A synergistic interaction between transcription factors nuclear factor-κB and signal transducers and activators of transcription 3 promotes gastric cancer cell migration and invasion
1 Department of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea
2 Cancer Research Institute, Department of Tumor Biology, Seoul National University College of Medicine, Seoul, 110-799, South Korea
3 Department of Economics, Cornell University, Ithaca, NY, 14853, USA
4 Radiation Health Research Institute, Korea Hydro & Nuclear Power Co., Ltd, Seoul, 132-703, South Korea
5 Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799, South Korea
6 Department of Pathology, Seoul National University Bundang Hospital, Seongnam, 463-707, South Korea
7 Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, 110-799, South Korea
BMC Gastroenterology 2013, 13:29 doi:10.1186/1471-230X-13-29Published: 12 February 2013
The transcription factor nuclear factor-κB (NF-κB) has been implicated in gastric cancer metastasis, but the underlying molecular mechanisms remain unclear. We investigated the role of the interaction between NF-κB and signal transducers and activators of transcription 3 (STAT3) in controlling metastatic potential of gastric cancer cells.
Immunohistochemistry for NF-κB p65 (RelA), phospho-Tyr705-STAT3 (pSTAT3), or matrix metalloproteinase 9 (MMP9) was performed on tissue array slides containing 255 gastric carcinoma specimens. NF-κB inhibition in SNU-638 and MKN1 gastric cancer cell lines were performed by transduction with a retroviral vector containing NF-κB repressor mutant of IκBα, and STAT3 was silenced by RNA interference. We also did luciferase reporter assay, double immunofluorescence staining and immunoblotting. Cell migration and invasion were determined by wound-healing assay and invasion assay, respectively.
NF-κB and STAT3 were constitutively activated and were positively correlated (P = 0.038) in gastric cancer tissue specimens. In cell culture experiments, NF-κB inhibition reduced STAT3 expression and activation, whereas STAT3 silencing did not affect NF-κB activation. Moreover, both NF-κB inhibition and STAT3 silencing decreased gastric cancer cell migration and invasion in a synergistic manner. In addition, both NF-κB activation and STAT3 activation were positively correlated with MMP9 in gastric cancer tissues (P = 0.001 and P = 0.022, respectively), decreased E-cadherin expression and increased Snail and MMP9 expressions in cultured cells.
NF-κB and STAT3 are positively associated and synergistically contribute to the metastatic potential of gastric cancer cells. Thus, dual use of NF-κB and STAT3 inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.