導致癌症死亡主要原因有晚期診斷、預後不良、抗藥性和癌細胞轉移等。在許多惡性轉移的癌細胞中，腫瘤抑制蛋白WWOX表現量常有減少的現象。另外，在我們最近的研究中，發現由溫度所調節的細胞冒泡死亡（bubbling cells death, BCD）發生時，基本上大多的細胞會分泌exosomes-like顆粒並釋放到細胞外。而這些exosomes的功能在目前研究上有很大程度是未知且尚未確定的。於本研究中，將觀察extracellular vesicles (EV)/exosomes如何影響WWOX調節的細胞遷移。首先以UV照射和冷衝擊的方式誘導乳腺癌細胞產生BCD，然後使用高速離心分離培養血清中的exosomes，並將此特定分離的物質稱為deathosome。我們結果發現在deathosome處理後，Wwox+/+小鼠胚胎纖維細胞（MEF）的遷移明顯被阻斷，而Wwox-/- MEF細胞的遷移則對deathosome刺激不敏感。此外，deathosome也不會對Wwox+/+細胞產生毒性，並增加其細胞進入S週期。deathosome在乳癌細胞中增強了Hyal-2、ERK和JNK的表達，顯示其參與的細胞存活機制。但我們在通過螢光共振能量轉移（FRET）顯微鏡成像證實deathosome通過Hyal-2受體的信號Smad4/Hyal-2/WWOX會誘導細胞死亡。總和以上結果，我們發現從乳腺癌細胞4T1-luc在BCD所分離出的deathosome，通過異位的Smad4 / Hyal-2 / WWOX信號誘導細胞死亡。

Cancer death remains one of the leading causes of death due to the late diagnosis, poor prognosis, and frequent occurrence of drug resistance and metastasis. Tumor suppressor WW domain-containing oxidoreductase (WWOX) protein is involved in cancer suppression, but it is frequently deficient in metastatic cancer cells. WWOX participates in the temperature-regulated “bubbling cell death” which involves generation of nitric oxide at low temperatures. Essentially every cell type releases exosome-like particles to the extracellular space during BCD. The function of exosome-like particles is largely unknown. Here, we investigated how extracellular vesicles (EV)/exosomes affect WWOX-regulated cell migration. EV/Exosomes were isolated from breast cancer cell lines treated with UV irradiation/cold shock overnight to induce BCD, followed by isolation using stepwise high speed centrifugation. The isolated material is hereby designated “deathosomes” for their enhanced release during BCD. Migration of Wwox+/+ mouse embryonic fibroblast (MEF) cells was significantly blocked after treating with deathosomes, whereas the migration of Wwox-/- MEF cells were not susceptible to changes upon deathosomes challenge. Wwox-/- MEF cells migrated individually, even under deathosomes treatment. Furthermore, deathosomes did not cause toxicity in the Wwox+/+ MEF cells and increased cell cycle progression into the S phase. Deathosomes upregulated Hyal2, ERK and JNK in 4T1-luc cells. The deathosomes-enhanced Smad/Hyal-2/WWOX complex formation was confirmed by real time tri-molecular FRET (Förster resonance energy transfer) microscopy. In conclusion, we demonstrated that deathosomes isolated from death breast cancer cells 4T1-luc induced cell death via ectopic Smad4/Hyal-2/WWOX signaling.

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