近些年,非常多研究指出長鏈非編碼RNA重要性，尤其是在癌症進程中。在這,我們研究一個新穎的腫瘤相關長鏈非編碼RNA,LINAT。臨床上,我們發現：LINAT高度表現和多種癌症病人的低生存率成正相關。進一步,LINAT過度表現和肝癌,乳癌病人中淋巴結入侵,惡化的病理學階段以及血管入侵成正相關。然而,LINAT表現量在正常及肝癌組織中沒有差異。這些結果暗示：LINAT在癌症進程中扮演重要角色,比如入侵或轉移階段,但不在腫瘤起始階段。我們為了揭示LINAT在癌症進程中角色,操作了LINAT的表現量。在結直腸癌,乳癌細胞中將LINAT過度或降低表現。結果顯示,LINAT誘導了惡性的病理學形態,包含上皮細胞間質轉化形態,轉移和入侵。為了揭示LINAT是如何誘導上皮細胞間質轉化,我們做了RNA定序,並用生資工具發現LINAT可能參與TGF-β訊號通路。實驗發現,TGF-β訊號通路中下游目標基因表現量及啟動子活性都在LINAT表現量降低時降低了。這表示了LINAT在TGF-β訊號通路中扮演促進者角色。我們進一步又發現Smad3/4介導的TGF-β也可誘導多種癌細胞中LINAT的表現。當我們降低LINAT表現量時,會降低TGF-β訊號通路的強度。因此,我們的研究指出LINAT會參與到一個回饋控制的TGF-β訊號通路。結論,我們找到一個新穎癌症相關的長鏈非編碼RNA, LINAT,且揭示了其在皮細胞間質轉化中及TGF-β訊號通路中的角色。LINAT所誘導的新穎正回饋調節之TGF-β訊號通路,突出其在癌症惡性中的角色。

Recent studies have emerged that long non-coding RNAs (lncRNAs) play vital role in tumor progression. Here, we identified a novel tumor related lncRNA termed LINAT (Long Intergenic Noncoding RNA Activated by TGF-β). Clinically, high expression of LINAT correlates with poor survival among colorectal, breast and liver cancer patients. Furthermore, LINAT overexpression is associated with lymph node invasion, deteriorated pathology stage as well as vascular invasion in liver and breast cancer patients. However, the expression level of LINAT has no significant difference between normal and tumor tissue. These findings imply that LINAT plays a role in tumor progression, such as invasion/metastasis, but not tumor initiation. To address the role of LINAT in tumor progression, we manipulated LINAT expression in breast and colorectal cancer cell lines by overexpression and knockdown approaches. The data revealed that LINAT induces malignant phenotypes, including epithelial-mesenchymal transition (EMT) phenotype, migration and invasion both in morphological and molecular levels. To uncover how LINAT induces EMT, we conducted RNA-seq to identify LINAT-induced transcriptome and utilized bioinformatics tools, including Ingenuity Pathway Analysis and Gene Set Enrichment Analysis, to characterize its features and compare with the signatures of different signaling pathways. Strikingly, LINAT-induced transcriptome has a significant correlation with the signature of TGF-β signaling. Consistently, both the expression level and promoter activity of TGF-β downstream genes are reduced significantly in LINAT knockdown lines, indicating a promoting role of LINAT in TGF-β signaling. We further found that TGF-β is able to induce LINAT expression in multiple tumor cell lines through a Smad3/4 dependent manner. Our following study shows that LINAT knockdown can decrease the amplitude and duration of TGF-β signaling. Thus, our data indicate that LINAT participates in a feedback control of TGF-β signaling. In conclusion, our results not only identify a novel tumor-promoting lncRNA, LINAT, but also dissect its role in EMT and TGF-β signaling. The LINAT-induced novel positive feedback regulation of TGF-β highlights its role in tumor malignancy and supports our findings from the clinical specimens.

謝辭 i
中文摘要 ii
Abstract iii
I. Introduction 01
1. Tumor progression and metastasis 01
2. TGF-β pathway 05
2.1 Overview of TGF-β pathway 05
2.2 Mechanism of TGF-β signaling pathway 07
2.3 The role of TGF-β pathway in EMT and metastasis 08
3. Long noncoding RNA (LncRNA) 10
3.1 Characteristics of long noncoding RNA 10
3.2 Molecular mechanism of long noncoding RNA 11
3.3 The functions of lncRNA in tumor progression and metastasis 13
4. LncRNA in TGF-β pathway 15
5. LINAT 16
II. Materials and Methods 18
Cell culture 18
Plasmids 18
Patient specimens 18
Lentivirus transduction 19
RNA extraction, RT/real-time PCR 20
Cell migration and invasion assays 21
Cell lysate preparation and western blot 21
Luciferase reporter assay and transfection 23
Subcellular fractionation assay. 23
Statistical Analysis 24
III. Results 25
LINAT expression correlates tumor progression and poor prognosis in several cancer types 25
LINAT induces malignant phenotypes in breast and colorectal cancer cell lines 26
LINAT - induced gene expression - an association with TGF-β signaling 27
LINAT knockdown impairs TGF-β signaling 27
LINAT is induced by TGF-β signaling through Smad3/4 28
LINAT is involved a feedback control of TGF-β signaling 29
IV. Discussion 30
V. References 34
VI. Figures 42
Figure 1. The clinical significance of LINAT in various cancer types 42
Figure 2. The expression levels of LINAT in various breast cancer cells 43
Figure 3. Knockdown of LINAT impairs EMT, migration and invasion 44
Figure 4. Overexpression of LINAT promotes EMT, migration and invasion 45
Figure 5. LINAT is mainly located at nucleus 46
Figure 6. Knockdown of LINAT reduces the expression of Smad target genes 47
Figure 7. Knockdown of LINAT reduces the promoter activity of Smad target genes 48
Figure 8. LINAT is induced by TGF-β signaling through Smad3/4 49
Figure 9. LINAT KD decreases the amplitude and duration of TGF-β induced genes expression 50
Figure 10. The model shows the mechanism for LINAT in TGF-β pathway 51
VII. Appendix 52

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