Elucidation of functions of PTEN in pancreatic carcinogenesis and its therapeutic application

Abstract

[한글]

[영문]PTEN has been emerged as a tumor suppressor gene frequently deleted or mutated in various human cancer. Recently, PTEN in hematopoiteic stem cells is suggested as the key for maintaining normal hematopoietic stem cell population and preventing the development of leukemia-initiating cells. However, the mutation or deletion of PTEN in pancreatic cancer is reportedly very rare. Although PTEN deletion is reported to be related to the centroacinar cell expansion and emergence of metaplastic duct and pancreatic cancer via transgenic mouse experiment, it does not seem to be physiologic in pancreatic cancer. So this study was intended to analyze the real condition of PTEN and relating molecular event in pancreatic cancer. On the contrary to the previous reports, PTEN is overexpressed in pancreatic cancer cell lines and human pancreatic cancer. Furthermore, pancreatic cancer with overexpressing PTEN showed poorer prognosis. With these controversial data, further experiments were performed with hypotheses that the overexpressed PTEN in pancreatic cancer might be related to the unexpected tumor promoting acitivity, so called “antagonistic duality”. For validating this hypothesis, a transient knock down of PTEN via siRNA technique was used. After knocking down of PTEN, pancreatic cancer cells showed two different molecular and phenotypical changes. Interestingly, PTEN knock down pancreatic cancer cells harboring wild p53 (HPAC) showed the predicted activation of Akt and its downstream signals. On the contrary, pancreatic cancer cells harboring gain of function mutation or frame shift mutation did not show the activation of Akt. And GSK3 was inactivated which in turn, result in activation of p21. Furthermore, these mutant p53 pancreatic cancer cells showed decreased cell proliferative activity in the condition of PTEN knock-down. With these findings, PTEN can be thought to have tumor promoting activity in specific conditions including gain of function mutation of p53. Considering the current paradigm of anti-cancer treatment is shifting to target the specific tumor associated pathway including PTEN pathway, this experimental outcome should be considered for the therapeutic strategies that aim at manipulating PTEN or p53 in human pancreatic cancer.