乳癌好發生於乳腺上皮組織，是女性中最常發生的癌症，轉移是導致癌症死亡的主要原因，也是在乳癌治療上的一大挑戰。在人體基因組中，只有約2 %的基因能轉譯出蛋白，稱為蛋白質編碼基因，而將近98 %的基因則為非編碼核醣核酸。目前非編碼核醣核酸的研究大多聚焦在小片段核糖核酸（MicroRNA）以及長片段非編碼核醣核酸（Long non-coding RNA），這些非編碼核醣核酸在基因的調控、正常的細胞功能以及癌症的發展均扮演重要的角色，其中某些長片段非編碼核醣核酸已被報導在許多腫瘤中會異常表現，並且在癌細胞生長與轉移中扮演重要的角色。然而仍然有許多參與在乳癌轉移的長片段非編碼核醣核酸未被發現，並且生物功能尚未清楚。在這個研究中，我們利用微陣列方法（Microarray）分析兩株轉移能力不同的乳癌細胞株，分別為MB-231-P和MB-231-IV2-1，找出了213個在MB-231-IV2-1細胞中高度表現以及301個低度表現的長片段非編碼核醣核酸。另外利用The Cancer Genome Atlas （TCGA）資料庫，我們進一步分析這些長片段非編碼核醣核酸在乳癌中的表現量，我們得到一些與乳癌轉移相關的長片段非編碼核醣核酸。其中我們選擇LINC01420，進一步探討在乳癌中的生物功能，首先，利用即時定量PCR分析，我們發現在乳癌病人檢體中，LINC01420的表現量明顯比正常組織高，接著利用cDNA末端快速擴增（RACE）技術定出LINC01420基因序列全長，我們找出LINC01420有三種不同的選擇性剪接異構物（Alternative splicing isoform）。利用細胞實驗發現，在乳癌細胞中抑制LINC01420基因表現會使乳癌細胞週期停滯在S期以抑制乳癌細胞生長。其中若抑制LINC01420-V1和 -V3這兩個異構物，對於細胞生長以及細胞侵犯的能力上有顯著抑制效果。這結果提供我們認為LINC01420-V1和 -V3這兩個isoform在乳癌上可能扮演重要的調控角色，以及外顯子2可能為主要致癌基因功能區。並且LINC01420在乳癌腫瘤增生上可能扮演功能上致癌基因角色。

Breast cancer occurs in mammary gland epithelial tissue and is the most commonly diagnosed cancer in women throughout the world. Previous studies indicated that invasion of cancer cells was the major cause of the death, which had been a major challenge in the treatment of breast cancer. In human genome, recent studies reveal that there is < 2 % of the total genome sequence as protein-coding genes, however, at least 98 % of genome are transcribed into non-coding RNA (ncRNA). So far, the study of ncRNA is mainly concentrated on the microRNA (miRNA) and long non-coding RNA (lncRNA). An increasing number of researches reveal that ncRNAs have been shown to play an important role in gene regulation, normal cellular functions and disease processes. However, the detail biological function of lncRNA involving in breast metastasis is still unclear. In this study, we performed the expression profiles of two breast cancer cell lines, MB-231-P and MB-231-IV2-1, by microarray approach (Agilent SurePrint G3 Human V2 GE; including 34092 protein-coding genes and 8715 lncRNAs). After finishing the microarray profiling, we identified about 213 lncRNAs upregulated and 301 lncRNAs downregulated in MB-231-IV2-1 cell line compared to MB-231-P, respectively. Finally, we successfully identified several metastasis-related lncRNA candidates according microarray data and The Cancer Genome Atlas (TCGA). Among them, LINC01420 was selected for further study in this study. We assessed the expression levels of LINC01420 in breast cancer tissues by real-time PCR approach. Our data revealed that the expression levels of LINC01420 were significantly increased in breast cancer compared with adjacent normal tissues. We further identified the full length of LINC01420 by 5’ and 3’ rapid amplification of cDNA ends (RACE) in breast cancer cell. Our results revealed that LINC01420 could generate three splicing transcripts (V1, V2 and V3) via alternative splicing. Furthermore, knockdown of LINC01420 could suppress breast cancer cell growth by inducing cell cycle arrest at S phase. Interesting, the cell growth and the invasion ability of MB-231-IV2-1 cell significantly decreased after LINC01420-V1 and -V3 knockdown. These results implied that LINC01420-V1 and -V3 might be critical isoforms and exon 2 might be a functional oncogene region involving in modulating biological function in breast cancer. Our results suggest that LINC01420 might be a functional oncogene in breast tumorigenesis.

Chinese Abstract……………………………………………………………….....i
English Abstract……………………………………………………………………....ii
Table of contents………………………………………………………………..... iv
List of Figures……………………………………………………………………...vii
List of Tables…………………………………………………………………………....ix
I. Introduction………………………………………………………………………1
II. Specific Aims……………………………………………………………………….6
III. Methods & Materials
3.1 Cell culture……………………………………………………………………..7
3.2 Transwell invasion assay……………………………………………….....7
3.3 RNA extraction…………………………………………………………………8
3.4 Reverse transcription………………………………………………………………..8
3.5 Real-time PCR analysis……………………………………………………...8
3.6 Western blot…………………………………………...9
3.7 Microarray…………………………………………………………….............10
3.8 Subcellular fractionation localization…………………………………...10
3.9 For full length, RNA ligase-mediated rapid amplification of 5’ and 3’ cDNA ends (RLM-RACE)…………………………………………………………….............11
3.10 LINC01420 cDNA Sequences……………………………………………….12
3.10.1 Isoform-1……………………………………………………………..12
3.10.2 Isoform-2………………………………………………………….12
3.10.3 Isoform-3………………………………………………………….13
3.11 Polymerase chain reaction, PCR………………………………………….….14
3.12 RNA Interference……………………………………………………….........14
3.13 Transfection………………………………………………….............…...14
3.14 Proliferation……………………………………………………………….…15
3.15 Colony formation assay………………………………………………...……15
3.16 Image flow cytometry assay…………………………………………………16
3.17 Chemicals……………………………………………………………………16
3.18 Cell Synchronization……………………………………………………..….16
IV. Results
4.1 Generation of lncRNA expression profiles in breast cancer samples
4.1.1 MB-231-P and MB-231-IV2-1 cells have different invasive ability..…17
4.1.2 Identify oncogene and tumor suppressor gene in breast cancer…….....18
4.1.3 The effects of protein-coding gene on different pathways…………18
4.2 Identification of metastasis-associated lncRNA candidates in breast cancer
4.2.1 LINC01420 is overexpression in breast cancer………………….....….19
4.2.2 Examine the subcellular fractionation localization of LINC01420..19
4.2.3 Identify full length of LINC01420 sequence………………………20
4.3 The biological role of LINC01420 in breast cancer
4.3.1 Knockdown of LINC01420 suppresses breast cancer cell proliferation…………………………………………………………………....21
4.3.2 Knockdown of LINC01420 induces cell cycle arrest at S-phase in breast cancer cell……………………………………………………………………..23
4.3.3 Knockdown of LINC01420 inhibits invasion ability on breast cancer cell………………………………………………………………………………...25
V. Discussion……………………………………………………………………..26
VI. Conclusion……………………………………………………………………...…32
VII. References………………………………………………………………..……33
VIII. Tables……………………………………………………………..……………41
IX. Figures…………………………………………………………………………49

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