分析精神分裂症及癌症之基因網路：發掘潛在抑癌效果之路徑及藥物

Analysis of the Genetic Network for Schizophrenia and Cancers: Discovery of Potential Pathways and Drugs for Tumor Suppression Effect

黃國權(Kuo-Chuan Huang)

指導教授 ： 高成炎

國立臺灣大學/電機資訊學院/資訊工程學研究所/博士(2013年)

https://doi.org/10.6342/NTU.2013.01430

摘要

研究目的
精神分裂症患者的癌症發病率較低，顯示精神分裂症可能是一種對抗癌症的保護因子。為了研究兩種疾病之間的基因相關性，我們建構一個由精神分裂症和肝細胞癌的候選基因組成之蛋白質交互作用網路。藉由精神分裂症與肝癌網路（SHCN）分析，基團可被發現為潛在的功能模組或蛋白質聚合物。這項研究結果用來對照相關信息途徑資料庫如KEGG，Reactome，PID和ConsensusPathDB，等。

研究結果
SHCN中介基因的功能顯示在精神分裂症的致病機轉中，免疫系統和細胞週期調控的功能具有重要作用。例如，過度表達的精神分裂症候選基因，SIRPB1，SYK和LCK，負責信號傳導的細胞激素的產生，精神分裂症的病因學機制相關的免疫反應則與IL-2和TREM-1/DAP12通路有關。藉由尋找FDA核准的藥物的目標基因中發現潛在的蛋白複合物和途徑並提出新的治療方法。研究結果發現，維生素A，視黃素和其他的免疫反應藥劑與其編碼基因:RARA， LCK基因可能具有潛在治療精神分裂症和肝細胞癌的效果。

研究結論
這是首篇精神分裂症與肝癌的基因網路顯示特定中介基因可能有抑制腫瘤的研究。研究並顯示精神分裂症蛋白質相互作用及調控癌症之免疫系統對精神分裂症致病因素的重要性。

關鍵字

基因網路 ； 蛋白質交互作用 ； 肝癌 ； 精神分裂症

並列摘要

ABSTRACT

Background
Schizophrenic patients show lower incidences of cancer, implicating schizophrenia may be a protective factor against cancer. To study the genetic correlation between the two diseases, a specific PPI network was constructed with candidate genes of schizophrenia and hepatocellular carcinoma. The network, designated schizophrenia-hepatocellular carcinoma network (SHCN) was analysed and cliques were identified as potential functional modules or complexes. The findings were compared with information from pathway databases such as KEGG, Reactome, PID and ConsensusPathDB.
Results
The functions of mediator genes from SHCN show immune system and cell cycle regulation have important roles in the eitology mechanism of schizophrenia. For example, the over-expressing schizophrenia candidate genes, SIRPB1, SYK and LCK, are responsible for signal transduction in cytokine production; immune responses involving IL-2 and TREM-1/DAP12 pathways are relevant for the etiology mechanism of schizophrenia. Novel treatments were proposed by searching the target genes of FDA approved drugs with genes in potential protein complexes and pathways. It was found that Vitamin A, retinoid acid and a few other immune response agents modulated by RARA and LCK genes may be potential treatments for both schizophrenia and hepatocellular carcinoma.
Conclusions
This is the first study showing specific mediator genes in the SHCN may suppress tumor. We also show that the schizophrenic protein interactions and modulation with cancer implicates the importance of immune system for etiology of schizophrenia.

並列關鍵字

genetic network ； protein protein interaction ； hepatocellular carcinoma ； schizophrenia

參考文獻

1. Muller N, Schwarz MJ: Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders. Expert Rev Neurother 2006, 6:1017-1038.

3. Richard MD, Brahm NC: Schizophrenia and the immune system: pathophysiology, prevention, and treatment. Am J Health Syst Pharm 2012, 69:757-766.

4. Boyd AD, Brown D, Henrickson C, Hampton J, Zhu B, Almani F, Ben-Josef E, Zalupski M, Simeone DM, Taylor JM, et al: Screening for depression, sleep-related disturbances, and anxiety in patients with adenocarcinoma of the pancreas: a preliminary study. ScientificWorldJournal 2012, 2012:650707.

5. Linden W, Vodermaier A, Mackenzie R, Greig D: Anxiety and depression after cancer diagnosis: Prevalence rates by cancer type, gender, and age. J Affect Disord 2012.

6. Mystakidou K, Parpa E, Tsilika E, Panagiotou I, Zygogianni A, Giannikaki E, Gouliamos A: Geriatric depression in advanced cancer patients: The effect of cognitive and physical functioning. Geriatr Gerontol Int 2012.