title: CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer.
abstract: The chemokine (C-X-C motif) ligand 1 (CXCL1) regulates tumor-stromal interactions and tumor invasion. However, the precise role of CXCL1 on gastric tumor growth and patient survival remains unclear. In the current study, protein expressions of CXCL1, vascular endothelial growth factor (VEGF) and phospho-signal transducer and activator of transcription 3 (p-STAT3) in primary tumor tissues from 98 gastric cancer patients were measured by immunohistochemistry (IHC). CXCL1 overexpressed cell lines were constructed using Lipofectamine 2000 reagent or lentiviral vectors. Effects of CXCL1 on VEGF expression and local tumor growth were evaluated in vitro and in vivo. CXCL1 was positively expressed in 41.4% of patients and correlated with VEGF and p-STAT3 expression. Higher CXCL1 expression was associated with advanced tumor stage and poorer prognosis. In vitro studies in AGS and SGC-7901 cells revealed that CXCL1 increased cell migration but had little effect on cell proliferation. CXCL1 activated VEGF signaling in gastric cancer (GC) cells, which was inhibited by STAT3 or chemokine (C-X-C motif) receptor 2 (CXCR2) blockade. CXCL1 also increased p-STAT3 expression in GC cells. In vivo, CXCL1 increased xenograft local tumor growth, phospho-Janus kinase 2 (p-JAK2), p-STAT3 levels, VEGF expression and microvessel density. These results suggested that CXCL1 increased local tumor growth through activation of VEGF signaling which may have mechanistic implications for the observed inferior GC survival. The CXCL1/CXCR2 pathway might be potent to improve anti-angiogenic therapy for gastric cancer.
authors: Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China; Gastric Cancer Center of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China.
authors: Zhe-Wei
authors: ZW
authors: Wei
authors: Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China; Gastric Cancer Center of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China.
authors: Guang-Kai
authors: GK
authors: Xia
authors: Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China; Gastric Cancer Center of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China.
authors: Ying
authors: Y
authors: Wu
authors: Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China; Gastric Cancer Center of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China.
authors: Wei
authors: W
authors: Chen
authors: Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China; Gastric Cancer Center of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China.
authors: Zhen
authors: Z
authors: Xiang
authors: Indiana University School of Medicine, South Bend, and IU Health Goshen Center for Cancer Care, 200 High Park Avenue, Goshen, IN 46526, USA.
authors: Roderich E
authors: RE
authors: Schwarz
authors: Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors: Rolf A
authors: RA
authors: Brekken
authors: Indiana University School of Medicine, South Bend, and IU Health Goshen Center for Cancer Care, 200 High Park Avenue, Goshen, IN 46526, USA.
authors: Niranjan
authors: N
authors: Awasthi
authors: Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China; Gastric Cancer Center of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China. Electronic address: huasundy@yahoo.com.
authors: Yu-Long
authors: YL
authors: He
authors: Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China; Gastric Cancer Center of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China. Electronic address: zhchangh@mail.sysu.edu.cn.
authors: Chang-Hua
authors: CH
authors: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054360:Chemokine CXCL1 / Q000502:physiology*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; CXCL1; Gastric cancer; Prognosis; STAT3; VEGF