目前對於卵巢癌治療最大之挑戰為其極高的復發率。目前已知上皮細胞轉型成間質細胞 (epithelial-mesenchymal transition, EMT) 會造成癌細胞脫離原位而進入腹水中，這在卵巢癌復發過程中扮演著關鍵角色。近期許多團隊都證明，腫瘤之分子亞型為間質型的卵巢癌病人存活率較差。然而，目前對於其中機制仍有許多不清楚之處。我們的策略是希望找出同時在復發腫瘤(與原位腫瘤比)與間質型腫瘤(與非間質型腫瘤比)中表現量皆為上升的微小核糖核酸(microRNA)。藉由這個策略，我們找到一個新的生物標記microRNA-150-5p (miR-150-5p)，並發現其表現量與配對之原位腫瘤相比，在16個復發的檢體中都有顯著性的上升。另外，分析其他研究團隊之病人檢體，也證明miR-150-5p在術後較早復發的檢體中表現量較多，並與卵巢癌病人較差的存活率有關。在卵巢癌細胞中抑制miR-150-5p，會明顯看到細胞爬行能力受到抑制，且細胞型態由間質細胞轉型成上皮細胞 (mesenchymal-epithelial transition, MET)。同時證實在卵巢癌中c-Myb為miR-150-5p之標靶基因，且miR-150-5p/c-Myb/Slug訊號在調控卵巢癌之上皮細胞轉型成間質細胞中扮演重要角色。更重要的是，在臨床上，MYB的表現量與卵巢癌病人較佳的預後有顯著相關性，且與SNAI2的表現量呈現負相關。miR-150-5p與Slug能夠抑制miR-506-3p的表現 (已知對上皮細胞轉型成間質細胞與轉移扮演抑制角色)。同時帶有高表現miR-150-5p與低表現miR-506-3p的卵巢癌病人呈現更差的預後。於低氧環境中培養卵巢癌細胞，會導致miR-150啟動子的活化，並誘發miR-150-5p表現。上述結果指出低氧誘發miR-150-5p表現上升，而藉由c-Myb-Slug路徑調控復發卵巢癌的惡化。未來透過抑制miR-150-5p防止卵巢癌復發與轉移，也許能成為一項新的治療策略。

Treatment of ovarian cancer (OvCa) remains a challenge due to its high recurrence rates. Epithelial-mesenchymal transition (EMT), which causes the detachment of cancer cells to the peritoneal fluid, plays a key role in relapse of OvCa. Recently, several groups demonstrated that patients with mesenchymal OvCa subtype had relatively poor overall survival. However, the mechanisms of this process remain largely unclear. Our strategy is to identify the potential miRNAs which are consistently elevated in both recurrent ovarian tumors (compared to primary tumors) and mesenchymal subtype tumors (compared to non-mesenchymal subtype) OvCa. Using this strategy, we identified a novel biomarker, microRNA-150-5p (miR-150-5p), that was significantly upregulated in 16 recurrent ovarian tumor tissues compared with their matched primary specimens. Analysis of cohorts from other two groups also proved that expression of miR-150-5p was associated with early-relapse and poor survival of ovarian cancer patients. Inhibition of miR-150-5p significantly inhibited the migration of ovarian cancer cells and induced a mesenchymal-epithelial transition (MET) phenotype. We demonstrated that c-Myb was a miR-150-5p target in ovarian cancer cells and miR-150-5p/c-Myb/Slug axis played important roles in regulating EMT of ovarian cancer cells. Expression of MYB was significantly correlated with good clinical outcome in ovarian cancer and negatively correlated with SNAI2 expression in clinical specimens. MiR-506-3p, known to be a EMT or metastasis suppressor, could be suppressed by miR-150-5p and Slug. High miR-150-5p and low miR-506-3p predicted much poorer outcomes of OvCa patinets. Hypoxia activated the miR-150-5p expression and its promoter activity in ovarian cancer. Collectively, these results suggest that hypoxia-induced upregulation of miR-150-5p mediated the progression of recurrent ovarian cancer by targeting the c-Myb-Slug pathway. Inhibition of miR-150-5p may serve as a new therapeutic strategy for preventing recurrence of ovarian cancer in the future.

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