NLRP6 targeting suppresses gastric tumorigenesis via P14ARF–Mdm2–P53-dependent cellular senescence
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Haibin Wang1,*, Guoxing Xu2,*, Zhengjie Huang1,3,*, Weizheng Li4, Huali Cai1, Yunda Zhang1, Disheng Xiong1, Gang Liu1, Shengjie Wang1, Zengfu Xue4 and Qi Luo1
1Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China
2Department of Endoscopy Center, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China
3Department of Gastrointestinal Surgery, First Clinical Medical College of Fujian Medical University, Fuzhou 350004, China
4Department of Cancer Prevention, Diagnosis and Treatment, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian, China
*These authors have contributed equally to this work
Zengfu Xue, email: email@example.com
Qi Luo, email: firstname.lastname@example.org
Keywords: NLRP6; gastric cancer; senescence; P14ARF; P53
Received: July 17, 2017 Accepted: November 15, 2017 Published: December 04, 2017
NLRP6, a member of the Nod-like receptor family, protects against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms involved in this NLRP6-mediated protection remain unclear. Here, we show that NLRP6 was down-regulated in approximately 75% of primary gastric cancer cases and exhibited significant associations with advanced clinical-stage lymph node metastasis and poor overall survival. Functional studies established that ectopic overexpression or down-regulation of NLRP6 inhibited cancer cell proliferation by inducing cell cycle arrest at the G1 phase via P21 and Cyclin D1 both in vitro and in vivo. Activation of the P14ARF-P53 pathway played a crucial role in the observed cellular senescence. We further demonstrated that ectopic overexpression of NLRP6 combined with inactivation of NF-κB(p65) and Mdm2 activates P14ARF-P53 to promote the senescence of gastric cancer cells. These findings indicate that NLRP6 functions as a negative regulator of gastric cancer and offer a potential new option for preventing gastric cancer.
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