Department of Hematology-Oncology, College of Medicine, Yeungnam University, Daegu, Korea.
Oncol Res. 2010;19(2):67-76. doi: 10.3727/096504010x12864748215043.
Hepatoma-derived growth factor (HDGF) is highly expressed in tumor cells and may play an important role in the development and progression of carcinomas. However, the molecular mechanism by which HDGF participates in gastric carcinomatosis requires further analysis. In this study, we determined the role of HDGF in tumorigenesis and elucidated the mechanisms of action. To determine aggressive biological behavior, we knocked down HDGF expression with HDGF-specific shRNA in two gastric cancer cell lines. First, using cDNA microarrary, we showed that hepatocyte growth factor (HGF) induced HDGF and confirmed this by Western blotting. HGF increased HDGF in a dose-dependent manner. We also determined whether HDGF induces angiogenic factor, and found the vascular endothelial growth factor (VEGF) was induced by HDGF. Downregulation of HDGF resulted in a decrement of VEGF. HDGF knock-down was found to induce the expression of the proapoptotic protein, Bad, and also inactivate ERK, which in turn led to dephosphorylation of Bad at ser112 and ser136, and induced apoptosis. Transfection with HDGF-siRNA resulted in a decrement of cell proliferation, as determined with a MMT assay. In an in vitro invasion assay, significantly fewer cells transfected with HDGF-siRNA than control cells were able to invade across a Matrigel membrane barrier. Our results suggest that HDGF is involved in cell growth, cell invasion, and apoptosis. These qualities may contribute to the HDGF-associated aggressive biological behavior of gastric cancer and thus serve as a potential target for cancer therapy.
肝癌衍生生长因子（HDGF）在肿瘤细胞中高度表达，可能在癌的发生和发展中发挥重要作用。然而，HDGF 参与胃癌转移的分子机制仍需进一步分析。在本研究中，我们确定了 HDGF 在肿瘤发生中的作用，并阐明了其作用机制。为了确定侵袭性生物学行为，我们使用 HDGF 特异性 shRNA 在两种胃癌细胞系中敲低 HDGF 表达。首先，我们通过 cDNA 微阵列显示，肝细胞生长因子（HGF）诱导 HDGF，并通过 Western blot 证实了这一点。HGF 以剂量依赖的方式增加 HDGF。我们还确定了 HDGF 是否诱导血管生成因子，发现血管内皮生长因子（VEGF）被 HDGF 诱导。下调 HDGF 导致 VEGF 减少。下调 HDGF 导致促凋亡蛋白 Bad 的表达增加，并使 ERK 失活，进而导致 Bad 在丝氨酸 112 和丝氨酸 136 处去磷酸化，并诱导细胞凋亡。用 HDGF-siRNA 转染导致 MMT 测定的细胞增殖减少。在体外侵袭实验中，与对照细胞相比，转染 HDGF-siRNA 的细胞穿过 Matrigel 膜屏障的侵袭细胞明显减少。我们的结果表明，HDGF 参与细胞生长、细胞侵袭和细胞凋亡。这些特性可能有助于与 HDGF 相关的胃癌侵袭性生物学行为，因此可作为癌症治疗的潜在靶点。
