TGFβ1 induces CXCL1 to promote stemness features in lung cancer

Abstract

Chemokines critically orchestrate the tumorigenesis, metastasis, and stemness features of cancer cells that lead to poor outcomes. High plasma levels of transforming growth factor-beta 1 (TGF beta 1) correlate with poor prognostic features in advanced lung cancer patients, thus suggesting the importance of TGF beta 1 in the lung tumor microenvironment. However, the role of chemokines in TGF beta 1-induced tumor stemness features remains unclear. Here, we clarify the previously undocumented role of CXCL1 in TGF beta 1-induced lung cancer stemness features. CXCL1 and its receptor CXCR2 were significantly upregulated in TGF beta 1-induced lung cancer stem cells (CSCs). CXCL1 silencing (shCXCL1) suppressed stemness gene expression, tumorsphere formation, colony formation, drug resistance, and in vivo tumorigenicity in TGF beta 1-induced lung tumorspheres. Immunohistochemistry staining showed that patients with stage II/III lung cancer had higher expression levels of CXCL1. The levels of CXCL1 were positively associated with lymph node metastasis and correlated with the expression of the CSC transcription factor Oct-4. Furthermore, online database analysis revealed that CXCL1 expression was negatively correlated with lung cancer survival in patients. Patients with high TGF beta 1/CXCL1/CD44 co-expression had a worse survival rate. We suggest that CXCL1 serves as a crucial factor in TGF beta 1-induced stemness features of lung cancer.