliferation and regulating T cell function. γδ T cells are a class of nontraditional T cells that have long attracted attention due to their potential in immunotherapy. In this study, we revealed the immunomodulatory function of Que through regulation of the JAK/STAT1 signaling pathway, which was followed by the synergistic killing of breast cancer cells. Methods In the experimental design, we first screened target genes with or without Que treatment, and we intersected the Que target with the disease target by functional enrichment analysis. Second, MCF-10A, MCF-10AT, MCF-7 and MDA-MB-231 breast cancer cell lines were treated with Que for 0 h, 24 h and 48 h. Then, we observed the expression of its subsets by coculturing Que and γδ T cells and coculturing Que and γδ T cells with breast tumor cells to investigate their synergistic killing effect on tumor cells. Finally, Western blotting was used to reveal the changes in proteins related to the JAK/STAT1 signaling pathway after Que treatment in MCF-10AT and MCF-7 cells for 48 h. Results The pathway affected by Que treatment was the JAK/STAT1 signaling pathway and was associated with precancerous breast cancer, as shown by network pharmacology analysis. Que induced apoptosis of MCF-10AT, MCF-7 and MDA-MB-231 cells in a time- and concentration-dependent manner (P < 0.05). Most importantly, Que promoted the differentiation of γδ T cells into the Vδ2 T cell subpopulation. The best ratio of effector cells to target cells (E/T) was 10:1, the killing percentages of γδ T cells against MCF-10A, MCF-10AT, MCF-7, and MDA-MB-231 were 61.44 ± 4.70, 55.52 ± 3.10, 53.94 ± 2.74, and 53.28 ± 1.73 (P = 0.114, P = 0.486, and P = 0.343, respectively), and the strongest killing effect on precancerous breast cancer cells and breast cancer cells was found when the Que concentration was 5 μM and the E/T ratio was 10:1 (64.94 ± 3.61, 64.96 ± 5.45, 55.59 ± 5.98, and 59.04 ± 5.67, respectively). In addition, our results showed that Que increased the protein levels of IFNγ-R, p-JAK2 and p-STAT1 while decreasing the protein levels of PD-L1 (P < 0.0001). Conclusions In conclusion, Que plays a synergistic role in killing breast cancer cells and promoting apoptosis by regulating the expression of IFNγ-R, p-JAK2, p-STAT1 and PD-L1 in the JAK/STAT1 signaling pathway and promoting the regulation of γδ T cells. Que may be a potential drug for the prevention of precancerous breast cancer and adjuvant treatment of breast cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

To explore immune synergistic function of Quercetin in inhibiting breast cancer cells

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Our data demonstrate that CD4 + T H 1 cells, with high IFN expression and potential for direct cytotoxicity, are responsible for nevus rejection in NSG mice. CD4 + T H 1 cells' induction of melanocytes' death likely incorporates direct cytotoxicity (48), cytokine-mediated [e.g., IFN (51,52)] and ligand-mediated [e.g., Fas ligand (53)] cytotoxicity, and downstream activation of CD8 + cytotoxic T cells (47). The contribution of each of these effector mechanisms downstream of CD4 + T H 1 activation to nevus rejection will be examined in future studies.…”

Section: Discussionmentioning

confidence: 99%

Rejection of benign melanocytic nevi by nevus-resident CD4 ⁺ T cells

et al. 2021

View full text Add to dashboard Cite

Melanoma and melanocytic nevi harbor shared lineage-specific antigens and oncogenic mutations. Yet, the relationship between the immune system and melanocytic nevi is unclear. Using a patient-derived xenograft (PDX) model, we found that 81.8% of the transplanted nevi underwent spontaneous regression, while peripheral skin remained intact. Nevus-resident CD4+ T helper 1 cells, which exhibited a massive clonal expansion to melanocyte-specific antigens, were responsible for nevus rejection. Boosting regulatory T cell suppressive function with low-dose exogenous human interleukin-2 injection or treatment with a human leukocyte antigen (HLA) class II–blocking antibody prevented nevus rejection. Notably, mice with rejected nevus PDXs were protected from melanoma tumor growth. We detected a parallel CD4+ T cell–dominant immunity in clinically regressing melanocytic nevi. These findings reveal a mechanistic explanation for spontaneous nevus regression in humans and posit the activation of nevus-resident CD4+ effector T cells as a novel strategy for melanoma immunoprevention and treatment.

show abstract

“…Conventionally, STATs were activated by cell surface receptor JAKs binding to the ligand and regulated the immune system, inhibited cell proliferation, and promoted apoptosis by regulating genes expression associated with the cell cycle (37,38). In recent years, studies have found that STAT1 may act as a tumor promoter (39), suggesting that the function of STAT1 might change with the cellular and external environment (40).…”

Section: Discussionmentioning

confidence: 99%

Down-Regulating Hexokinase 2 Inhibits Proliferation of Endometrial Stromal Cells Through a Noncanonical Pathway Involving Phosphorylated-STAT1 in Endometriosis

Hou¹,

Lei²,

Peng³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Endometriosis is a benign gynecologic disease that causes chronic pelvic pain, dysmenorrhea and infertility and shares several characteristics with malignant tumors, afflicting women of reproductive age. Hexokinase 2 (HK2) plays a pivotal role as the first rate-limiting enzyme in the metabolic glycolysis pathway, and its abnormal elevation in tumors is associated with tumor genesis and metastasis. However, the expression and role of HK2 in endometriosis remain unclear.Methods: We sequenced the primary endometrial stromal cells from patients with endometrioma and adopted immunohistochemistry, quantitative real-time PCR and western blot to determine the expression of HK2. Then wound healing assays, cell invasion assays, cell proliferation assays were performed to explore the functions of HK2 in endometrial stromal cells. Furthermore, mice models of endometriosis were recruited to observe the effects of HK2 inhibitors in vivo. Lastly, glycolysis metabolism detection and transcriptome sequencing were carried out in HK2-knockdown endometrial stromal cells to analyze the mechanism of HK2 affecting cell function.Results: Endometriotic stromal cells displayed active glycolysis metabolism and elevated expression of HK2. Downregulating HK2 reduced the migration, invasion and proliferation capacity of endometrial stromal cells. Knockdown of HK2 induced upregulation of signal transducer and activator of transcription 1 (STAT1) and their phosphorylation to attenuate the proliferation of endometrial stromal cells.Conclusions: HK2 was associated with the migration, invasion and proliferation of endometrial stromal cells, which might provide new insights into the pathogenesis and treatment of endometriosis.

show abstract

IFN‑γ induces apoptosis in human melanocytes by activating the JAK1/STAT1 signaling pathway

Cited by 18 publications

References 30 publications

To explore immune synergistic function of Quercetin in inhibiting breast cancer cells

To explore immune synergistic function of Quercetin in inhibiting breast cancer cells

Rejection of benign melanocytic nevi by nevus-resident CD4 ⁺ T cells

Down-Regulating Hexokinase 2 Inhibits Proliferation of Endometrial Stromal Cells Through a Noncanonical Pathway Involving Phosphorylated-STAT1 in Endometriosis

Contact Info

Product

Resources

About

IFN‑γ induces apoptosis in human melanocytes by activating the JAK1/STAT1 signaling pathway

Cited by 18 publications

References 30 publications

To explore immune synergistic function of Quercetin in inhibiting breast cancer cells

To explore immune synergistic function of Quercetin in inhibiting breast cancer cells

Rejection of benign melanocytic nevi by nevus-resident CD4 + T cells

Down-Regulating Hexokinase 2 Inhibits Proliferation of Endometrial Stromal Cells Through a Noncanonical Pathway Involving Phosphorylated-STAT1 in Endometriosis

Contact Info

Product

Resources

About

Rejection of benign melanocytic nevi by nevus-resident CD4 ⁺ T cells