&lt;p&gt;PD-L1 Expression Is Regulated By NF-κB During EMT Signaling In Gastric Carcinoma&lt;/p&gt;

Xu, Dan; Li, Jing; Li, Ruiyang; Lan, Ting; Xiao, Chi; Gong, Ping

doi:10.2147/ott.s224053

Cited by 32 publications

(24 citation statements)

References 39 publications

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“…Activated NF-κB signaling was related to the high level of PD-L1 in several cancers [36,[84][85][86][87][88]. Multiple oncogenic signals could impair immune surveillance by activating the NF-κB-PD-L1 axis.…”

Section: Nf-κb Pathwaymentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

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Section: Nf-κb Pathwaymentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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“…In malignant diseases, EMT is usually considered as an important factor for promoting cell invasion, migration and drug resistance ( 10 ). The expression levels of N-cadherin and E-cadherin are important biomarkers of EMT progress ( 11 ). Previous studies have reported that EMT participates during colon cancer carcinogenesis and development ( 12 ); therefore, identifying novel therapeutic targets to prevent EMT may be valuable for CRC.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑199a‑5p suppresses cell proliferation, migration and invasion by targeting ITGA3 in colorectal cancer

Tian

Chen

et al. 2020

Mol Med Rep

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as a member of the integrin family, integrin α3β1 (iTGa3) has been linked to intercellular communication and serves an important role in the signaling among cells and the extracellular matrix. Microrna (mir)-199a-5p has been demonstrated to be related to the pathogenesis and progression of multiple malignant diseases. However, the biological functions of mir-199a-5p and iTGa3 in colorectal cancer (crc) have rarely been reported. The aim of the present study was to explore the roles of mir-199a-5p and iTGa3 in crc. immunohistochemistry staining and western blotting were applied to detect the protein expression of iTGa3 in crc tissues and cells. reverse transcription-quantitative Pcr was performed to investigate the expression of mir-199a-5p and iTGa3 mrna. HcT-116 cells were transfected with mir-199a-5p mimics, mimics control, short hairpin rna targeting iTGa3, or pcdna-iTGa3 for the functional experiments. dual luciferase reporter assay was applied to confirm whether mir-199a-5p targeted the 3' untranslated region (3'uTr) of iTGa3. The MTT, Transwell and wound healing assays were used to evaluate the proliferation, invasion and migration of CRC cells. Immunofluorescence assay was used to monitor the epithelial-mesenchymal transition (eMT) biomarker expression. The results demonstrated downregulation of mir-199a-5p and upregulation of iTGa3 in crc tissues and cell lines. mir-199a-5p mimics and knockdown of iTGa3 suppressed the proliferation, invasion and migration of crc cells. Bioinformatics analysis and luciferase reporter assay indicated that mir-199a-5p targeted the 3'uTr of the iTGa3 transcript, and overexpression of iTGa3 reversed the tumor-suppressive effects of mir-199a-5p elevation. In addition, the immunofluorescence assay suggested that mir-199a-5p mimics suppressed the eMT of crc cells, whereas the overexpression of iTGa3 restored this effect. in conclusion, mir-199a-5p may act as a tumor suppressor by targeting and negatively regulating iTGa3 in crc.

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“…Pharmacological blockade of NF‐κB, exemplified by OA here, could be a promising approach for immunotherapy against gastric cancer. However, a recent study showed that TGF‐β1‐induced EMT resulted in PD‐L1 upregulation dependent on NF‐κB activation in gastric carcinoma SGC‐7901 cells, [ 29 ] suggesting complex mechanisms could be involved in NF‐κB regulation of PD‐L1. Furthermore, an interesting study showed that OA differently regulated the ERK, JNK, and AKT pathways in various cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF‐κB is required for oleanolic acid to downregulate PD‐L1 by promoting DNA demethylation in gastric cancer cells

Yang

et al. 2020

J Biochem & Molecular Tox

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Gastric cancer is one of the most common causes of cancer‐related death worldwide. Immunotherapy via programmed cell death protein 1 (PD‐1)/programmed cell death‐ligand 1 (PD‐L1) blockade has shown benefits for gastric cancer. Epigenetic DNA methylation critically regulates cancer immune checkpoints. We investigated how the natural compound oleanolic acid (OA) affected PD‐L1 expression in gastric cancer cells. Interleukin‐1β (IL‐1β) at 20 ng/mL was used to stimulate human gastric cancer MKN‐45 cells. IL‐1β significantly increased PD‐L1 expression, which was abolished by OA. Next, OA‐treated MKN‐45 cells were co‐cultured with activated and PD‐1‐overexpressing Jurkat T cells. OA restored IL‐2 levels in the co‐culture system and increased T cell killing toward MKN‐45 cells. Overexpression of PD‐L1 eliminated OA‐enhanced T cell killing capacity; however, PD‐1 blocking antibody abrogated the cytotoxicity of T cells. Moreover, OA abolished IL‐1β‐increased DNA demethylase activity in MKN‐45 cells. DNA methyltransferase inhibitor 5‐azacytidine rescued OA‐reduced PD‐L1 expression; whereas DNA demethylation inhibitor gemcitabine inhibited PD‐L1 expression, and, in combination with OA, provided more potent inhibitory effects. Furthermore, OA selectively reduced the expression of DNA demethylase TET3 in IL‐1β‐treated MKN‐45 cells, and overexpression of TET3 restored OA‐reduced PD‐L1 expression. Finally, OA disrupted nuclear factor κB (NF‐κB) signaling IL‐1β‐treated MKN‐45 cells, and overexpression of NF‐κB restored OA downregulation of TET3 and PD‐L1. The cytotoxicity of T cells toward MKN‐45 cells was also weakened by NF‐κB overexpression. Altogether, OA blocked the IL‐1β/NF‐κB/TET3 axis in gastric cancer cells, leading to DNA hypomethylation and downregulation of PD‐L1. Our discoveries suggested OA as an epigenetic modulator for immunotherapy or an adjuvant therapy against gastric cancer.

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<p>PD-L1 Expression Is Regulated By NF-κB During EMT Signaling In Gastric Carcinoma</p>

Cited by 32 publications

References 39 publications

Regulation of PD-L1 expression in the tumor microenvironment

Regulation of PD-L1 expression in the tumor microenvironment

MicroRNA‑199a‑5p suppresses cell proliferation, migration and invasion by targeting ITGA3 in colorectal cancer

Inhibition of NF‐κB is required for oleanolic acid to downregulate PD‐L1 by promoting DNA demethylation in gastric cancer cells

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