Identification and Exploration of the Functional 1ncRNAs in Multiple Cancer Types

Long non-coding RNA (LncRNA) is a common subtype of non-coding RNA which can regulate gene expression at multiple levels, such as transcriptional, post-transcriptional, and epigenetic levels. In recent years, accumulated studies proved that lncRNA-mediated lncRNA/microRNA(miRNA)/mRNA triplets contribute to the occurrence and development of cancer. However, identification of such significative, cancer-related triplets still remains a major challenge. Besides, the dynamic changes among the factors of the lncRNA-mediated triplets are less well understood. In this study, I proposed a novel computational framework to identify the triplets termed as "lncRNA-perturbated triplets" by integrating target information and expression datasets. I applied the framework to five cancer datasets in The Cancer Genome Atlas (TCGA) project and identified 109 lncRNA-perturbated triplets. I showed that the paired miRNAs and mRNAs were widely perturbated by lncRNAs in different cancer types. LncRNA perturbators and lncRNA-perturbated mRNAs showed significantly higher evolutionary conservation than other lncRNAs and mRNAs. Importantly, the lncRNA-perturbated triplets exhibited high cancer specificity. The pan-cancer perturbator OIP5-AS1 showed higher expression level than that of the cancer-specific perturbators. These lncRNA perturbators were significantly enriched in known cancer-related pathways. Furthermore, among the 25 lncRNAs in the 109 triplets, lncRNA SNHG7 was identified as a stable potential biomarker in lung adenocarcinoma (LUAD) by combining the TCGA dataset and two independent GEO datasets. Finally, results from cell transfection also indicated that overexpression of lncRNA SNHG7 and TUG1 enhanced the expression of the corresponding mRNA PNMA2 and CDC7 in LUAD. In summary, the study provides a systematic dissection of lncRNA-perturbated triplets and facilitates our understanding of the molecular roles of lncRNAs in cancers.長非編碼RNA（lncRNA）是非編碼RNA最常見的類型之一。LncRNA可以在不同的層面上調控基因的表達，例如轉錄調控層面，轉錄後調控層面以及表觀遺傳調控層面。近些年來，越來越多的證據表明lncRNA介導的lncRNA/microRNA (miRNA)/mRNA三元組在癌症的發生及發展中發揮重要的作用。然而，識別這些有效的三元組對目前的癌症研究來說，仍然是一個主要的挑戰。此外，三元組中成員之間的動態變化之前也未探索。在這個研究中，通過整合靶點資訊及癌症病人表達譜信息，我們提出了一個新的計算框架來識別lncRNA介導的癌症相關三元組，並稱它們為"被lncRNA擾動的三元組"。我們將這個計算框架應用到TCGA的5種癌症資料集，並從中識別出了109個癌症相關的、被lncRNA擾動的三元組。我們的結果表明，在不同的癌症類型中，成對的miRNAs與mRNAs廣泛的被lncRNAs影響。 此外，相比其他lncRNAs與mRNAs，我們的結果還指出lncRNA擾動子及被lncRNA擾動的mRNAs展示出了更高的進化保守性。更重要的是，被lncRNA擾動的三元組展示出了高度的癌症特異性。相比之下，我們也找到了一個泛癌擾動子，lncRNA OIP5-AS1。相比癌症特異的擾動子而言，泛癌擾動子lncRNA OIP5-AS1展示出了更高的表達水準。我們又進一步的對這些擾動子進行了富集分析，結果表明，這些lncRNA擾動子顯著的富集在已知的、與癌症相關的通路上。接著，對這109個三元組中的25個lncRNA擾動子，我們進行了生存分析。通過整合TCGA資料集及兩個獨立的GEO驗證資料集，我們發現了一個潛在的、肺腺癌中的穩定靶點, lncRNA SNHG7。在研究的最後，我們在肺腺癌細胞系上進行了細胞轉染實驗，實驗指出，過表達的lncRNA SNHG7和 TUG1 能夠增強對應mRNA PNMA2 和 CDC7在肺腺癌A549細胞系中的表達。總而言之，我們的研究系統地剖析了被lncRNA擾動的癌症三元組，促進了對lncRNA在癌症中分子作用的理解。WEI, Yunzhen.Ph.D. Chinese University of Hong Kong 2021.Includes bibliographical references (leaves )Abstracts in English and Chinese.Title from PDF title page (viewed on ...