CXCL12 expression promotes esophageal squamous cell carcinoma proliferation and worsens the prognosis

Yusuke Uchi, Hiroya Takeuchi, Sachiko Matsuda, Yoshiro Saikawa, Hirofumi Kawakubo, Norihito Wada, Tsunehiro Takahashi, Rieko Nakamura, Kazumasa Fukuda, Tai Omori, Yuukou Kitagawa

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: The chemokine CXCL12 and its corresponding receptor CXCR4 are key players in the development of several cancers. Therefore, we hypothesized that there is a functional causality between CXCL12 expression and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Methods: We performed an immunohistochemical analysis in 79 consecutive patients with ESCC. We performed in vitro and in vivo cell proliferation assays using ESCC cell lines and a newly established transfectant stably overexpressing CXCL12. Results: Immunohistochemistry revealed positive CXCR4 and CXCL12 expression in 48 (61 %) and 62 (78 %) patients, respectively. Additionally, the expression levels did not significantly correlate with any clinicopathological factors. The MIB-1 proliferation index was markedly higher in ESCC with a positive expression of CXCR4 or CXCL12. Positive CXCL12 expression was significantly correlated with lower recurrence-free survival (RFS, p = 0.02). Cox's hazard models revealed CXCL12 expression as an independent predictive factor for recurrence. In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression. In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03). Conclusions: CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC. Our findings indicate that positive CXCL12 expression may be a useful marker for predicting the outcome in patients with ESCC and is a potentially new therapeutic target for ESCC.

Original languageEnglish
Article number514
JournalBMC Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - 2016 Jul 21

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Cell Proliferation
Proportional Hazards Models
Esophageal Squamous Cell Carcinoma
CXCR4 Receptors
Chemokine CXCL12
Recurrence
Neoplasms
Causality
Immunohistochemistry
Cell Line
Survival

Keywords

  • Chemokine
  • Chemokine receptor
  • CXCL12
  • CXCR4
  • Esophageal squamous cell carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

CXCL12 expression promotes esophageal squamous cell carcinoma proliferation and worsens the prognosis. / Uchi, Yusuke; Takeuchi, Hiroya; Matsuda, Sachiko; Saikawa, Yoshiro; Kawakubo, Hirofumi; Wada, Norihito; Takahashi, Tsunehiro; Nakamura, Rieko; Fukuda, Kazumasa; Omori, Tai; Kitagawa, Yuukou.

In: BMC Cancer, Vol. 16, No. 1, 514, 21.07.2016.

Research output: Contribution to journalArticle

Uchi, Yusuke ; Takeuchi, Hiroya ; Matsuda, Sachiko ; Saikawa, Yoshiro ; Kawakubo, Hirofumi ; Wada, Norihito ; Takahashi, Tsunehiro ; Nakamura, Rieko ; Fukuda, Kazumasa ; Omori, Tai ; Kitagawa, Yuukou. / CXCL12 expression promotes esophageal squamous cell carcinoma proliferation and worsens the prognosis. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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AU - Uchi, Yusuke

AU - Takeuchi, Hiroya

AU - Matsuda, Sachiko

AU - Saikawa, Yoshiro

AU - Kawakubo, Hirofumi

AU - Wada, Norihito

AU - Takahashi, Tsunehiro

AU - Nakamura, Rieko

AU - Fukuda, Kazumasa

AU - Omori, Tai

AU - Kitagawa, Yuukou

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N2 - Background: The chemokine CXCL12 and its corresponding receptor CXCR4 are key players in the development of several cancers. Therefore, we hypothesized that there is a functional causality between CXCL12 expression and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Methods: We performed an immunohistochemical analysis in 79 consecutive patients with ESCC. We performed in vitro and in vivo cell proliferation assays using ESCC cell lines and a newly established transfectant stably overexpressing CXCL12. Results: Immunohistochemistry revealed positive CXCR4 and CXCL12 expression in 48 (61 %) and 62 (78 %) patients, respectively. Additionally, the expression levels did not significantly correlate with any clinicopathological factors. The MIB-1 proliferation index was markedly higher in ESCC with a positive expression of CXCR4 or CXCL12. Positive CXCL12 expression was significantly correlated with lower recurrence-free survival (RFS, p = 0.02). Cox's hazard models revealed CXCL12 expression as an independent predictive factor for recurrence. In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression. In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03). Conclusions: CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC. Our findings indicate that positive CXCL12 expression may be a useful marker for predicting the outcome in patients with ESCC and is a potentially new therapeutic target for ESCC.

AB - Background: The chemokine CXCL12 and its corresponding receptor CXCR4 are key players in the development of several cancers. Therefore, we hypothesized that there is a functional causality between CXCL12 expression and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Methods: We performed an immunohistochemical analysis in 79 consecutive patients with ESCC. We performed in vitro and in vivo cell proliferation assays using ESCC cell lines and a newly established transfectant stably overexpressing CXCL12. Results: Immunohistochemistry revealed positive CXCR4 and CXCL12 expression in 48 (61 %) and 62 (78 %) patients, respectively. Additionally, the expression levels did not significantly correlate with any clinicopathological factors. The MIB-1 proliferation index was markedly higher in ESCC with a positive expression of CXCR4 or CXCL12. Positive CXCL12 expression was significantly correlated with lower recurrence-free survival (RFS, p = 0.02). Cox's hazard models revealed CXCL12 expression as an independent predictive factor for recurrence. In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression. In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03). Conclusions: CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC. Our findings indicate that positive CXCL12 expression may be a useful marker for predicting the outcome in patients with ESCC and is a potentially new therapeutic target for ESCC.

KW - Chemokine

KW - Chemokine receptor

KW - CXCL12

KW - CXCR4

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