遠端轉移為癌細胞由原發處轉移至遠端臟器之動態過程。臨床上，三陰性乳癌之病患因遠端轉移發生之機率高，而導致其預後結果不佳。三陰性乳癌之遠端轉移主要發生於肺臟、腦、肝臟及骨骼等重要器官。長鏈非編碼核醣核酸是一群缺乏蛋白質轉譯能力，長度超過200個核苷酸之轉錄本。近期研究證實其在乳癌遠端轉移之過程中扮演重要角色。然而，長鏈非編碼核醣核酸於調控三陰性乳癌遠端轉移之詳細機轉仍未明。本研究藉由RNA測序技術與功能性鑑定發現長鏈非編碼核醣核酸ZNF469-3高度表現於具肺轉移能力之LM2-4175細胞株。過度表現長鏈非編碼核醣核酸ZNF469-3於細胞中，不僅能促進細胞移行、侵犯能力及癌幹細胞特性，亦可藉由小鼠模式發現其增強肺轉移之機率。此外，長鏈非編碼核醣核酸ZNF469-3可與小分子核醣核酸574-5p進行交互作用，並作為誘餌以干擾其調控鋅指結構E-Box-結合同源框1之表現。更重要的是，三陰性乳癌病患之組織染色分析結果發現，合併高表現長鏈非編碼核醣核酸ZNF469-3和鋅指結構E-Box-結合同源框1，與腫瘤復發於肺臟之間有正相關性。
另外，我們亦發現長鏈非編碼核醣核酸SLITRK6-6高度表現於具侵犯能力之MDA-MB-231 1-5細胞株。過度表現長鏈非編碼核醣核酸SLITRK6-6於細胞中，不但能強化其移行及侵犯能力，亦可於小鼠模式中發現其提升腦轉移之機率。此外，長鏈非編碼核醣核酸SLITRK6-6除可與小分子核醣核酸483-3p進行交互作用外，亦能增強基質金屬蛋白酶9之蛋白表現及其酵素活性。值得注意的是，由病患之組織染色分析結果發現，高度表現長鏈非編碼核醣核酸SLITRK6-6與腫瘤復發於肝臟之間有正相關性。綜上所述，本篇研究結果顯示上述新穎之長鏈非編碼核醣核酸皆具有促進三陰性乳癌細胞遠端轉移之能力，並作為腫瘤復發之預後標記的可能性。

Triple-negative breast cancer (TNBC) lack expressions of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2) and importantly, TNBC tumors tend to metastasize to the lungs, brain, liver and bone in patients, which contribute to poor prognosis and 5-year survival. Recently, long non-coding RNAs (lncRNAs) represent a class of non-protein-coding transcripts with ≥ 200 nucleotides (nt) and have been revealed as crucial modulators in metastatic cancers. Nonetheless, the detailed mechanisms of how lncRNAs involve in TNBC invasion and metastasis remain elusive. In this study, RNA sequencing (RNA-seq) and functional characterization found that linc-ZNF469-3 was significantly upregulated in lung-metastatic LM2-4175 cells and linc-ZNF469-3 overexpression enhanced cell migration, invasion and stemness properties as well as promoted lung metastasis in mice. Mechanistically, linc-ZNF469-3 interacted with miR-574-5p and functioned as a decoy to regulate ZEB1 expression. More importantly, concurrent high linc-ZNF469-3 and ZEB1 expressions significantly correlated with tumor recurrence in TNBC patients with lung metastasis.
In addition, high linc-SLITRK6-6 expression was also found in highly invasive MDA-MB-231 1-5 cells and overexpression of linc-SLITRK6-6 enhanced both migration and invasion abilities in vitro as well as increased the incidence of brain metastasis in vivo. Furthermore, our data showed that linc-SLITRK6-6 not only interacted with miR-483-3p but also enhanced MMP9 expression and its gelatinase activity. Notably, significantly high level of linc-SLITRK6-6 showed correlation with tumor recurrence in TNBC patients with liver metastasis. Taken together, our findings suggest that both linc-ZNF469-3 and linc-SLITRK6-6 can promote organotropic metastasis of TNBC through context-dependent signaling axis and have potential as potential prognostic markers for TNBC patients in the future.

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