Hui Cao1, Sihong Jiang2, Ruitao Yuan2, Wei Zhang2, Yun Liu2, Chen Shao3, Shihe Shao4,5. 1. Digestive Disease Center, Shanghai East Hospital, Tongji University, Shanghai, 200120, China. 2. School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China. 3. Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212013, Jiangsu, China. osam94@163.com. 4. Digestive Disease Center, Shanghai East Hospital, Tongji University, Shanghai, 200120, China. shaoshihe2007@sina.com. 5. School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China. shaoshihe2007@sina.com.
Abstract
BACKGROUND: IκB kinase 2 (IKK2) is the primary catalytic subunit of the IKK complex. Activation of IKK phosphorylates the inhibitors of NF-κB (IκB), triggering the translocation of NF-κB. AIMS: Although IKK2 has been investigated in the inflammation-cancer transformation of gastric epithelium, its role in gastric cancer (GC) cells remained unexplored. METHODS: The IKK2 distribution and expression were measured by immunochemistry staining in clinical specimens. The proliferation, apoptosis, and migration of GC cells were analyzed after IKK2 expression intervention. Using Erk and β-catenin inhibitors, we investigated the relationship between IKK2 and Erk and β-catenin pathways. In the GC-burdened mice, we confirmed the effects of IKK2 inhibition on tumor growth. RESULTS: Here, we found that IKK2 expression in the GC area was even higher than adjacent inflammatory area, and the GC patients with high expression of IKK2 showed worse overall and disease-free survival. Introduction of IKK2 inhibitor SC-514 inhibited the cell proliferation and induced apoptosis of SGC-7901 cells, in turn overexpression of IKK2 in MGC-823 cells showed the reverse effects. The proliferative activity of IKK2 on GC cells was dependent on the activation of β-catenin and Erk pathways. Additionally, IKK2 alteration affected the migration of GC cells. In vivo, IKK2 inhibition mitigated the tumor growth. Decreased expression of PCNA as well as an increase in cleaved caspase 3 and p53 were observed. CONCLUSION: Our results indicate that IKK2 promotes the GC cell proliferation and inhibits their apoptosis, suggesting it may be a potential target for GC therapy.
BACKGROUND: IκB kinase 2 (IKK2) is the primary catalytic subunit of the IKK complex. Activation of IKK phosphorylates the inhibitors of NF-κB (IκB), triggering the translocation of NF-κB. AIMS: Although IKK2 has been investigated in the inflammation-cancer transformation of gastric epithelium, its role in gastric cancer (GC) cells remained unexplored. METHODS: The IKK2 distribution and expression were measured by immunochemistry staining in clinical specimens. The proliferation, apoptosis, and migration of GC cells were analyzed after IKK2 expression intervention. Using Erk and β-catenin inhibitors, we investigated the relationship between IKK2 and Erk and β-catenin pathways. In the GC-burdened mice, we confirmed the effects of IKK2 inhibition on tumor growth. RESULTS: Here, we found that IKK2 expression in the GC area was even higher than adjacent inflammatory area, and the GC patients with high expression of IKK2 showed worse overall and disease-free survival. Introduction of IKK2 inhibitor SC-514 inhibited the cell proliferation and induced apoptosis of SGC-7901 cells, in turn overexpression of IKK2 in MGC-823 cells showed the reverse effects. The proliferative activity of IKK2 on GC cells was dependent on the activation of β-catenin and Erk pathways. Additionally, IKK2 alteration affected the migration of GC cells. In vivo, IKK2 inhibition mitigated the tumor growth. Decreased expression of PCNA as well as an increase in cleaved caspase 3 and p53 were observed. CONCLUSION: Our results indicate that IKK2 promotes the GC cell proliferation and inhibits their apoptosis, suggesting it may be a potential target for GC therapy.
Authors: Michael Sigal; Catriona Y Logan; Marta Kapalczynska; Hans-Joachim Mollenkopf; Hilmar Berger; Bertram Wiedenmann; Roeland Nusse; Manuel R Amieva; Thomas F Meyer Journal: Nature Date: 2017-08-16 Impact factor: 49.962
Authors: Florian R Greten; Lars Eckmann; Tim F Greten; Jin Mo Park; Zhi-Wei Li; Laurence J Egan; Martin F Kagnoff; Michael Karin Journal: Cell Date: 2004-08-06 Impact factor: 41.582
Authors: Sergei Grivennikov; Eliad Karin; Janos Terzic; Daniel Mucida; Guann-Yi Yu; Sivakumar Vallabhapurapu; Jürgen Scheller; Stefan Rose-John; Hilde Cheroutre; Lars Eckmann; Michael Karin Journal: Cancer Cell Date: 2009-02-03 Impact factor: 31.743
Authors: Ulrich Pannicke; Bernd Baumann; Sebastian Fuchs; Philipp Henneke; Anne Rensing-Ehl; Marta Rizzi; Ales Janda; Katrin Hese; Michael Schlesier; Karlheinz Holzmann; Stephan Borte; Constanze Laux; Eva-Maria Rump; Alan Rosenberg; Teresa Zelinski; Hubert Schrezenmeier; Thomas Wirth; Stephan Ehl; Marlis L Schroeder; Klaus Schwarz Journal: N Engl J Med Date: 2013-12-26 Impact factor: 91.245
Authors: Yifeng Xia; Roanna C Padre; Tatiana Hurtado De Mendoza; Virginie Bottero; Vinay B Tergaonkar; Inder M Verma Journal: Proc Natl Acad Sci U S A Date: 2009-02-05 Impact factor: 11.205