三陰性乳癌(TNBC)是一種具有高度侵襲性的乳腺癌，它的特徵是缺乏三種常見的受體，分別是雌激素受體(ER)、孕激素受體(PR)和人表皮生長因子受體 2 (HER2)。 三陰性乳癌佔據了大約 15-20%的乳腺癌病例，而且與不良預後有高度 相關性。治療三陰性乳癌時往往會遇到的一個挑戰就是它會遠處轉移至大腦、肺、肝 臟、骨骼以及其他器官，此外三陰性乳癌的遠處轉移會顯著降低三陰性乳癌患者的 5 年內生?率至 12%。長鏈非編碼核糖核酸(lncRNA)被定義為由 200 個或更多核苷 酸組成的非編碼轉錄本。目前已有研究指出長鏈非編碼核糖核酸會在乳腺癌中異常表 達，並在腫瘤轉移中扮演轉移因子的角色。我們在此假設長鏈非編碼核糖核可能會調 控三陰性乳癌的轉移並與三陰性乳癌患者的癌症進展有相關性。基於初步的核糖核酸 定序結果中，觀察到在高度轉移性的三陰性乳癌細胞中長鏈非編碼核糖核酸 MIR4500HG003 的表達會顯著上升。 而在細胞實驗結果中，MIR4500HG003 的過度 表達不僅會使三陰性乳癌細胞的遷移和侵襲能力增加，而且加速了三陰性乳癌在小鼠 體內轉移的進展並且導致腫瘤轉移比例的增加。此外，我們的研究結果顯示， MIR4500HG003 的高度表達與乳腺癌和三陰性乳癌患者較差的整體生?率和無病生 ?率有著正相關。在 MIR4500HG003 所介導的轉移的潛在機制中，我們的研究結果 顯示了 MIR4500HG003 的過度表達會使 MMP9 表現量增加，而 MMP9 是一種與上 皮-間質轉化相關的蛋白，該蛋白在降解基底膜和促進細胞侵襲中扮演著重要角色。 根據長鏈非編碼核糖核酸的目前的已知功能中，我們研究了會與 MIR4500HG003 和 MMP9-3'UTR 會同時結合的微小核糖核酸(miRNA)。我們發現微小核糖核酸 483- 3p 在與會跟 MIR4500HG003 結合的微小核糖核酸們中排名靠前，並且與 MMP9- 3'UTR 有著強烈的結合力。此外，我們的回補實驗也證實出了 MIR4500HG003 會去 吸附微小核糖核酸 483-3p 然後抑制微小核糖核酸 483-3p 的功能，從而上調 MMP9 的 表現。目前的研究結論是，長鏈非編碼核糖核酸 MIR4500HG003 會藉由通過微小核 糖核酸 483-3p-MMP9 的訊息傳遞路徑去促進三陰性乳癌的轉移能力。綜合以上敘述， 長鏈非編碼核糖核酸 MIR4500HG003 可以作為三陰性乳癌病人腫瘤轉移的診斷以及 預後指標。

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer characterized by the absence of three common receptors, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC accounts for approximately 15-20% of all breast cancer cases and is associated with a poor prognosis. A key challenge in treating TNBC is its tendency for distant metastasis to the brain, lungs, liver, and bones, which significantly contributes to the lower 5-year survival rate of TNBC patients, reducing it to 12%. Long non-coding RNAs (lncRNAs) are defined as non-coding transcripts consisting of more than 200 nucleotides. They have been reported to be aberrantly expressed in breast cancer and play a role as metastasis factors in the disease. We hypothesize that lncRNAs may regulate TNBC metastasis and be associated with the progression of TNBC patients. Based on the RNA sequencing from preliminary results, it is observed that the expression of lncRNA MIR4500HG003 is significantly upregulated in highly metastatic TNBC cells. The overexpression of MIR4500HG003 not only demonstrates an increase in migration and invasion capabilities of TNBC cells in vitro but also accelerates the progression of TNBC metastasis and leads to an increased proportion of metastasis in vivo. Furthermore, our findings indicate that high expression of MIR4500HG003 is associated with poor overall survival and disease-free survival in both breast cancer (BC) and TNBC patients. In the underlying mechanism of MIR4500HG003- mediated metastasis, our results indicate the upregulation of MMP9, an epithelial- mesenchymal transition (EMT) related gene that plays a crucial role in degrading the basement membrane and promoting cell invasion. According to the cellular functions of lncRNA, we investigate the miRNA candidates, which can bind with MIR4500HG003 and MMP9-3’UTR. MiR-483-3p is identified that is top-ranked in the MIR4500HG003 associated candidate miRNAs and has strong binding force with MMP9-3’UTR. Furthermore, our restore experiments verify the functional role of MIR4500HG003 as a sponge for sequestering miR-483-3p, thereby up-regulating the expression of MMP9. The conclusion of the current study is that lncRNA MIR4500HG003 promotes metastasis through the MIR4500HG003/miR-483-3p/MMP9 axis in TNBC. Collectively, our results demonstrate that MIR4500HG003 has the potential to serve as a diagnostic and prognostic marker for TNBC patients.

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