| 摘要: | 肺癌是世界上最廣泛發生的癌症之一，它也因為晚期的診斷及轉移而造成了高死亡率。轉移是癌細胞從原位器官擴散到其他非鄰近部位的機制，通常癌細胞藉由淋巴或血液進行轉移，因此轉移成了癌症惡化的關鍵。當癌症開始產生轉移時，癌細胞會產生上皮-間質轉型(epithelial-mesenchymal transition, EMT)。上皮-間質轉型的過程中，上皮細胞會失去細胞間的粘附性、細胞成紡錘狀、產生偽足，並增加細胞的運動性及移行的能力，最後形成間質化的細胞。當上皮-間質轉型進行中，細胞也會和週遭的細胞外基質(extracellular matrix, ECM)產生交互作用，並使自身能夠穿越胞外組織移動到其他部位。Periostin就是一種細胞外基質，分子量90kDa的蛋白質。因Periostin原先在骨膜(periosteum)及牙周韌帶(periodontal ligament)被發現，因此又稱特異性造骨因子-2(osteoblast-specific factor-2)。Periostin在人體中具有許多重要的功能，包括幫助細胞外基質的骨架形成、骨骼及牙齒的構成及維持、心臟瓣膜的發育、胚胎的發展。而近年的研究也發現，在數種癌症患者血液中具有較高濃度的periostin，而且隨著癌症的進展而升高。更有研究發現，periostin可能參與EMT的作用。因此，我們想要研究periostin是否參與了肺癌細胞的EMT作用，進而幫助肺癌的轉移，並且找出調控的機轉。在我們的研究中，我們發現了Periostin在肺癌細胞株A549及CL1-0中能夠促進N-cadherin, vimentin, twist及snail等EMT marker的表現，並且同時減少E-cadherin的表現。另外，periostin也會促進這些肺癌細胞株的移行(migration)及侵襲(invasion)能力。這些結果表示periostin能夠引發肺癌細胞的上皮-間質轉型並促進其轉移。我們也利用MAPK的抑制劑及siRNA發現periostin是透過ERK及p38等MAPK訊息傳遞路徑調控細胞的EMT作用。此外，有鑑於近年有不少研究著重在microRNA對癌症的調控，我們也發現microRNA-381在periostin調控EMT中，扮演調控轉錄因子twist及snail的角色。總地來說，我們的研究發現periostin透過MAPK訊息傳遞路徑調控microRNA-381及轉錄因子twist及snail，促進肺癌細胞的EMT及轉移。
Lung cancer is one of the most common cancer in the world, and it usually causes high mortality due to late stage and metastasis. Metastasis is a process that cancer cells leave the original tumor site and migrate to other parts of the body via the blood or the lymphatic system, so it is a key stage that leads cancer to be severe. When cancer metastasis start, cancer cells will carry out epithelial-mesenchymal transition (EMT). Epithelial-mesenchymal transition is a process by which epithelial cells lose their polarity and cell-cell adhesion, presence of spindle-shaped cells, emission of pseudopodia, and increased intercellular separation, obtain motility and migratory abilities to form mesenchymal cells. When EMT progress, cancer cells may interact with the extracellular matrix (ECM) to help themselves moving forward to another destination. Periostin is a kind of ECM, and it’s a secreted cell adhesion protein. Because periostin was originally found in the periosteum and periodontal ligament, it also called osteoblast-specific factor 2. Periostin has many important functions in human body such as being a scaffold protein the extracellular matrix, development and maintenance of bone, tooth and heart. In addition, high periostin level has been found in many kinds of cancers. Furthermore, recent studies have showed that periostin may involve in EMT. Therefore, we attempt to study whether periostin implicates in EMT of lung cancer cells and further increases metastasis, and figure out the mechanism regulates this process. In our research progress, we find that periostin can increase the expression of some EMT markers such as N-cadherin, Vimentin, Twist and Snail, and decrease the expression of E-cadherin in A549 and CL1-0 cell lines. Moreover, periostin is also able to enhance the abilities of migration and invasion of these cell lines. These results indicate that periostin may induces EMT of lung cancer and promotes metastasis. We also used MAPK inhibitors and siRNAs, and found that periostin promotes EMT through ERK and p38. Because there are many studies focus on microRNA regulation of cancer, we found that microRNA-381 plays a role in regulating transcription factors like twist and snail in MAPK pathway induce by periostin. In conclusion, we demonstrate that periostin regulates twist and snail through MAPK pathway and microRNA-381, then induces EMT and further metastasis of lung cancer. |
