miR141-CXCL1-CXCR2 signaling-induced Treg recruitment regulates metastases and survival of non-small cell lung cancer

• Published in: Molecular cancer therapeutics 2014-12, Vol.13 (12), p.3152-3162
• Main Authors: Lv, Mingming, Xu, Yujun, Tang, Ruijing, Ren, Jing, Shen, Sunan, Chen, Yueqiu, Liu, Baorui, Hou, Yayi, Wang, Tingting
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Chemokine CXCL1 - genetics; Chemokine CXCL1 - metabolism; Chemotaxis, Leukocyte - genetics; Chemotaxis, Leukocyte - immunology; Disease Models, Animal; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Lymphocyte Count; Mice; MicroRNAs - genetics; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Receptors, Interleukin-8B - genetics; Receptors, Interleukin-8B - metabolism; Signal Transduction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-14-0448

Patients with non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) have a short median survival time and increased regulatory T cells (Treg). However, it is unclear whether some specific factors in MPE are involved in Treg recruitment in the progression of NSCLC. Here, we found that Treg population was increased in MPE and inversely correlated with patient survival (P < 0.001). Increased level of CXCL1 in MPE was associated with recruitment of Tregs (P < 0.01). Moreover, miR141 regulated expression of CXCL1 in lung cancer cells, whereas the luciferase test confirmed that CXCL1 is a target of miR141. Chemotaxis assay showed that the miR141-CXCL1-CXCR2 pathway regulates migration of Tregs into MPE. Furthermore, miR141 significantly inhibited tumor growth and metastasis in an immune-competent mouse model. This suppressive function was mediated by the CXCL1-CXCR2 pathway and recruitment of Tregs. Our study uncovered a causative link between microRNA and development of MPE. Mechanistically, decreased expressions of miR141, associated with the survival of patients with NSCLC with MPE, resulted in the increased production of CXCL1 and recruitment of Tregs to promote immune escape of tumor.