CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer

Zhe Wei Wei, Guang Kai Xia, Ying Wu, Wei Chen, Zhen Xiang, Roderich E. Schwarz, Rolf A. Brekken, Niranjan Awasthi, Yu Long He, Chang Hua Zhang

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)335-343
Number of pages9
JournalCancer Letters
Volume359
Issue number2
DOIs
StatePublished - Apr 10 2015

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Vascular Endothelial Growth Factor A
Stomach Neoplasms
Ligands
Survival
Growth
STAT3 Transcription Factor
Neoplasms
Chemokine CXCL1
CCR Receptors
Janus Kinase 2
Microvessels
Protein C
Heterografts
Cell Movement
Stomach
Immunohistochemistry
Cell Proliferation
Cell Line

Keywords

  • Angiogenesis
  • CXCL1
  • Gastric cancer
  • Prognosis
  • STAT3
  • VEGF

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer. / Wei, Zhe Wei; Xia, Guang Kai; Wu, Ying; Chen, Wei; Xiang, Zhen; Schwarz, Roderich E.; Brekken, Rolf A.; Awasthi, Niranjan; He, Yu Long; Zhang, Chang Hua.

In: Cancer Letters, Vol. 359, No. 2, 10.04.2015, p. 335-343.

Research output: Contribution to journalArticle

Wei, ZW, Xia, GK, Wu, Y, Chen, W, Xiang, Z, Schwarz, RE, Brekken, RA, Awasthi, N, He, YL & Zhang, CH 2015, 'CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer', Cancer Letters, vol. 359, no. 2, pp. 335-343. https://doi.org/10.1016/j.canlet.2015.01.033
Wei, Zhe Wei ; Xia, Guang Kai ; Wu, Ying ; Chen, Wei ; Xiang, Zhen ; Schwarz, Roderich E. ; Brekken, Rolf A. ; Awasthi, Niranjan ; He, Yu Long ; Zhang, Chang Hua. / CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer. In: Cancer Letters. 2015 ; Vol. 359, No. 2. pp. 335-343.
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AU - Schwarz, Roderich E.

AU - Brekken, Rolf A.

AU - Awasthi, Niranjan

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AU - Zhang, Chang Hua

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AB - 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.

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