PMID- 34345201 OWN - NLM STAT- MEDLINE DCOM- 20220317 LR - 20231107 IS - 1449-2288 (Electronic) IS - 1449-2288 (Linking) VI - 17 IP - 11 DP - 2021 TI - TNF-alpha augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell. PG - 2683-2702 LID - 10.7150/ijbs.61350 [doi] AB - Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-alpha (TNF-alpha), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-alpha- mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-alpha activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-kappaB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells in vivo. We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3beta phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases. CI - (c) The author(s). FAU - Wang, Zhengcheng AU - Wang Z AD - Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Qingdao University, Qingdao 266000, China. FAU - Ao, Xiang AU - Ao X AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Shen, Zhilin AU - Shen Z AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Ao, Luoquan AU - Ao L AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Wu, Xiaofeng AU - Wu X AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Pu, Chengxiu AU - Pu C AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Guo, Wei AU - Guo W AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Xing, Wei AU - Xing W AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - He, Min AU - He M AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Yuan, Hongfeng AU - Yuan H AD - Department of Ophthalmology, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Yu, Jianhua AU - Yu J AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. FAU - Li, Ling AU - Li L AD - Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Qingdao University, Qingdao 266000, China. FAU - Xu, Xiang AU - Xu X AD - Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210626 PL - Australia TA - Int J Biol Sci JT - International journal of biological sciences JID - 101235568 RN - 0 (CXCL10 protein, human) RN - 0 (CXCR3 protein, human) RN - 0 (Chemokine CXCL10) RN - 0 (Receptors, CXCR3) RN - 0 (TNF protein, human) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) SB - IM MH - Animals MH - Cell Line, Tumor MH - Cell Movement MH - Chemokine CXCL10/*metabolism MH - Colonic Neoplasms/*metabolism MH - *Epithelial-Mesenchymal Transition MH - Gene Expression Regulation, Neoplastic MH - Glycogen Synthase Kinase 3 beta/metabolism MH - Humans MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Phosphatidylinositol 3-Kinases/metabolism MH - Receptors, CXCR3/*metabolism MH - Signal Transduction MH - Tumor Microenvironment MH - Tumor Necrosis Factor-alpha/*metabolism PMC - PMC8326125 OTO - NOTNLM OT - CC OT - CXCL10/CXCR3 OT - EMT OT - TNF-alpha OT - invasion OT - migration COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2021/08/05 06:00 MHDA- 2022/03/18 06:00 PMCR- 2021/01/01 CRDT- 2021/08/04 07:05 PHST- 2021/04/09 00:00 [received] PHST- 2021/06/13 00:00 [accepted] PHST- 2021/08/04 07:05 [entrez] PHST- 2021/08/05 06:00 [pubmed] PHST- 2022/03/18 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - ijbsv17p2683 [pii] AID - 10.7150/ijbs.61350 [doi] PST - epublish SO - Int J Biol Sci. 2021 Jun 26;17(11):2683-2702. doi: 10.7150/ijbs.61350. eCollection 2021.