肺癌是全世界最常見以及死亡率最高的癌症，此外大約有90%的病患死於肺癌的轉移。癌症的轉移是一個非常複雜的過程，其中有許多細胞內的因子以及細胞外腫瘤微環境的因素可能會影響到肺癌細胞的轉移。然而，影響肺癌細胞轉移的分子機制目前還不是很清楚。因此，了解肺癌細胞轉移的分子機制以及發現早期的生物標誌對於肺癌的診斷和治療是非常需要的。最近，有許多研究報告指出胞外泌體在細胞之間的訊息溝通中扮演重要角色。特別是癌細胞會藉由胞外泌體將癌症轉移相關的分子傳遞給其他的癌細胞，使得癌細胞更具爬行與侵襲的能力並且促使腫瘤轉移的發生。因此，在本篇研究中，我們想探討是否高轉移性的癌細胞所分泌的胞外泌體會促進肺癌細胞爬行與侵襲的能力。在我們的實驗中，首先我們證明了CL1-5細胞的培養液能夠促進CL1-0細胞的爬行與侵襲，此外我們也發現CL1-5細胞的胞外泌體可以增加CL1-0細胞爬行與侵襲的能力。次世代定序的結果發現一個新穎的長鏈非編碼RNA U16在CL1-5細胞與胞外泌體中大量表現，而在CL1-0細胞與胞外泌體中表現量是相對較少的。功能分析的結果發現過表現長鏈非編碼RNA U16會促進CL1-0細胞的爬行與侵襲。相反地，降低長鏈非編碼RNA U16的表現量會抑制CL1-5細胞的爬行與侵襲。此外分子機制的分析中發現過表現長鏈非編碼RNA U16最顯著地活化CL1-0細胞中Notch的訊息傳遞路徑，並且調控HES5和HEY2的表現量。有趣的是，爬行與侵襲的實驗發現過表達長鏈非編碼RNA U16的胞外泌體具有促進細胞爬行與侵襲的能力，能夠促進CL1-0細胞的爬行與侵襲。相反地，降低長鏈非編碼RNA U16的表現量可以抑制CL1-5的胞外泌體所引起的細胞爬行與侵襲。結論是我們的研究證明了CL1-5細胞可以藉由胞外泌體將長鏈非編碼RNA U16傳送給CL1-0細胞並且促進CL1-0細胞的爬行與侵襲。

Lung cancer is the most common and deadly cancer throughout the world. Furthermore, approximately 90% of all lung cancer deaths are caused by tumor metastasis. Metastasis is an intricate process that a lot of cell intrinsic and extrinsic tumor microenvironment factors affect the metastasis of lung cancer cells. However, the underlying mechanisms that promote the lung cancer metastasis remain largely unclear. Thus, it is urgent to understand the molecular mechanisms of lung cancer metastasis and discover early biomarker for lung cancer diagnostics and treatment. Recently, some studies have indicated that exosomes play an important role in intercellular communications, especially, tumor-derived exosomes could potentially promote tumor metastasis through delivery of migration-related molecules. Taken together, we want to investigate whether exosomes derived from high metastatic cell promote cell migration and invasion in lung cancer. In this study, we first demonstrated that conditioned media of CL1-5 cells exosome-dependently promoted migration and invasion of CL1-0 cells. Moreover, we revealed that exosomes derived from CL1-5 cells facilitated migration and invasion of CL1-0 cells. The RNA-sequencing identified that a novel lncRNA U16 is upregulated in CL1-5 cells and exosomes compared with CL1-0 cells and exosomes. Functional assay indicated that overexpression of lncRNA U16 promoted migration and invasion of CL1-0 cells. Conversely, knockdown of lncRNA U16 suppressed migration and invasion of CL1-5 cells. Further mechanism study revealed that lncRNA U16 mainly activated Notch signaling, and regulated HES5 and HEY2 expression. Interestingly, migration and invasion assay showed that lncRNA U16-overexpressed exosomes have higher promoting ability in cell migration and invasion of CL1-0 cells. Reciprocally, knockdown of lncRNA U16 decreased CL1-5 derived exosomes-induced cell migration and invasion of CL1-0 cells. In conclusion, our findings indicated that exosomes derived from CL1-5 cells promoted cell migration and invasion of CL1-0 cells through delivery of lncRNA U16.

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