在胃癌的發生過程中，致病因子包含了幽門螺旋桿菌的感染、抽菸、飲食以及宿主基因的多型性都會導致癌症產生。致癌基因的活化伴隨著逃脫宿主免疫的監控 (如丙型干擾素抗性)，對於癌細胞的生長以及存活都扮演著重要的角色。因此，本研究著重探討胃癌細胞對於丙型干擾素抗性及細胞過度增生之間的交互作用。處理丙型干擾素會抑制具有轉移特性胃癌細胞株MKN45細胞生長，然而卻無法對具有過度增生的原發性胃癌細胞株AGS細胞生長有所影響。探究其原因發現AGS細胞由於缺少了內生性的訊息傳導和轉錄激活因子1 (STAT1)，而不是因為接受器的表現受到了改變使的無法對於丙型干擾素有所反應。值得注意的是，磷酸肌醇3激酶 (PI3K)/AKT以及Ras/Raf/MEK/ERK訊息的活化促使了癌細胞的過度增生，然而只有PI3K/AKT的訊息才會誘導癌細胞產生丙型干擾素的抗性。異常的SHP2 (Src homology-2 domain-containing phosphatase 2) 大量表現決定丙型干擾素的抗性但是卻不會影響癌細胞過度生長或者是ERK的活化。在具有丙型干擾素抗性的AGS細胞中，PI3K/AKT所誘導的肝醣合成酶激酶-3β (GSK-3β) 對於SHP2的活化是重要的，但卻不會影響到細胞的過度增生作用。另外，PTEN蛋白質表現缺失以及半乳糖苷結合凝集素-3 (galectin-3) 的異常增加造成了AKT/GSK-3β/SHP2不正常的訊息傳遞，進而影響了丙型干擾素抗性以及細胞過度增生。此外，整合素連接激酶 (intergrin-linked kinase) 的異常表現決定了ERK的表現並促使了細胞過度增生，卻無法調控AKT/GSK-3β/SHP2路徑進而不會改變對丙型干擾素之抗性。更進一步發現由於AKT以及ERK的訊號分別調控了NF-κB的活化，而使得細胞過度增生。其上游的PI3K，則是大量表現在AGS細胞。然而在胃癌組織裡，免疫組織染色也顯示出細胞的過度增生和galectin-3、SHP2以及STAT1表現有關。這些結果都證實了PTEN的缺失對於在胃癌細胞中丙型干擾素抗性以及細胞的過度增生的交互作用具有雙重的影響。

Risk factors for gastric carcinogenesis include Helicobacter pylori infection, tobacco, diet and host gene polymorphism. Oncogenic activation-accompanied escape from immune surveillance, such as IFN-γ resistance, is critical for the growth and survival of cancer cells. In this study, we investigated the crosstalk signaling between IFN-γ resistance and hyperproliferation in gastric cancer cells. IFN-γ inhibited the cell growth of metastatic MKN45 cells but not hyperproliferating primary AGS cells. AGS cells did not respond to IFN-γ because of a deficiency in STAT1 but not due to dysfunctional IFN-γ receptors. Signaling of PI3K/AKT, as well as Ras/Raf/MEK/ERK, was required for the hyperproliferation; notably, PI3K/AKT alone mediated the IFN-γ resistance. Aberrant Src homology-2 domain-containing phosphatase (SHP) 2 determined IFN-γ resistance but unexpectedly had no effects on hyperproliferation or ERK activation. In the IFN-γ resistant cells, inactivation of glycogen synthase kinase (GSK)-3β by PI3K/AKT was important for SHP2 activation but not for hyperproliferation. An imbalance of AKT/GSK-3β/SHP2, caused by a reduction of PTEN and an increase of galectin-3, was important for the crosstalk between IFN-γ resistance and hyperproliferation. In addition, deregulated PI3K/PTEN-increased integrin-linked kinase determined ERK but not AKT/GSK-3β/SHP2, thus regulating hyperproliferation but not IFN-γ resistance. AKT and ERK regulated NF-κB activation to facilitate cell heperproliferation, individually. PI3K is constitutively expressed in AGS cells and immunohistochemical staining showed a correlation between hyperproliferation and expression of galectin-3, SHP2, and STAT1 in gastric tumors. These results demonstrate the dual effects of a reduction of PTEN on the crosstalk between IFN-γ resistance and hyperproliferation in gastric cancer cells.

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