Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma

Yohei Mano, Shinichi Aishima, Nobuhiro Fujita, Yuki Tanaka, Yuichiro Kubo, Takashi Motomura, Akinobu Taketomi, Ken Shirabe, Yoshihiko Maehara, Yoshinao Oda

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Abstract

Objective: Signal transducer and activator of transcription 3 (STAT3) is activated in hepatocellular carcinoma (HCC), and tumor-associated macrophage plays an important role in tumor progression. Therefore, we examined STAT3 activation, cytokine expression and infiltration of tumor-associated macrophages in resected HCCs as well as the alteration of cell growth and migration by cytokine stimulation in HCC cell lines. Methods: Immunohistochemical staining of phosphorylated STAT3 (pSTAT3), CD163, interleukin (IL)-6, Ki-67 and Bcl-XL was performed for 101 cases of resected HCC, and correlations between pSTAT3 staining and clinicopathological findings were analyzed. In HCC cell lines (PLC/PRF/5 and Huh7), cell proliferation and migration by IL-6 stimulation and S3I-201 (STAT3 inhibitor) treatment were analyzed. Results: In HCC specimens, the pSTAT3-positive group showed high levels of α-fetoprotein (p = 0.0276), large tumor size (p = 0.0092), frequent intrahepatic metastasis (p = 0.0214), high Ki-67 (p = 0.0002) and Bcl-XL (p = 0.0001), poor prognosis (p = 0.0234), and high recurrence rate (p = 0.0003). CD163-positive cells were frequently observed in the pSTAT3-positive group (p = 0.0013). In two HCC cell lines, IL-6 stimulation promoted cell proliferation and migration via the STAT3 phosphorylation, and S3I-201 inhibited this activation. Conclusions: STAT3 activation was correlated with aggressive behavior of HCC and may be mediated via tumor-associated macrophage. We expect that STAT3 signaling and tumor-associated macrophages can be attractive therapeutic targets in HCC patients.

Original languageEnglish
Pages (from-to)146-154
Number of pages9
JournalPathobiology
Volume80
Issue number3
DOIs
Publication statusPublished - Mar 1 2013

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STAT3 Transcription Factor
Hepatocellular Carcinoma
Macrophages
NSC 74859
Neoplasms
Cell Movement
Interleukin-6
Cell Line
Transcriptional Activation
Cell Proliferation
Fetal Proteins
Staining and Labeling
Cytokines
Phosphorylation
Neoplasm Metastasis
Recurrence
Therapeutics
Growth

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma. / Mano, Yohei; Aishima, Shinichi; Fujita, Nobuhiro; Tanaka, Yuki; Kubo, Yuichiro; Motomura, Takashi; Taketomi, Akinobu; Shirabe, Ken; Maehara, Yoshihiko; Oda, Yoshinao.

In: Pathobiology, Vol. 80, No. 3, 01.03.2013, p. 146-154.

Research output: Contribution to journalArticle

Mano, Y, Aishima, S, Fujita, N, Tanaka, Y, Kubo, Y, Motomura, T, Taketomi, A, Shirabe, K, Maehara, Y & Oda, Y 2013, 'Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma', Pathobiology, vol. 80, no. 3, pp. 146-154. https://doi.org/10.1159/000346196
Mano, Yohei ; Aishima, Shinichi ; Fujita, Nobuhiro ; Tanaka, Yuki ; Kubo, Yuichiro ; Motomura, Takashi ; Taketomi, Akinobu ; Shirabe, Ken ; Maehara, Yoshihiko ; Oda, Yoshinao. / Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma. In: Pathobiology. 2013 ; Vol. 80, No. 3. pp. 146-154.
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AU - Tanaka, Yuki

AU - Kubo, Yuichiro

AU - Motomura, Takashi

AU - Taketomi, Akinobu

AU - Shirabe, Ken

AU - Maehara, Yoshihiko

AU - Oda, Yoshinao

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AB - Objective: Signal transducer and activator of transcription 3 (STAT3) is activated in hepatocellular carcinoma (HCC), and tumor-associated macrophage plays an important role in tumor progression. Therefore, we examined STAT3 activation, cytokine expression and infiltration of tumor-associated macrophages in resected HCCs as well as the alteration of cell growth and migration by cytokine stimulation in HCC cell lines. Methods: Immunohistochemical staining of phosphorylated STAT3 (pSTAT3), CD163, interleukin (IL)-6, Ki-67 and Bcl-XL was performed for 101 cases of resected HCC, and correlations between pSTAT3 staining and clinicopathological findings were analyzed. In HCC cell lines (PLC/PRF/5 and Huh7), cell proliferation and migration by IL-6 stimulation and S3I-201 (STAT3 inhibitor) treatment were analyzed. Results: In HCC specimens, the pSTAT3-positive group showed high levels of α-fetoprotein (p = 0.0276), large tumor size (p = 0.0092), frequent intrahepatic metastasis (p = 0.0214), high Ki-67 (p = 0.0002) and Bcl-XL (p = 0.0001), poor prognosis (p = 0.0234), and high recurrence rate (p = 0.0003). CD163-positive cells were frequently observed in the pSTAT3-positive group (p = 0.0013). In two HCC cell lines, IL-6 stimulation promoted cell proliferation and migration via the STAT3 phosphorylation, and S3I-201 inhibited this activation. Conclusions: STAT3 activation was correlated with aggressive behavior of HCC and may be mediated via tumor-associated macrophage. We expect that STAT3 signaling and tumor-associated macrophages can be attractive therapeutic targets in HCC patients.

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