Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia

Wang, Xi; Li, Jinge; Dong, Ke; Lin, Fang; Long, Min; Ouyang, Yongri; Jin, Wei; Chen, Xi; Weng, Yuanyuan; He, Tengbing; Zhang, Huizhong

doi:10.1016/j.cellsig.2014.12.003

Cited by 272 publications

(219 citation statements)

References 35 publications

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“…Yang et al showed that miR-34c was lower expressed and served as a biomarker in predicting prognosis in patients with AML [28]. Wang et al reported that miR-34a expression was reduced and acted as a tumor suppressor and a potential immunotherapeutic target by targeting PD-L1 in AML [17]. Zauli et al found that miR-34a decreased the levels of oncogenes E2F1 and B-Myb in leukemic cells [29].…”

Section: Discussionmentioning

confidence: 99%

“…showed that miR-519 enhanced cell proliferation and induced cell apoptosis in AML HL-60 cell line by decreasing the level of RNA-binding protein human antigen R [14]. MiR-34a is the first identified tumor suppressor gene that is lower expressed in many forms of tumors, including breast cancer, lung cancer and AML [15-17]. MiR-34a plays a critical role in many cellular processes including p53-induced cell cycle arrest, apoptosis and other biological behaviors by negatively regulating its target genes [18, 19].…”

Section: Introductionmentioning

confidence: 99%

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MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Liu

Ren

Chen

2017

Cell Physiol Biochem

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Background: MiR-34a is identified as a tumor suppressor gene and involved in acute myeloid leukemia (AML) development. However, the regulatory mechanism of miR-34a in AML is unclear. Methods: The expression of miR-34a and HMGB1 in HL-60, THP-1 and HS-5 cells were detected by qRT-PCR and western blot. Lipofectamine 2000 was used to transfect with miR-34a mimics, miR-34a inhibitor, si-HMGB1, pcDNA 3.1-HMGB1, and corresponding controls. The apoptosis and autophagy of transfected AML cells were assessed by flow cytometry and western blot, respectively. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-34a. The effects of miR-34a mimics or si-HMGB1 on chemotherapy-induced autophagy were further explored in HL-60 cells treated with all-trans retinoic acid (ATRA) along with lysosomal protease inhibitors E64d and pepstatin A. Results: MiR-34a was lower expressed and HMGB1 mRNA and proteins were both higher expressed in HL-60 and THP-1 cells compared with that in HS-5 cells. Higher expression levels of MiR-34 and lower expression levels of HMGB1 both significantly promoted apoptosis and inhibited autophagy in HL-60 and THP-1 cells. Dual luciferase reporter system confirmed that HMGB1 was a potential target of miR-34a. Moreover, overexpression of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by higher expression level of miR-34a. Higher expression level of miR-34a and lower expression level of HMGB1 both inhibited chemotherapy-induced autophagy by stimulating the LC3 conversion. Conclusion: MiR-34a promoted cell apoptosis and inhibited autophagy by targeting HMGB1. Therefore, miR-34a may be a potential promising molecular target for AML therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Liu

Ren

Chen

2017

Cell Physiol Biochem

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“…62 On the other hand, overexpression of miR-34a blocked programmed cell death 1 (PD1) and programmed cell death 1 ligand 1 (PD-L1)-specific apoptosis of T lymphocytes. 63 In macrophages, miR-34a promotes M2 polarization linked to immunosuppression. 64 Therefore, age-related overexpression of miR-34a seems to be an important pro-inflammatory immunoaging-contributing factor.…”

Section: Discussionmentioning

confidence: 99%

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

Owczarz

Budzinska

Domaszewska-Szostek

et al. 2017

Exp Biol Med (Maywood)

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Impact statementHigh expression of sirtuins, particularly SIRT1, lowers the risk of age-related diseases and probably slows down the rate of aging; therefore, their sustained expression should be one of the features of longevity. However, in this work we show that in peripheral blood mononuclear cells (PBMC) of long-lived individuals, expression of majority of the SIRT genes is significantly lower than in cells of young study subjects. In long-lived individuals, downregulation of SIRT1 coexists with upregulation of SIRT1 mRNA-interacting miR-34a and miR-9, indicating the role of epigenetic drift in age-dependent deregulation of SIRT1 expression. Such constellation of SIRT1, miR-34a, and miR-9 expression in PBMC of successfully aging long-lived individuals indicates that, at least in these individuals, it is not a risk factor for morbidity and mortality. It might however affect the function of the immune system and, therefore, aging individuals can profit from interventions increasing the level of SIRT1. AbstractIncreased expression of sirtuins lowers the risk of age-related diseases, while their role in the regulation of longevity is not firmly established. Since aging is associated with immunosenescence, we tested whether sirtuin expression was modified in peripheral blood mononuclear cells (PBMC) in an age-related manner and whether this might result from altered expression of the selected miRNAs. The expression of seven SIRT genes and of SIRT1 mRNA-interacting miR-9, miR-34a, miR-132, and miR-199a-5p was evaluated by real-time PCR in PBMC originating from young (Y, n ¼ 57, mean age 27 AE 4.3 years), elderly (E, n ¼ 52, 65 AE 3.4 years), and long-lived (L, n ¼ 56, 94 AE 3.5 years) individuals. Older age was associated with a decreased expression of the majority of the SIRT genes. Most severely affected were median expressions of SIRT1 (P ¼ 0.000001 for the whole studied group, Y vs. E: P < 0.000001, Y vs. L: P < 0.000001), and of SIRT3 (P ¼ 0.000001, Y vs. E: P ¼ 0.000004, Y vs. L: P ¼ 0.000028). Older age was also associated with the increased median expression of miR-34a (P ¼ 0.000001, Y vs. E: P ¼ 0.001, Y vs. L: P ¼ 0.000004) and of miR-9 (P ¼ 0.05, Y vs. L: P ¼ 0.054). In functional studies, miR-9 interacted with the 3 0 UTR of SIRT1 mRNA. The SIRT1 mRNA level negatively correlated with the expression of miR34a (r ¼ À0.234, P ¼ 0.003). In conclusion, age-related decrease of SIRT1 expression in PBMC might in part result from overexpression of miR-34a and miR-9. In addition, the sustained expression of the SIRT genes in PBMC is not a prerequisite to longevity in humans but might be one of the reasons for the immune system dysfunction in the elderly.

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“…Besides, the increase of PD-L1 expression protein was induced by inhibition of phosphatase and tensin homolog (PTEN) in glioma cancer and colorectal cancer [22]. Recent studies reported that PD-L1 expression was inhibited by p53 through regulating miR-34a and miR-200 [76,77].…”

Section: Regulation Of Pd-l1mentioning

confidence: 99%

The function and regulation of PD-L1 in immunotherapy

Guo¹,

Lin²,

Kwok³

2017

ADMET DMPK

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PD-L1, also known as B7-H1, is a type I transmembrane protein, which is expressed in different kinds of tumor cells. It is correlated with poor clinical outcome of patients with various types of tumors. PD-L1 can regulate tumor microenvironment or tumor related immune response through suppressing T cell or NK cell mediated immune response. PD-L1 expression is regulated by various cytokines, such as LPS, GM-CSF, IL-4, TGF-β, TNF-α. PD-1 and PD-L1 are the members of B7 and CD28 superfamily, respectively. The B7/CD28 interaction plays a central role in immune tolerance. PD-L1 can bind to PD-1, which leads to the suppression of lymphocyte activation and apoptosis of lymphocytes. Anti-PD-L1 therapy is one of the immunotherapies to treat cancer (especially solid tumor). PD-L1 expression may be associated with efficacy

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Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia

Cited by 272 publications

References 35 publications

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

The function and regulation of PD-L1 in immunotherapy

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