| 摘要: | 肝細胞癌患者的預後已有所改善，然而晚期肝癌和轉移患者在治療的選擇上仍然很少。了解肝癌細胞的存活以及轉移的分子機制，是成功開發治療肝癌患者的關鍵。先前的研究顯示，前列腺素E2 (PGE2)可藉由活化其受體以及下游的訊息途徑,增強乳癌、胃癌、胰腺癌、肺癌、和前列腺癌細胞的生長以及轉移能力。然而前列腺素E2在肝細胞癌所扮演的腳色及其誘導之EP接受體種類仍不清楚。本實驗中，我們發現前列腺素E受體2（EP2）和前列腺素E受體4（EP4）的mRNA以及蛋白的表現量在人類肝癌組織中高度的表達。 此外我們發現，前列腺素E2促進HA22T肝癌細胞的增生能力,並活化存活訊息途徑EGFR, PI3K, Akt及其下游的抗凋亡蛋白的表現量。數據亦顯示，PGE2同時提高HA22T肝癌細胞的爬行能力, 並降低E-cadherin和GSK3-β的蛋白表現量進而誘導β-catenin的蛋白表現量上升。同時前列腺素E2也誘導表皮細胞間質化相關蛋白snail和vimentin的表現量上升。然而我們發現MMP-2以及MMP-9在HA22T肝癌細胞的活性並不受到前列腺素E2的調控。經由化學抑制劑及基因siRNA阻斷,我們進一步確認EP2和EP4受體在前列腺素E2誘導HA22T肝癌細胞株的生存以及轉移的能力中扮演了絕對的角色。我們相信，尋找中草藥或新開發藥物來阻斷前列腺素E2或前列腺素E受體2和前列腺素E受體4將可抑制肝小細胞癌的細胞生存及轉移能力。同時前列腺素E2、前列腺素E受體2和前列腺素E受體4在組織中的含量可作為肝癌的預後和治療指標。
Though the prognosis of hepatocellular Carcinoma (HCC) patients has been improved, their treatment options are limited and are often inefficient. Therefore, understanding the molecular mechanisms is critical for developing successful therapies to eradicate this disease. Earlier studies have shown that, Prostaglandin E2 (PGE2) enhances the growth of various cancers including breast, stomach, pancreas, lung and prostate by activating proteins that are involved in controlling proliferation and survival pathway. At first we found that Prostaglandin E Receptor 2 (EP2) and Prostaglandin E Receptor 4 (EP4) were overexpressed in liver cancer patients and in cell lines. Using cell line modes we found that PGE2 enhanced HA22T cell proliferation by inducing survival pathway marker such as p-EGFR, p-PI3K, p-Akt and their downstream anti-apoptotic proteins. Furthermore, PGE2 enhanced HA22T cell migration by inducing β-catenin expression and by decreasing E-cadherin and GSK3-β expression. We also found that PGE2 could not up-regulate MMP2 and MMP9 expression, however, PGE2 treatment increased EMT marker such as snail and vimentin in HA22T cells. All these results suggest us that, PGE2 enhanced HA22T cells survival and migration is by activating EP2 and EP4 receptor. |
