Kwon Sungwon, Munroe Xander, Crawley Suzanne C, Lee Hwa Young, Spong Suzanne, Bradham Douglass, Gum James R, Sleisenger Marvin H, Kim Young S
Gastrointestinal Research Laboratory, Veterans Affairs Medical Center, San Francisco, CA 94132, USA.
Int J Oncol. 2007 Oct;31(4):693-703.
Connective tissue growth factor (CTGF/CCN2) is thought to play a role in normal wound repair and bone remodeling, but also promotes fibrosis in several disease processes including diabetic nephropathy, sclerodoma and pancreatitis. A contribution to desmoplasia associated with pancreatic cancer progression has also been proposed. CTGF is induced by TGFbeta in diverse cell types, but TGFbeta receptor mediated signaling is impaired in pancreatic cancers and cell lines, usually due to DPC4/Smad4 mutations which arise during the later stages of intraepithelial neoplastic progression. Therefore, in order to define signaling pathways that mediate basal and TGFbeta-induced CTGF expression in normal and transformed cells, we compared CTGF gene regulation in pancreatic cancer cells and fibroblasts by measuring the effects of small molecule inhibitors and dominant negative mutants of signaling proteins on CTGF promoter reporter activity, message, and protein expression. We determined that the previously identified TEF-1 cis element is essential for CTGF promoter reporter activity in pancreatic cancer cell lines. Whereas p38 mediated CTGF induction by TGFbeta in fibroblasts, MEK/ERK signaling mediated TGFbeta-induced CTGF expression in pancreatic cancer cells and was also responsible for basal CTGF expression in pancreatic cancer cell lines with defective Smad signaling. Since activating Ras mutations occur in the earliest stages of pancreatic cancer, CTGF may be induced independent of Smad4 in pancreatic cancer cells.
结缔组织生长因子（CTGF/CCN2）被认为在正常伤口修复和骨重塑中发挥作用，但在包括糖尿病肾病、硬皮病和胰腺炎在内的多种疾病过程中也会促进纤维化。也有人提出它与胰腺癌进展相关的促结缔组织增生有关。CTGF在多种细胞类型中由TGFβ诱导产生，但在胰腺癌和细胞系中，TGFβ受体介导的信号传导受损，这通常是由于上皮内肿瘤进展后期出现的DPC4/Smad4突变所致。因此，为了确定在正常细胞和转化细胞中介导基础及TGFβ诱导的CTGF表达的信号通路，我们通过测量小分子抑制剂和信号蛋白的显性负性突变体对CTGF启动子报告基因活性、信使核糖核酸和蛋白质表达的影响，比较了胰腺癌细胞和成纤维细胞中CTGF基因的调控情况。我们确定，先前鉴定的TEF-1顺式元件对胰腺癌细胞系中的CTGF启动子报告基因活性至关重要。在成纤维细胞中p38介导TGFβ诱导CTGF表达，而在胰腺癌细胞中MEK/ERK信号传导介导TGFβ诱导CTGF表达，并且在Smad信号传导缺陷的胰腺癌细胞系中也负责基础CTGF表达。由于激活的Ras突变发生在胰腺癌的最早阶段，CTGF可能在胰腺癌细胞中独立于Smad4被诱导产生。
