Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Pathobiology. 2013;80(3):146-54. doi: 10.1159/000346196. Epub 2013 Jan 25.
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.
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.
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.
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.
信号转导子和转录激活子 3（STAT3）在肝细胞癌（HCC）中被激活，肿瘤相关巨噬细胞在肿瘤进展中发挥重要作用。因此，我们研究了在切除的 HCC 中 STAT3 的激活、细胞因子的表达和肿瘤相关巨噬细胞的浸润，以及细胞因子刺激对 HCC 细胞系中细胞生长和迁移的改变。
对 101 例切除的 HCC 进行磷酸化 STAT3（pSTAT3）、CD163、白细胞介素（IL）-6、Ki-67 和 Bcl-XL 的免疫组织化学染色，并分析 pSTAT3 染色与临床病理特征的相关性。在 HCC 细胞系（PLC/PRF/5 和 Huh7）中，分析了 IL-6 刺激和 S3I-201（STAT3 抑制剂）处理对细胞增殖和迁移的影响。
在 HCC 标本中，pSTAT3 阳性组的甲胎蛋白（AFP）水平较高（p = 0.0276），肿瘤较大（p = 0.0092），肝内转移频繁（p = 0.0214），Ki-67 和 Bcl-XL 高表达（p = 0.0002 和 p = 0.0001），预后不良（p = 0.0234），复发率高（p = 0.0003）。pSTAT3 阳性组中经常观察到 CD163 阳性细胞（p = 0.0013）。在两种 HCC 细胞系中，IL-6 刺激通过 STAT3 磷酸化促进细胞增殖和迁移，而 S3I-201 抑制这种激活。
STAT3 的激活与 HCC 的侵袭性行为相关，可能通过肿瘤相关巨噬细胞介导。我们期望 STAT3 信号通路和肿瘤相关巨噬细胞能成为 HCC 患者有吸引力的治疗靶点。
