Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer

Liu, Chenying; Qian, Xiaolong; Yu, Chunyan; Xia, Xiaoqing; Li, Jiazhen; Li, Yaqing; Xie, Yongjie; Gao, Guangshen; Song, Yuanming; Zhang, Meiyan; Xue, Huiqin; Wang, Xiaozi; Sun, Hui; Liu, Jing; Deng, Weimin; Guo, Xiaojing

doi:10.1016/j.canlet.2024.216642

Cancer Letters

2024

DOI: 10.1016/j.canlet.2024.216642

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Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer

Chenying Liu,

Xiaolong Qian,

Chunyan Yu

et al.

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Cited by 3 publications

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Ozone-Induced Lung Injury are Mediated Via PPAR-Mediated Ferroptosis in Mice

Li,

Wei,

Wang

et al. 2024

Biol Trace Elem Res

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Ozone-Induced Lung Injury are Mediated Via PPAR-Mediated Ferroptosis in Mice

Li,

Wei,

Wang

et al. 2024

Biol Trace Elem Res

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Tumor-secreted LCN2 impairs gastric cancer progression via autocrine inhibition of the 24p3R/JNK/c-Jun/SPARC axis

Huang,

Li,

Qian

et al. 2024

Cell Death Dis

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Gastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.

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Impact of Neoadjuvant Therapy on PD-L1 Expression in Triple-Negative Breast Cancer and Correlation with Clinicopathological Factors

Ilieva,

Pencheva,

Hadzhiev

et al. 2024

Diagnostics

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Background: This study aims to deliver more insights on the impact of neoadjuvant treatment on Pd-L1 expression and to evaluate its correlation with clinicopathological factors. Methods: We reviewed 88 TNBC cases for the period 2021–2023. Data on age, tumor size, stage, and treatment were collected. Histological slides were assessed for subtype, grade, and TILs. A total of 48 received neoadjuvant treatment. HER2 and Ki67 were evaluated via immunohistochemistry. PD-L1 expression was tested on primary and residual tumors. Statistical analysis was performed using IBM SPSS (p < 0.05). Results: In this study, PD-L1 positive expression was found in 44.3% of primary tumors, with 52.9% of initially positive cases losing expression post-treatment. TILs were significantly higher in PD-L1-positive tumors (mean 41.79% vs. 27.55%, p = 0.001). A notable correlation was found between PD-L1 expression and Ki-67 proliferation index, with PD-L1-positive tumors having a median Ki-67 of 64.49 compared to 52.86 in negative cases (p = 0.015). Neoadjuvant immunotherapy led to a lower mean residual cancer burden (0.95 vs. 2.55, p = 0.002) compared to chemotherapy alone. Higher Ki-67 levels (≥50%) were associated with better treatment outcomes, showing a mean RCB score of 1.60 versus 3.16 for lower levels (p = 0.022). HER2-negative cases had a higher prevalence of favorable pathological response (54.5%) compared to HER2-low tumors (25%, p = 0.048), because of the strong correlation to high proliferative index. Conclusions: In conclusion, PD-L1 expression in TNBC shows significant discordance post-treatment, highlighting the need for routine testing and further research on predictive biomarkers.

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Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer

Cited by 3 publications

References 56 publications

Ozone-Induced Lung Injury are Mediated Via PPAR-Mediated Ferroptosis in Mice

Ozone-Induced Lung Injury are Mediated Via PPAR-Mediated Ferroptosis in Mice

Tumor-secreted LCN2 impairs gastric cancer progression via autocrine inhibition of the 24p3R/JNK/c-Jun/SPARC axis

Impact of Neoadjuvant Therapy on PD-L1 Expression in Triple-Negative Breast Cancer and Correlation with Clinicopathological Factors

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