L1CAM overexpression promotes tumor progression through recruitment of regulatory T cells in esophageal carcinoma
| Autor: | Yu Qi, Yang Yang, Jianyi Zhao, Qitai Zhao, Tan Xie, Feng Li, Shasha Liu, Xinfeng Chen, Xuan Zhao, Song Zhao, Yi Zhang, Zhen Zhang, Lan Huang |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
L1 Regulatory T cell Biology tgf-β Immune system Carcinoma medicine Protein kinase B RC254-282 PI3K/AKT/mTOR pathway Tumor microenvironment business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cell migration Cell cycle medicine.disease ccl22 tregs esophageal squamous cell carcinoma medicine.anatomical_structure Oncology Tumor progression l1cam Cancer research Original Article Signal transduction business |
| Zdroj: | Cancer Biology & Medicine, Vol 18, Iss 2, Pp 547-561 (2021) Cancer Biology & Medicine |
| ISSN: | 2095-3941 |
| Popis: | Objective: L1 cell adhesion molecule (L1CAM) exhibits oncogenic activity in tumors. However, the link between L1CAM and the tumor microenvironment remains poorly understood in patients with esophageal squamous cell carcinoma (ESCC). In this study, we investigated how L1CAM expression in ESCC affects the oncogenic characteristics of tumor cells and the tumor microenvironment. Methods: Human ESCC samples were collected, and the mRNA and protein levels of L1CAM were examined by real-time PCR and immunohistochemistry. Overexpression and knockdown gene expression assays were used for mechanistic studies. The cell proliferation and cell cycle were measured with CCK-8 assays and flow cytometry. Cell migration and invasion ability were measured with Transwell assays. Multiplex bead-based assays were performed to identity the factors downstream of L1CAM. Xenograft studies were performed in nude mice to evaluate the effects of L1CAM on tumor growth and regulatory T cell (Treg) recruitment. Results: L1CAM expression was significantly elevated in ESCC tissues (P < 0.001) and correlated with poorer prognosis (P < 0.05). Ablation of L1CAM in ESCC cells inhibited tumor growth and migration, and increased tumor cell apoptosis (P < 0.05). In the tumor microenvironment, L1CAM expression correlated with Treg infiltration in ESCC by affecting CCL22 secretion. Mechanistically, L1CAM facilitated CCL22 expression by activating the PI3K/Akt/NF-κB signaling pathway. Furthermore, CCL22 promoted Treg recruitment to the tumor site; the Tregs then secreted TGF-β, which in turn promoted L1CAM expression via Smad2/3 in a positive feedback loop. Conclusions: Our findings provide new insight into the mechanism of immune evasion mediated by L1CAM, suggesting that targeting L1CAM-CCL22-TGF-β crosstalk between tumor cells and Tregs may offer a unique means to improve treatment of patients with ESCC. |
| Databáze: | OpenAIRE |
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