Molecule Information

General Information of the Molecule (ID: Mol00134)

• Name: Programmed cell death 1 ligand 1 (PD-L1) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: CD274
• Gene ID: 29126
• Location: chr9:5450503-5470566[+]
• Sequence:
  MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEME
  DKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGG
  ADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTT
  TTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTH
  LVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET
• 3D-structure: PDB ID: 7XAD; Classification: Immune system; Method: X-ray diffraction; Resolution: 3.00 Å
• Function: Plays a critical role in induction and maintenance of immune tolerance to self. As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response. Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10).
• Uniprot ID: PD1L1_HUMAN
• Ensembl ID: ENSG00000120217
• HGNC ID: HGNC:17635

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.29E-16; Fold-change: 5.17E-02; Z-score: 8.28E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vivo Model: BALB/c mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Transfection of a miR-3609 mimic markedly suppressed PD-L1 protein expression in MDA-MB-231 and MDA-MB-468 cells in a dose-dependent manner and increased the sensitivity of MCF7/ADR cells to adriamycin, whereas transfection of a miR-3609 inhibitor enhanced PD-L1 protein expression in HBL-100 and MCF-7 cells.

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioma [ICD-11: 2A00.1] [2]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.63E-05; Fold-change: -1.58E-01; Z-score: -6.10E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR34a/PD-L1 signaling pathway; Regulation; N.A.
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U87-P cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Annexin V/PI apoptosis assay; Cell cycle assay; MTT assay
• Mechanism Description: miR34a attenuates glioma cells progression and chemoresistance via targeting PD-L1.

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Epithelial ovarian cancer [ICD-11: 2B5D.0] [3]

• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PD-L1/PD-1 signaling pathway; Regulation; N.A.
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: T-cell apoptosis assay
• Mechanism Description: High expression levels of miR-424(322) were positively correlated with the PFS of ovarian cancer patients. miR-424(322) overexpression reduced PD-L1 and CD80 expression through direct binding to the 3'-UTR of these genes. Furthermore, low miR-424(322) and high PD-L1 expression were significantly correlated and strongly associated with chemoresistant phenotypes in ovarian cancer cells and tissues. Restoration of miR-424(322) expression (+) the sensitivity of cancer cells to drug treatment and was accompanied by T-cell activation by blocking the PD-L1 immune checkpoint in both in vitro and in vivo models. Our current findings indicate that miR-424(322) regulates PD-L1 and CD80 expression. Therefore, miR-424(322) might serve as a therapeutic target to enhance the chemosensitivity of ovarian cancer cells through checkpoint blockage, which thereby promotes the T-cell response in attacking tumour cells.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: egfr-mutant luad [ICD-11: 2C25.0] [4]

• Resistant Disease: egfr-mutant luad [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results suggested that PD-L1 might play a role in promoting autophagy and inhibiting apoptosis, which was responsible for the generation of primary resistance to EGFR-TKIs, and the combination therapy exerted a synergistic antitumor effect by inhibiting the activation of the MAPK/ERK signaling pathway.

Disease Class: egfr-mutant luad [ICD-11: 2C25.0] [4]

• Resistant Disease: egfr-mutant luad [ICD-11: 2C25.0]
• Resistant Drug: Gefitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results suggested that PD-L1 might play a role in promoting autophagy and inhibiting apoptosis, which was responsible for the generation of primary resistance to EGFR-TKIs, and the combination therapy exerted a synergistic antitumor effect by inhibiting the activation of the MAPK/ERK signaling pathway.

Irinotecan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [ICD-11: 2B90.1] [5]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Irinotecan
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF+kB signaling pathway; Activation; hsa04218
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: Immunoblotting assay; qRT-PCR; Immunofluorescence staining assay; Reporter Gene assay; RNA sequencing assay
• Experiment for Drug Resistance: Cell cytotoxicity assay; Tumorigenicity assay
• Mechanism Description: Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.19E-01; Fold-change: -2.03E-02; Z-score: -5.60E-02
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-01; Fold-change: -9.42E-01; Z-score: -3.08E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.52E-02; Fold-change: 5.74E-01; Z-score: 7.69E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.63E-05; Fold-change: -7.58E-01; Z-score: -2.71E+00

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.29E-16; Fold-change: 1.13E-01; Z-score: 3.89E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.55E-03; Fold-change: 9.99E-02; Z-score: 2.19E-01

References

• Ref 1: miR3609 sensitizes breast cancer cells to adriamycin by blocking the programmed death-ligand 1 immune checkpoint. Exp Cell Res. 2019 Jul 1;380(1):20-28. doi: 10.1016/j.yexcr.2019.03.025. Epub 2019 Mar 20.
• Ref 2: miR-34a attenuates glioma cells progression and chemoresistance via targeting PD-L1. Biotechnol Lett. 2017 Oct;39(10):1485-1492. doi: 10.1007/s10529-017-2397-z. Epub 2017 Jul 18.
• Ref 3: miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat Commun. 2016 May 5;7:11406. doi: 10.1038/ncomms11406.
• Ref 4: PD-L1 induces autophagy and primary resistance to EGFR-TKIs in EGFR-mutant lung adenocarcinoma via the MAPK signaling pathway. Cell Death Dis. 2024 Aug 1;15(8):555.
• Ref 5: Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer. Cancers (Basel). 2024 Oct 15;16(20):3491.