SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial–mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway

• Published in: Cancer letters 2012-09, Vol.322 (2), p.169-176
• Main Authors: Li, Xuqi, Ma, Qingyong, Xu, Qinhong, Liu, Han, Lei, Jianjun, Duan, Wanxing, Bhat, Kruttika, Wang, Fengfei, Wu, Erxi, Wang, Zheng
• Format: Article
• Language: English
• Subjects: Biomedical research; Biotechnology; Cell adhesion & migration; Cell culture; cell invasion; Cell Line, Tumor; Cell migration; cell movement; Chemokine CXCL12 - metabolism; CXCR4; CXCR4 protein; Epithelial-Mesenchymal Transition; Gene Expression; Hedgehog pathway; Hedgehog protein; Hedgehog Proteins - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Ligands; Mesenchyme; Neoplasm Invasiveness; Pancreas; Pancreatic cancer; Pancreatic cancer invasion; pancreatic neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Proteins; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; SDF-1 protein; Signal Transduction; siRNA; Smoothened Receptor; Transcription; Transcription factors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2012.02.035

In our previous study, we found that blockade of SDF-1/CXCR4 signaling inhibits pancreatic cancer cell migration and invasion in vitro. However, the mechanism governing the downstream regulation of SDF-1/CXCR4-mediated invasion remains unclear. Here we report the role of SDF-1/CXCR4 in pancreatic cancer and the possible mechanism of SDF-1/CXCR4-mediated pancreatic cancer invasion. We show that there is a cross-talk between SDF-1/CXCR4 axis and non-canonical Hedgehog (Hh) pathway in pancreatic cancer. Furthermore, our data demonstrate that the ligand of CXCR4, SDF-1 induces CXCR4-positive pancreatic cancer invasion, epithelial–mesenchymal transition (EMT) process and activates the non-canonical Hh pathway. Moreover, we also demonstrate that the invasion of a pancreatic cancer and EMT resulting from the activation of SDF-1/CXCR4 axis is effectively inhibited by Smoothened (SMO) inhibitor cyclopamine and siRNA specific to Gli-1. Collectively, these data demonstrate that SDF-1/CXCR4 modulates the non-canonical Hh pathway by increasing the transcription of SMO in a ligand-independent manner. Taken together, SDF-1/CXCR4 axis may represent a promising therapeutic target to prevent pancreatic cancer progression.