PMID- 29855462 OWN - NLM STAT- MEDLINE DCOM- 20191129 LR - 20231112 IS - 2041-4889 (Electronic) VI - 9 IP - 6 DP - 2018 May 31 TI - STX2 promotes colorectal cancer metastasis through a positive feedback loop that activates the NF-kappaB pathway. PG - 664 LID - 10.1038/s41419-018-0675-x [doi] LID - 664 AB - Metastatic progression is the main contributor to the poor prognosis of colorectal cancer (CRC). Thus, identifying the determinants of CRC metastasis will be of great significance. Based on our previous bioinformatics analysis, Syntaxin2 (STX2) may be upregulated and correlated with the poor prognosis of CRC patients. In this study, we found that STX2 expression was associated with CRC invasion and metastasis and poor patient survival. Gain- and loss-of-function analyses demonstrated that STX2 functioned as a key oncogene by promoting CRC invasion and metastasis. Mechanistically, STX2 selectively interacted with tumor necrosis factor receptor-associated factor 6 (TRAF6) and activated the nuclear transcription factor-kappaB (NF-kappaB) signaling pathway. Furthermore, chromatin immunoprecipitation (ChIP) analysis revealed that NF-kappaB directly bound to the STX2 promoter and drove STX2 transcription. Therefore, STX2 activated the NF-kappaB pathway, and in turn, NF-kappaB increased STX2 expression, forming a positive signaling loop that eventually promoted CRC metastasis. Collectively, our results reveal STX2 as a crucial modulator of the aggressive CRC phenotype and highlight STX2 as a potential prognostic biomarker and therapeutic target for combating CRC metastasis. FAU - Wang, Yongxia AU - Wang Y AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China. FAU - Xu, Honghai AU - Xu H AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Jiao, Hongli AU - Jiao H AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Wang, Shuyang AU - Wang S AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Xiao, Zhiyuan AU - Xiao Z AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Zhao, Yali AU - Zhao Y AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Bi, Jiaxin AU - Bi J AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Wei, Wenting AU - Wei W AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Liu, Shanshan AU - Liu S AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Qiu, Junfeng AU - Qiu J AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Li, Tingting AU - Li T AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Liang, Li AU - Liang L AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. FAU - Ye, Yaping AU - Ye Y AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. 149941225@qq.com. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. 149941225@qq.com. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. 149941225@qq.com. FAU - Liao, Wenting AU - Liao W AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. liaowt2002@gmail.com. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. liaowt2002@gmail.com. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. liaowt2002@gmail.com. FAU - Ding, Yanqing AU - Ding Y AD - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. dyq@fimmu.com. AD - Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. dyq@fimmu.com. AD - Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. dyq@fimmu.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180531 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (NF-kappa B) RN - 0 (STX2 protein, human) RN - 0 (Syntaxin 1) RN - 0 (TNF Receptor-Associated Factor 6) SB - IM MH - Animals MH - Cell Line, Tumor MH - Colorectal Neoplasms/genetics/*metabolism/*pathology MH - Down-Regulation/genetics MH - *Feedback, Physiological MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Male MH - Mice, Nude MH - Middle Aged MH - NF-kappa B/*metabolism MH - Neoplasm Metastasis MH - Promoter Regions, Genetic/genetics MH - *Signal Transduction MH - Syntaxin 1/genetics/*metabolism MH - TNF Receptor-Associated Factor 6/metabolism MH - Treatment Outcome MH - Up-Regulation/genetics PMC - PMC5981218 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/06/02 06:00 MHDA- 2019/11/30 06:00 PMCR- 2018/05/31 CRDT- 2018/06/02 06:00 PHST- 2018/04/01 00:00 [received] PHST- 2018/04/27 00:00 [accepted] PHST- 2018/04/26 00:00 [revised] PHST- 2018/06/02 06:00 [entrez] PHST- 2018/06/02 06:00 [pubmed] PHST- 2019/11/30 06:00 [medline] PHST- 2018/05/31 00:00 [pmc-release] AID - 10.1038/s41419-018-0675-x [pii] AID - 675 [pii] AID - 10.1038/s41419-018-0675-x [doi] PST - epublish SO - Cell Death Dis. 2018 May 31;9(6):664. doi: 10.1038/s41419-018-0675-x.