Yamamoto Tetsushi, Matsuda Yoko, Kawahara Kiyoko, Naito Zenya, Ishiwata Toshiyuki
Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan.
Oncol Lett. 2012 Feb;3(2):307-310. doi: 10.3892/ol.2011.466. Epub 2011 Oct 31.
Keratinocyte growth factor (KGF), also known as fibroblast growth factor-7, is mainly synthesized by mesenchymal cells. KGF modulates proliferation, differentiation, migration and adhesion to extracellular matrices of epithelial cells that specifically express the KGF receptor (KGFR). We previously reported that KGF is expressed in cancer cells and adjacent stromal fibroblasts in human pancreatic cancer tissues. Furthermore, KGF is thought to stimulate the growth of certain pancreatic cancer cell lines. The aim of the present study was to examine whether the mitogen-activated protein kinase (MAPK) pathway contributes to exogenous KGF-induced pancreatic cancer cell growth. Recombinant human KGF (rhKGF) was administered to MIA PaCa-2 cells, which expressed KGFR and negligible levels of KGF. Cell growth rates in MIA PaCa-2 cells were significantly increased in a dose-dependent manner following the addition of rhKGF. In the MAPK pathway, phosphorylation of extracellular signal-regulated kinase (ERK) in MIA PaCa-2 cells was increased in a dose-dependent manner, and phosphorylation of p38 was slightly increased following the administration of 100 ng/ml rhKGF. In contrast, JNK was not phosphorylated following the addition of rhKGF in MIA PaCa-2 cells. U0126, a specific inhibitor of ERK activation, decreased the rhKGF-induced phosphorylation of ERK and the growth rates of MIA PaCa-2 cells. These findings indicated that phosphorylation of the ERK signaling pathway plays a significant role in exogenous KGF-induced pancreatic cancer cell growth.
角质形成细胞生长因子（KGF），也被称为成纤维细胞生长因子-7，主要由间充质细胞合成。KGF可调节特定表达KGF受体（KGFR）的上皮细胞的增殖、分化、迁移以及与细胞外基质的黏附。我们之前报道过KGF在人胰腺癌组织的癌细胞及相邻基质成纤维细胞中表达。此外，KGF被认为可刺激某些胰腺癌细胞系的生长。本研究的目的是检测丝裂原活化蛋白激酶（MAPK）通路是否参与外源性KGF诱导的胰腺癌细胞生长。将重组人KGF（rhKGF）作用于表达KGFR且KGF水平可忽略不计的MIA PaCa-2细胞。添加rhKGF后，MIA PaCa-2细胞的生长速率呈剂量依赖性显著增加。在MAPK通路中，MIA PaCa-2细胞中细胞外信号调节激酶（ERK）的磷酸化呈剂量依赖性增加，给予100 ng/ml rhKGF后p38的磷酸化略有增加。相反，在MIA PaCa-2细胞中添加rhKGF后JNK未发生磷酸化。U0126是一种ERK激活的特异性抑制剂，它可降低rhKGF诱导的ERK磷酸化以及MIA PaCa-2细胞的生长速率。这些发现表明ERK信号通路的磷酸化在外源性KGF诱导的胰腺癌细胞生长中起重要作用。
