ING5 inhibits cancer aggressiveness via preventing EMT and is a potential prognostic biomarker for lung cancer
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Feng Zhang1,*, Xutao Zhang1,*, Jin Meng2,3,*, Yong Zhao4, Xinli Liu1, Yanxia Liu5, Yukun Wang1, Yuhua Li1, Yang Sun1, Zhipeng Wang1, Qibing Mei1 and Tao Zhang6
1 Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, China
2 Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China
3 Department of Pharmacy, No. 309 Hospital of PLA, Beijing, China
4 Laboratory Animal Center, Fourth Military Medical University, Xi’an, China
5 National Engineering Center for Biochip, Shanghai, China
6 Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
* These authors have contributed equally to this work
Tao Zhang, email:
Qibing Mei, email:
Keywords: ING5, lung cancer, proliferation, invasion, EMT
Received: December 15, 2014 Accepted: March 20, 2015 Published: April 15, 2015
The proteins of the Inhibitor of Growth (ING) candidate tumor suppressor family are involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. ING5 is the new member of the family whose actual role in tumor suppression is not known. Here we show that ING5 overexpression in lung cancer A549 cells inhibited cell proliferation and invasiveness, while ING5 knockdown in lung cancer H1299 cells promoted cell aggressiveness. ING5 overexpression also abrogated tumor growth and invasive abilities of lung cancer cells in mouse xenograft models. Further study showed that ING5 overexpression inhibited EMT indicated by increase of E-cadherin and decrease of N-cadherin, Snail and slug at mRNA and protein levels, which was accompanied with morphological changes. cDNA microarray and subsequent qRT-PCR validation revealed that ING5 significantly downregulated expression of EMT (epithelial to mesenchymal transition)-inducing genes including CEACAM6, BMP2 and CDH11. Clinical study by tissue microarray showed that nuclear ING5 negatively correlated with clinical stages and lymph node metastasis of lung cancer. Furthermore, high level of nuclear ING5 was associated with a better prognosis. Taken together, these findings uncover an important role for ING5 as a potent tumor suppressor in lung cancer growth and metastasis.
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