以生物資訊分析STIM1相關轉錄體圖譜與人類大腸癌之專一性

TMUIR > College of Pharmacy > Master Program for Clinical Pharmacogenomics and Pharmacoproteomics > Dissertations/Theses > Item 987654321/59396

Please use this identifier to cite or link to this item: http://libir.tmu.edu.tw/handle/987654321/59396

Title:	以生物資訊分析STIM1相關轉錄體圖譜與人類大腸癌之專一性 Bioinformatic Analysis Reveals STIM1-Associated Expression Profiles Specific to Colon Adenocarcinomas in Human
Authors:	黃順清 Wong, Henry Sung-Ching
Contributors:	張偉嶠
Keywords:	結直腸癌;鈣池調控鈣離子內流;STIM1;TCGA;微陣列分析;RNA定序分析;微小RNA;存活分析 Colorectal cancer;Store-operated calcium entry;Stromal interaction molecule 1;The Cancer Genome Atlas;Microarray;RNA-sequencing;miRNA;Survival
Date:	2015-07-05
Issue Date:	2020-08-19 16:17:09 (UTC+8)
Abstract:	在大腸癌 (Colorectal Cancer [CRC]) 細胞研究報導中曾提及鈣池調控鈣離子內流路徑(Store-operated Ca2+ entry [SOCE])有異常之活化，且合併內質網鈣離子偵測器STIM1 (Stromal interaction molecule 1)之過度表現 (Overexpression)，並與腫瘤細胞之侵蝕(Invasion)與移行能力(Migration)息息相關。為研究結腸癌 (Colon Adenocarcinoma [COAD]) 與直腸癌 (Rectal Adenocarcinoma [READ]) 之惡性度或侵襲性 (Cancer Aggressiveness) 之差異，本研究以STIM1表現量 (Expression Profile) 為經，而臨床數據 (Clinical Profile)，微陣列 (Array Profile) 與轉錄體表現量 (RNA-Sequencing Profile and miRNA Profile) 為緯，勾勒全基因臨床-轉錄體-交互作用體 (Phenome-Transcriptome-Interactome) 輪廓，釐清STIM1相關分子圖譜 (Molecular Signatures) 全貌。研究成果揭示STIM1過度表現與結腸癌相關，而非直腸癌。從結腸癌鑑定之STIM1相關分子圖譜，也指出STIM1之過度表現會牽動結腸癌其他轉錄分子之變化。上述在微陣列平台所觀測到的結果亦在RNA定序資料得到驗證。 STIM1過度表現之情形實質上反映了鈣池調控鈣離子路徑 (Store-operated calcium entry pathway [SOCE]) 之活化，也在研究中顯示與結腸癌之細胞移行，細胞活動 (Motility) 以及腫瘤侵蝕等表徵有關。此外，利用蛋白質-蛋白質交互作用資料庫，本研究也找到與STIM1過度表現以及淋巴侵蝕這二項表徵相關的蛋白質功能模組 (Functional Module) 網路。不僅如此，本研究也利用miRNA定序生物資訊分析鑑定在COAD與READ顯著差異 (Differentially Enriched) 之miRNA。結合mRNA與miRNA之分析，顯示11個mRNA/miRNA之預後因子 (Prognostic Factor)，可預測結腸癌病患之整體存活率 (Overall Survival [OS])，也進一步為STIM1之過度表現對臨床病理有重大影響提供有力佐證。本研究結果可促進人類對於大腸癌的在宏觀層次上的了解，也顯示STIM1具有成為COAD之生物標記 (Biomarker) 之潛力。 TCGA資料庫收錄不同癌症在基因層次 (Genomic level）以及轉錄體層次 (Transcriptomic level) 之高通量資料。本研究結合生物資訊以及資料庫之數據進行分析，結果展示癌症基因學（Oncogenomic）資料在宏觀鑑定STIM1基因過度表現對於結腸癌分子生物傳遞途徑之影響。此外，TCGA數據庫包含300多高通量平台樣本，足以支持結直腸癌病患分群 (Patient stratification) 之分析。我們的研究成果進一步揭示STIM1可作為結直腸癌病患預後之預測因子，未來可期用於標靶藥物篩選，實現個人化醫療 (Personalized medicine) 與藥物治療優化 (Optimization of cancer therapy)。 The store-operated Ca2+ entry (SOCE) pathway is known to be aberrantly activated in colorectal cancer (CRC), and overexpression of the endoplasmic reticulum (ER) Ca2+ sensor, stromal interaction molecule 1 (STIM1), is associated with cancer cell invasion and migration. To characterize the distinctive nature of aggressiveness between colon adenocarcinomas (COADs) and rectal adenocarcinomas (READs), we conducted a genome-wide scale integrative phenome-transcriptome-interactome analysis using bioinformatics techniques in CRC patients. Groups of COADs or READs were distinguished by the presence or absence of STIM1 overexpression to point out STIM1-related molecular signatures. Results indicated that a number of novel STIM1-associated signatures could be identified in COADs but not READs, revealing a manifest transcriptome profile correlated with STIM1 overexpression. Results of transcriptomic comparison between COADs and READs by array platform were also successfully validated by RNA-sequencing data. Specifically, the presence of STIM1 overexpression in COADs, which represented a disturbance of SOCE pathway, was associated with cell migration and cell motility properties and also critical for tumor invasive potential. By using information from protein-protein interaction database, we identified modules that are differentially expressed between COAD patients with different STIM1 expression profile and simultaneously are lymphatic invasion associated. We also identified differentially enriched miRNA in COADs and READs by applying miRNA-sequencing data analysis. Importantly, we identified 11 prognostic mRNA/miRNA predictors associated with the overall survival of COAD patients, and further provided evidence for an explanation of STIM1 or STIM1-associated features in patients’ clinicopathological outcomes. Our data suggested a designated and unifying transcriptomic and interactomic framework linking COADs/READs with varying STIM1 overexpression patterns underlying the prognoses. These findings enhance our understanding of differences between CRC subtypes in a panoramic view, and suggested STIM1 as a novel therapeutic biomarker for COADs.
Description:	碩士指導教授:張偉嶠委員:王照元委員:翁瑞宏委員:陳香吟
Data Type:	thesis
Appears in Collections:	[Master Program for Clinical Pharmacogenomics and Pharmacoproteomics] Dissertations/Theses

Files in This Item:

File	Description	Size	Format
index.html		0Kb	HTML	157	View/Open

View Licence

Loading...