Tumor-associated macrophages promote tumor metastasis via the TGF-β/SOX9 axis in non-small cell lung cancer

// Shuai Zhang 1 , Dehai Che 1 , Fang Yang 1 , Chunling Chi 2 , Hongxue Meng 3 , Jing Shen 1 , Li Qi 4 , Fang Liu 1 , Liyan Lv 5 , Yue Li 1 , Qingwei Meng 1 , Junning Liu 6 , Lihua Shang 1 and Yan Yu 1 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China 2 Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China 3 Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China 4 Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China 5 Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China 6 Department of Oncology, The First Affiliated Hospital of Qiqihar Medical College, Qiqihar, China Correspondence to: Yan Yu, email: yuyan@ems.hrbmu.edu.cn Keywords: non-small cell lung cancer (NSCLC), tumor-associated macrophages (TAMs), metastasis, TGF-β, SOX9 Received: March 21, 2017 Accepted: July 25, 2017 Published: September 16, 2017 ABSTRACT Tumor-associated macrophages (TAMs), most of which display the immunosuppressive M2 phenotype, affect the tumor microenvironment and promote progression and metastasis in lung carcinoma. In this study, we analyzed clinical non-small cell lung cancer (NSCLC) samples and found that high densities of TAMs were associated with a poor prognosis in NSCLC patients. Moreover, the number of TAMs present correlated positively with expression of sex determining region Y (SRY)-related high mobility group box 9 (SOX9) in NSCLC tissues. TAMs secreted TGF-β, which increased SOX9 expression and promoted epithelial-to-mesenchymal transition (EMT) in lung cancer cells, thereby promoting tumor proliferation, migration, and invasion. SOX9 knockdown inhibited EMT, indicating that TGF-β-mediated EMT is SOX9-dependent. TGF-β induced SOX9 expression by upregulating the C-jun/SMAD3 pathway. These results indicate that TGF-β secreted by TAMs promotes SOX9 expression via the C-jun/SMAD3 pathway, thereby promoting tumor metastasis. The TGF-β/SOX9 axis may therefore be an effective target for the treatment of lung cancer.