Abstract:The significance of periodic tryptophan protein 1 (PWP1) expression in human cancer and its molecular mechanism of action have not been reported so far. Materials and Methods: Immunohistochemistry was performed to analyze the expression of PWP1 in non-small cell lung cancer (NSCLC) tissues and statistical analysis was applied to analyze the relationship between PWP1 expression and the clinicopathological factors. The effects of PWP1 on NSCLC proliferation and invasion were determined by colony formation, trans… Show more
“…PD-L1 protein was spatially clustered with CD80 and ICOS proteins, markers of activated T cells, and both were strongly associated with genes involved in cancer progression, immunosuppression, and chemoresistance such as CDYL 25 and TBKBP1 26 . Also, HLA-DR, which was upregulated in GOLD 1–2, was strongly associated with TMEM205 and with PWP1 , another gene upregulated in malignant lung cancer 27 . Figure 6 Network of associations between top protein and genes and pathway analysis: ( A ) Alveoli-specific RNA–protein association network (restricted to top 10 RNAs per protein, ranked by p -value).…”
Section: Resultsmentioning
confidence: 94%
“…PD-L1 protein was spatially clustered with CD80 and ICOS proteins, markers of activated T cells, and both were strongly associated with genes involved in cancer progression, immunosuppression, and chemoresistance such as CDYL 25 and TBKBP1 26 . Also, HLA-DR, which was upregulated in GOLD 1-2, was strongly associated with TMEM205 and with PWP1, another gene upregulated in malignant lung cancer 27 .…”
Section: Network Of Genes and Proteins Within Lung Alveolar Bronchiol...mentioning
Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear. In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression: (1) via cutting-edge digital spatial proteomic and transcriptomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n = 19); and (2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n = 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract. PD-L1 expression was increased in the bronchiolar wall, parenchyma, and vascular wall from mild-moderate (GOLD 1–2) COPD patients compared to severe-very severe (GOLD 3–4) COPD patients and controls. Within all the COPD patients, PD-L1 protein expression was associated with upregulation of genes involved in tumor progression and downregulation of oncosuppressive genes, and strongly directly correlated with the FEV1% predicted, indicating higher PD-L1 expression in the milder vs. more severe COPD stages. In bronchioles, PD-L1 levels were strongly directly correlated with the number of functionally active AMs. In BAL, we confirmed that AMs from patients with both GOLD 1–2 COPD and NSCLC had the highest and similar, PD-L1 expression levels versus all the other groups, independently from active cigarette smoking. Intriguingly, AMs from patients with more severe COPD had reduced AM PD-L1 expression compared to patients with mild COPD. Acute CS extract stimulation increased PD-L1 mRNA expression only in never-and not in ever-smoker AMs. Lungs from patients with mild COPD and NSCLC are characterized by a similar strong PD-L1 expression signature in bronchioles and functionally active AMs compared to patients with severe COPD and controls. Active smoking does not affect PD-L1 levels. These observations represent a new resource in understanding the innate immune mechanisms underlying the link between COPD and lung cancer onset and progression and pave the way to future studies focused on the mechanisms by which CS promotes tumorigenesis and COPD.
“…PD-L1 protein was spatially clustered with CD80 and ICOS proteins, markers of activated T cells, and both were strongly associated with genes involved in cancer progression, immunosuppression, and chemoresistance such as CDYL 25 and TBKBP1 26 . Also, HLA-DR, which was upregulated in GOLD 1–2, was strongly associated with TMEM205 and with PWP1 , another gene upregulated in malignant lung cancer 27 . Figure 6 Network of associations between top protein and genes and pathway analysis: ( A ) Alveoli-specific RNA–protein association network (restricted to top 10 RNAs per protein, ranked by p -value).…”
Section: Resultsmentioning
confidence: 94%
“…PD-L1 protein was spatially clustered with CD80 and ICOS proteins, markers of activated T cells, and both were strongly associated with genes involved in cancer progression, immunosuppression, and chemoresistance such as CDYL 25 and TBKBP1 26 . Also, HLA-DR, which was upregulated in GOLD 1-2, was strongly associated with TMEM205 and with PWP1, another gene upregulated in malignant lung cancer 27 .…”
Section: Network Of Genes and Proteins Within Lung Alveolar Bronchiol...mentioning
Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear. In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression: (1) via cutting-edge digital spatial proteomic and transcriptomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n = 19); and (2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n = 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract. PD-L1 expression was increased in the bronchiolar wall, parenchyma, and vascular wall from mild-moderate (GOLD 1–2) COPD patients compared to severe-very severe (GOLD 3–4) COPD patients and controls. Within all the COPD patients, PD-L1 protein expression was associated with upregulation of genes involved in tumor progression and downregulation of oncosuppressive genes, and strongly directly correlated with the FEV1% predicted, indicating higher PD-L1 expression in the milder vs. more severe COPD stages. In bronchioles, PD-L1 levels were strongly directly correlated with the number of functionally active AMs. In BAL, we confirmed that AMs from patients with both GOLD 1–2 COPD and NSCLC had the highest and similar, PD-L1 expression levels versus all the other groups, independently from active cigarette smoking. Intriguingly, AMs from patients with more severe COPD had reduced AM PD-L1 expression compared to patients with mild COPD. Acute CS extract stimulation increased PD-L1 mRNA expression only in never-and not in ever-smoker AMs. Lungs from patients with mild COPD and NSCLC are characterized by a similar strong PD-L1 expression signature in bronchioles and functionally active AMs compared to patients with severe COPD and controls. Active smoking does not affect PD-L1 levels. These observations represent a new resource in understanding the innate immune mechanisms underlying the link between COPD and lung cancer onset and progression and pave the way to future studies focused on the mechanisms by which CS promotes tumorigenesis and COPD.
“…The expression of signal transducer DVLs have been found to be upregulated by CtBP2 [ 77 ], TMEM88 [ 78 ], PWP1 [ 79 ] and lncRNA LINC00673-v4 [ 80 ] (Table 2 ). CtBP2 directly interacts with DVL1 and activates Wnt/β-catenin signaling in NSCLC cells [ 77 ].…”
Section: The Positive Regulators Of Wnt/β-catenin Signalingmentioning
confidence: 99%
“…PWP1 interacts with DVL2 and activates Wnt/β-catenin signaling pathway. PWP1 overexpression was found in NSCLC and correlates with poor clinical features [ 79 ]. LINC00673-v4 overexpression was associated with adverse clinical outcome.…”
Section: The Positive Regulators Of Wnt/β-catenin Signalingmentioning
Wnt/β-catenin signaling is a critical pathway that influences development and therapeutic response of non-small cell lung cancer (NSCLC). In recent years, many Wnt regulators, including proteins, miRNAs, lncRNAs, and circRNAs, have been found to promote or inhibit signaling by acting on Wnt proteins, receptors, signal transducers and transcriptional effectors. The identification of these regulators and their underlying molecular mechanisms provides important implications for how to target this pathway therapeutically. In this review, we summarize recent studies of Wnt regulators in the development and therapeutic response of NSCLC.
“…Overexpression of PWP1 was detected in human pancreatic adenocarcinoma, in association with cell cycle regulation. Interestingly, and suggestive of PWP1 diagnostic and therapeutic potential, upregulated PWP1 expression has been correlated with unfavorable survival in head and neck squamous cell carcinoma, as well as in lung cancer [ 12 , 14 ]. In turn, molecular assays indicated that PWP1 enhances lung cancer cell malignancy through its interaction with DVL2 and Merlin to upregulate and downregulate, respectively, intracellular signaling mediated by the Wnt and Hippo pathways [ 14 ].…”
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