Grap2 and cyclin D1 interacting protein (GCIP)已被認為是抑癌基因的角色，其對抗腫瘤的分子機制還有一些未被研究。在此，我們的研究是探討關於非小細胞型肺癌(NSCLC) 的組織中GCIP隨癌症時程的表現及可能影響的細胞調控機制。在我們實驗中指出GCIP會與inhibitor of DNA binding / differentiation 1 (Id1) 於細胞核中結合，而在高度侵犯性的非小細胞型肺癌細胞H1299細胞株過度表現GCIP，則可以看到細胞的增生、細胞聚落的形成、侵犯和轉移減少以及增加該細胞對藥物的感受性。相反的，在較不侵犯型的非小細胞型肺癌細胞A549抑制GCIP的表現時則可以看到細胞的增生、細胞聚落的形成、侵犯、轉移以及對藥物的抗性增加。在過度表現GCIP 的細胞株於in vivo動物實驗裡也可以發現， 對於腫瘤的抑制具有明顯的效果；在探討GCIP抑制 NSCLC的過程，我們利用過度表現Id1的細胞株建立誘導型GCIP的表現，結果發現GCIP部分調控了Id1的訊息傳遞，這應是基於GCIP與Id1結合所致。另外，GCIP亦會抑制Id1的表現，以及GCIP和Id1在非小細胞型肺癌病人的檢體中，他們的表現呈現負相關。另一方面，肺癌所引起的癌症死亡居於所有癌症的首位，有85%的病患屬於非小細胞型肺癌且存活率低，所以對於肺癌的預防與治療急需找尋一個對策。探索肺癌的化學性預防用藥，我們以白藜蘆醇（resveratrol, RV）對於hRAD9蛋白調控的上皮 - 間質細胞轉換（EMT）以及老化現象在肺癌細胞做探討。白藜蘆醇已被證明是一種很有潛力的用於化學性預防癌症和抗癌藥劑。老化和上皮 - 間質轉換（EMT）在腫瘤進展過程中是一個相反的相對作用，老化作用相對腫瘤進展的影響是對腫瘤發生產生障礙，而間質轉換對於轉為侵入型的惡性腫瘤細胞是一種是必要 。在這裡我們提出，DNA損傷反應（DNA damage response）蛋白hRAD9在RV治療中，有助於誘發老化現象產生以及抑制肺癌細胞的間質轉換。我們以A549細胞作為模式，實驗結果顯示在RV誘導下hRAD9的表達對濃度和時間具有依賴性。有趣的是，使用低劑量RV會誘導腫瘤細胞提早衰老而不是凋亡。特別是，RV在20μM濃度下對間質轉換相關蛋白在A549細胞中影響其表現。在這個實驗中，我們建立了A549/shRAD9的肺癌細胞，並使用A549/shRAD9細胞作為模型。隨後的研究中發現，低劑量的RV處理A549細胞後以senescence-associated–β–galactosidase 染色，顯示會誘導細胞老化， 且p53和p21在A549細胞中的表現顯著增加，但在抑制hRAD9表現的細胞無此現象。此外，我們還探討RV抑制上皮 - 間質細胞轉換的相關蛋白，同樣的在A549/shRAD9細胞並無此現象。最後，我們的研究結果指出，GCIP在非小細胞型肺癌具有抑癌基因的角色，它是透過調控Id1這個原致癌基因所調控的下游訊息，這對於在抑制NSCLC癌症發展的過程GCIP也許是一個有潛能的關鍵。另外，在白藜蘆醇處理的A549 的細胞中，我們發現可能調控的機制是透過增加hRAD9蛋白表現。總結我們的研究結果顯示，RV經由hRAD9影響細胞老化及抑制上皮 - 間質細胞轉換相關蛋白發揮其抗癌和預防癌症的作用。

Grap2 and cyclin D1 interacting protein (GCIP) has been recognized as a putative tumor suppressor, but the molecular mechanisms underlying its anti-tumor properties remain undefined. Here, we report that GCIP is frequently downregulated in non-small cell lung cancer (NSCLC) tissues. Binding assays indicated that inhibitor of DNA binding/differentiation 1 (Id1) interacts with GCIP in the nucleus. Ectopic GCIP expression in the highly invasive NSCLC cell line, H1299, inhibited proliferation, colony formation, invasion and migration, and increased susceptibility to anticancer drugs. Conversely, silencing GCIP expression in the minimally invasive NSCLS cell line, A549, increased proliferation, colony formation, invasion, and migration in vitro, and increased survival and resistance to anticancer drugs. GCIP also suppresses tumorigenicity of NSCLC cells in vivo and GCIP suppression on NSCLC progression is mediated in part by interfering with Id1 signaling, which was confirmed in conditionally induced stable cell lines. In addition, GCIP downregulates the expression of Id1, and GCIP and Id1 are inversely expressed in NSCLC cell lines and specimens. On the other hand, lung cancer is the leading cause of cancer deaths worldwide. There is a need to investigate the strategies for lung cancer prevention and therapy. To explore the lung cancer chemopreventive agent, we investigated whether resveratrol (RV) affects hRAD9-reduced epithelial-mesenchymal transition (EMT) and senescence in lung cancer cell line. RV is a promising chemopreventive agent that has been shown to be a potential chemopreventive and anticancer agent. Senescence and EMT have opposing roles in tumor progression in that one is a barrier against tumorigenesis, while the other is required for invasive malignancies. Here we report that the DNA damage response (DDR) protein hRAD9 contributes in RV treatment induces the premature senescence and inhibits EMT of lung cancer cells. Using A549 cells as a model, we displayed here that RV induces hRAD9 expression in a concentration- and time-dependent manner in A549 cells. Interestingly, low dose RV treatment induced tumor cell premature senescence, but not apoptosis. Herein, we established A549/shRAD9 lung cancer cells and using A549/shRAD9 cells as a model. Subsequent studies we showed that low dose RV treatment induces a significant increase in senescence-associated β–galactosidase (SA- β -gal) staining and elevated expression of p53 and p21 in A549 cells, but not in RAD9 knockdown cells. Furthermore, we exhibited that RV inhibited EMT markers but not in A549/shRAD9 cells. Taken together, these results suggest that GCIP is a potential tumor suppressor in NSCLC and that suppression of Id1-mediated oncogenic properties may be a key mechanism by which GCIP can potently suppress NSCLC tumor progression. In addition, a possible regulatory mechanism of RV chemoprevention is through upregulation of hRAD9 in A549 cell. Our results suggest that RV may exert its anticancer and chemopreventive effects through the induction of premature senescence and inhibited EMT via hRAD9.

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