Basic research on the growth factor and cell adhesion factor in a mechanism of invasion and metastasis of pancreatic cancer

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[TGF-β signal and Function of RhoB protein] We induced epithelial mesenchymal transition (EMT) in the cultured cell by TGF-β stimulation. In addition, we found the relation between EMT and invasiveness of the cells stimulated by TGF-β. We also found that the protein and mRNA expression of RhoGTPases was suppressed in TGF-β signaling. Stable clones were established by using wild-type and mutant-type of RhoB expression vectors in order to analyze RhoB protein function. We examined, in these cells, the induction of EMT, cell proliferation, anchorage-independent cell proliferation, migration and invasion. The TGF-β stimulation signal pathway is thought to be chiefly composed of Smad signal pathway and MAPKs cascade (ERK1/2, JNK/SAPK and p38MAPK). We showed that the signal pathway which related to invasion and metastasis is MAPKs cascade. [Alteration of oncogene and invasion and metastasis in pancreatic cancer] We used pancreatic cancer cell lines with the different status of K-Ras, DPC4 and to TGF-βRII gene mutation. Stable clone with DNRas was established. Stable clones with DN and CA form of RhoB, MEK1/2 and SMAD4 were also established. The ability of invasion and metastasis stimulated by TGF-β was examined by using these cells. Moreover, the state of EMT, and the expression of RhoB protein, Cdc42 and cadherin were examined in response to the TGF-β stimulation. We showed alteration of TGF-β signaling and increased invasion and metastasis by enforced activation of Ras protein. We finally confirmed alteration of K-Ras and DPC4 in pancreatic cancer tissues.