The α5-nAChR/PD-L1 axis facilitates lung adenocarcinoma cell migration and invasion

Zhu, Ping; Kang, Guiyu; Jiao, Yang; Gui, Chengzhi; Fan, Huiping; Li, Xiangying; Jia, Yanfei; Zhang, Lulu

doi:10.1007/s13577-022-00709-1

Cited by 8 publications

(9 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PD-L1 overexpression in HeLa cells promoted migration and invasion; doubled the thymidine incorporation into DNA; and facilitated EMT by increasing SNAIL, SLUG, and ZEB1 levels, and H1975 cells overexpressing PD-L1 displayed more robust tumorigenesis in athymic mice. PD-L1 deletion or PD-L1 antibodies abrogated EGF and TGF-β -inducible migration, tumorigenesis, and metastasis ( 49 ). Most interestingly, the authors created an EGF gradient and measured directionality that connects the linear distance between the starting point and endpoint (D) to the total distance (T) traveled.…”

Section: Egfr/pd-l1mentioning

confidence: 99%

“…The cytoplasmic tail of PD-L1 was cloned into a yeast 2-hybrid bait construct, and >50 million connections have been examined to discover direct PD-L1 binders. The breakthrough occurred when filamin A and PLC-γ1 were identified as the two PD-L1 interaction partners with the maximum confidence scores ( 49 ). Each monomer of the F-actin crosslinking protein Filamin A consists of an actin-binding domain and a rod segment.…”

Section: Egfr/pd-l1mentioning

confidence: 99%

“…Notably, PLC-γ1 was not activated when EGFR was inactive, or PD-L1 was scarce; this process is known as the EGFR and PD-L1 two-hit model of PLC- activation. The attachment of PLC-γ1 to the cytoplasmic region of PD-L1 has also been associated with protection against IFN-γ cytotoxicity ( 49 ).…”

Section: Egfr/pd-l1mentioning

confidence: 99%

See 2 more Smart Citations

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Xiao

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

The development of techniques and immunotherapies are widely applied in cancer treatment such as checkpoint inhibitors, adoptive cell therapy, and cancer vaccines apart from radiation therapy, surgery, and chemotherapy give enduring anti-tumor effects. Minority people utilize single-agent immunotherapy, and most people adopt multiple-agent immunotherapy. The difficulties are resolved by including the biomarkers to choose the non-responders’ and responders’ potentials. The possibility of the potential complications and side effects are examined to improve cancer therapy effects. The Head and Neck Squamous Cell Carcinoma (HNSCC) is analyzed with the help of programmed cell death ligand 1 (PD-L1) and Insulin-like growth factor (IGF). But how IGF and PD-L1 upregulation depends on IL-6, EGFR, and LIN28/Let7-related mechanisms are poorly understood. Briefly, IL-6 stimulates gene expressions of IGF-1/2, and IL-6 cross-activates IGF-1R signaling, NF-κB, and STAT3. NF-κB, up-regulating PD-L1 expressions. IL-6/JAK1 primes PD-L1 for STT3-mediated PD-L1 glycosylation, stabilizes PD-L1 and trafficks it to the cell surface. Moreover, ΔNp63 is predominantly overexpressed over TAp63 in HNSCC, elevates circulating IGF-1 levels by repressing IGFBP3, and activates insulin receptor substrate 1 (IRS1).TP63 and SOX2 form a complex with CCAT1 to promote EGFR expression. EGFR activation through EGF binding extends STAT3 activation, and EGFR and its downstream signaling prolong PD-L1 mRNA half-life. PLC-γ1 binding to a cytoplasmic motif of elevated PD-L1 improves EGF-induced activation of inositol 1,4,5-tri-phosphate (IP3), and diacylglycerol (DAG) subsequently elevates RAC1-GTP. RAC1-GTP was convincingly demonstrated to induce the autocrine production and action of IL-6/IL-6R, forming a feedback loop for IGF and PD-L1 upregulation. Furthermore, the LIN28-Let7 axis mediates the NF-κB-IL-6-STAT3 amplification loop, activated LIN28-Let7 axis up-regulates RAS, AKT, IL-6, IGF-1/2, IGF-1R, Myc, and PD-L1, plays pivotal roles in IGF-1R activation and Myc, NF-κB, STAT3 concomitant activation. Therefore, based on a detailed mechanisms review, our article firstly reveals that IL-6, EGFR, and LIN28/Let7-related mechanisms mediate PD-L1 and IGF upregulation in HNSCC, which comprehensively influences immunity, inflammation, metabolism, and metastasis in the tumor microenvironment, and might be fundamental for overcoming therapy resistance.

show abstract

Section: Egfr/pd-l1mentioning

confidence: 99%

Section: Egfr/pd-l1mentioning

confidence: 99%

See 1 more Smart Citation

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Xiao

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Furthermore, an in vitro study showed that chronic nicotine exposure could increase α1-nAChR and PD-L1 expressions in a lung adenocarcinoma cell line ( 92 ). Another recent study showed that coexpression of α5-nAChR and PD-L1 are associated with a worse prognosis in patients with lung adenocarcinoma ( 93 ). However, the correlation between PD-L1 and DRD2 has not been well-investigated in context to human cancer except for one recent study where Paliperidone (a DRD2 antagonist) reduced PD-L1 expression in glioblastoma cells and increased survival in a mouse model of glioblastoma ( 94 ).…”

Section: Discussionmentioning

confidence: 99%

“…Nicotinic acetylcholine receptors such as a5, a7, or a9 have been shown to express in various immune cells where they regulate the secretion of immunomodulatory cytokines and immune response ( 96 ). Interestingly, nicotine-mediated activation of both a5 and a9 nAChRs have been shown to upregulate PD-L1 expression in cancer cells via STAT3 signaling pathways ( 90 , 93 ), so a positive correlation of nAChRs with PD-L1 may be expected ( Supplementary Figure 2 ). Surprisingly, the nAChRs correlated with DRD2 or PD-L1 are different between our study and TCGA database, but the difference may be attributed to the difference in stages, patient population, or tumor-infiltrating immune cells.…”

Section: Discussionmentioning

confidence: 99%

Expression, correlation, and prognostic significance of different nicotinic acetylcholine receptors, programed death ligand 1, and dopamine receptor D2 in lung adenocarcinoma

et al. 2022

View full text Add to dashboard Cite

ObjectiveThe objective of this study is to evaluate the expression of different nicotinic acetylcholine receptors (nAChRs), programmed death ligand-1 (PD-L1), and dopamine receptor D2 (DRD2) as prognostic factors in lung cancer and any correlation among them. Since all of the above genes are typically upregulated in response to smoking, we hypothesized that a correlation might exist between DRD2, PD-L1, and nAChR expression in NSCLC patients with a smoking history and a prediction model may be developed to assess the clinical outcome.MethodsWe retrospectively analyzed samples from 46 patients with primary lung adenocarcinoma who underwent surgical resection at Mayo Clinic Rochester from June 2000 to October 2008. The expression of PD-L1, DRD2, CHRNA5, CHRNA7, and CHRNA9 were analyzed by quantitative PCR and correlated amongst themselves and with age, stage and grade, smoking status, overall survival (OS), and relapse-free survival (RFS).ResultsOnly PD-L1 showed a statistically significant increase in expression in patients older than 65. All the above genes showed higher expression in stage IIIB than IIIA, but none reached statistical significance. Interestingly, we did not observe significant differences among never, former, and current smokers, but patients with pack years greater than 30 showed significantly higher expression of CHRNA9. We observed a strong positive correlation between PD-L1/DRD2, PD-L1/CHRNA5, and CHRNA5/CHRNA7 and a weak positive correlation between DRD2/CHRNA5 and DRD2/CHRNA7. Older age was independently associated with poor OS, whereas lower CHRNA7 expression was independently associated with better OS.ConclusionsWe observed strong positive correlations among PD-L1, DRD2, and some of the nAChRs. We investigated their prognostic significance in lung cancer patients and found CHRNA7 to be an independent prognostic factor. Overall, the results obtained from this preliminary study warrant a large cohort-based analysis that may ultimately lead to potential patient-specific stratification biomarkers predicting cancer-treatment outcomes.

show abstract

Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway

Jiao

Kang

Pan

et al. 2023

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The α5-nAChR/PD-L1 axis facilitates lung adenocarcinoma cell migration and invasion

Cited by 8 publications

References 49 publications

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Expression, correlation, and prognostic significance of different nicotinic acetylcholine receptors, programed death ligand 1, and dopamine receptor D2 in lung adenocarcinoma

Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway

Contact Info

Product

Resources

About