癌細胞常會有化學或是放射線治療引起的細胞抗性，造成治療上的困難。Gene expression profiling研究已經證實癌細胞發展出間葉細胞性質為預後腫瘤復發的主因。我們的實驗室已經建立了經放射線照射後，帶有間葉標誌─vimentin以及fibronectin的人類神經膠質母細胞瘤 (glioblastoma)─13-06 MG細胞株，這些細胞中的vimentin會由細胞質跑進細胞核，這些都是上皮─間葉轉移的現象。上皮─間葉轉移會經由Raf/MAPK訊息路徑以及TGF-β訊息路徑使細胞發生型態轉變或是分離的現象。TGF-β可以與Hyal-2互相作用並且累積WWOX蛋白。我們先同時轉殖三種不同型態─野生型、活化態或不活化態的Merlin基因以及WWOX基因進入13-06 MG細胞後，再用玻尿酸(hyaluronan)處理，經由共同免疫沉澱法(co-immuoprecipitation)得知三種型態的Merlin蛋白都可以與WWOX互相作用，顯示出WWOX蛋白參與了CD44/Merlin訊息路徑。根據MTT試驗，我們發現同時轉殖單一不同作用的Merlin基因以及WWOX基因可以增加細胞的存活率，尤其是同時轉殖不活化態的Merlin基因以及WWOX基因最為明顯。我們假設在放射線照射後表現出間葉標誌的13-06 MG細胞中，Merlin以及WWOX蛋白也許會參與TGF-β訊息傳遞路徑以及上皮─間葉轉移的過程。藉由西方點墨法(Western Blot)，我們發現經過12Gy放射劑量照射後，並同時轉殖單一不同作用的Merlin基因以及WWOX基因的13-06 MG細胞中，間葉標誌─vimentin以及fibronectin蛋白皆顯著增加，其中又以同時轉殖不活化態的Merlin基因以及WWOX基因的細胞最為明顯。我們同時也發現轉殖後的13-06 MG細胞處以玻尿酸(hyaluronan)後，WWOX蛋白可在細胞質以及細胞核中與Merlin蛋白相互作用。利用免疫細胞化學染色法可以發現，同時轉殖不活化態的Merlin基因以及WWOX基因並處以玻尿酸(hyaluronan)後，其間葉標誌─vimentin會從細胞質轉移到細胞核中。另外，對上述細胞給予TGF-β接收器─TβRI/II的抑制劑處理證實了以上的實驗結果必須經由TGF-β的訊息路徑。最後，我們則利用了clonogenic assay using soft agar colony formation證實了同時轉殖Merlin基因以及WWOX基因的13-06 MG的細胞群體確實明顯的大於控制組(vehicle control)細胞。根據上述的實驗結果，我們結論出在體外試驗中，Merlin蛋白以及WWOX蛋白皆參與於TGF-β訊息傳遞路徑，而且他們之間的交互作用會促進經放射線照射後的神經膠母細胞瘤生長，並且它是與上皮─間葉轉移有關。

Cancer radiotherapy may be complicated by chemo/radiation-induced resistance. Gene expression profiling studies have revealed that the tumor carries mesenchymal signature is a poor prognostic predictor. Our laboratory have generated post-irradiated 13-06 MG glioblastoma (GBM) cell line which expresses epithelial mesenchymal transition (EMT) markers such as vimentin, and fibronectin. Nuclear translocation of vimentin also occurs in these cells. These findings all indicate the occurrence of EMT. EMT requires cells transition and detachment, which is mainly driven by a hyperactive Raf/MAPK pathway via transforming growth factor-β (TGF-β) signaling. TGF-β signaling interacts with cell surface Hyal-2 and recruits WWOX. We treated 13-06 MG with hyaluronan (HA) and co-transfected with wild type, active form, and/or inactive form Merlin plus WWOX. By co-immuoprecipitation (Co-IP) assay, our data showed that WWOX interacted with Merlin in 13-06 MG cell line after treating with hyaluronan (HA). This finding suggested that WWOX participates in the regulation of CD44/Merlin signaling. According to our results, co-transfected WWOX with wild type or active form Merlin cells could increase cell viability in 13-06 MG after treated with HA. However, inactive form Merlin and WWOX co-tranfection that resulted in a growth permissive state was identified by MTT analysis. Given the presence of EMT marker proteins in post-irradiated 13-06 MG cells, we hypothesize that Merlin interacts with WWOX may interfere TGF-β signaling pathway and EMT. Analysis data from 13-06 MG cells after 12 Gy irradiation and transfected with WWOX plus individual types of Merlin, we found that EMT makers such as vimentin and fibronectin were significantly increased, especially in cells co-transfected with WWOX and inactive form of Merlin. We also found that WWOX interacted with Merlin in cytoplasm and nucleus in 13-06 MG treated with HA. Data obtained from cells treated with TβRI/II inhibitor suggested that these changes were TGF-β-dependent. Lastly, the colony size was also significantly increased in double-transfected 13-06 MG cells when compared to the vehicle controls by clonogenic assay using soft agar colony formation. According to these results, we conclude that TGF-β signaling recruited Merlin/WWOX and via its interaction to promote cell growth and EMT in post-irradiated 13-06 MG cell in vitro.

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