Irisin對人類神經膠質瘤細胞株U-87 MG之影響

臨床統計指出運動能有效降低罹癌風險及延緩癌症進程，並且具備無副作用之特性，然而，運動抗癌之生理機制尚未闡明。先前研究發現，運動使肌肉細胞釋放大量irisin，最後作用於白色脂肪細胞促進其browning成為類棕色脂肪細胞，這兩種脂肪細胞的能量代謝及激素分泌皆不同，其中最主要的差異在於類棕色脂肪會快速消耗能量，由此可知irisin具有調控脂肪代謝之功能。另外，研究證實腫瘤中含有白色脂肪細胞，白色脂肪細胞幫助癌細胞變得更具侵略性 (aggressive)。綜合以上所述，我們推測運動後產生之irisin能使腫瘤中白色脂肪細胞browning成為類棕色脂肪，進一步抵銷白色脂肪細胞對癌細胞之幫助，藉此抑制癌症進程。我的論文主要探討irisin對腫瘤細胞之影響，包含兩個方向：irisin是否直接影響癌細胞?或者先將白色脂肪細胞browning後，間接影響鄰近之癌細胞? 實驗主要分成三個階段：首先，於E.coli系統表現irisin，並且確認我們製備之irisin具有結合白色脂肪細胞及促進browning的能力。第二階段探討irisin對人類神經膠質瘤細胞株U-87 MG之影響，若直接以irisin處理U-87 MG，發現其細胞存活 (cell viability) 及遷移 (cell migration) 不受影響，而侵襲能力 (cell invasion) 則被抑制。若將irisin刺激產生的類棕色脂肪與U-87 MG共同培養，可觀察到U-87 MG的遷移和侵襲能力皆下降，且抑制效果比irisin直接處理癌細胞更顯著，證實irisin能透過將癌細胞周圍之白色脂肪細胞 browning 間接抑制癌細胞之遷移與侵襲。第三階段透過放射線標定irisin及小鼠PET影像系統，我們觀察到irisin聚集在皮下腫瘤，此現象說明irisin勢必在癌症中扮演重要角色。藉由第二及第三階段的實驗結果，本論文提議irisin很可能就是運動能延緩癌症進程的關鍵。

關鍵字

irisin ；脂肪細胞browning ；細胞遷移；細胞侵襲；細胞共培養

並列摘要

Clinical research indicated exercise could prevent cancer and delay cancer progression. Exercise has no side effect, therefore, the mechanism of how exercise affects cancer should be clarified for promoting development of cancer therapy. Previous studies found that exercise induces secretion of irisin from myocytes. Exercise-induced irisin finally targets to white adipocytes, and induces white adipocytes browning to brown-like adipocytes. Browning changes adipokine secretion and increases energy expenditure. Moreover, previous studies indicated white adipocytes also present in tumors and make tumor cells more aggressive. Based on above information, we speculated that exercise-induced irisin may affect cancer cells through inducing browning of cancer-associated adipocytes. First, recombinant irisin protein was produced in E.coli and purified by the Ni-NTA column. The white adipocyte binding and browning ability of the recombinant irisin were confirmed. Next, we investigated the effect of irisin on the human glioblastoma cell line, U-87 MG. After irisin treatment, the cell viability and migration of U-87 MG remained unchanged, but the cell invasion was decreasing. Moreover, the cell migration and invasion of U-87 MG were both decreasing by co-culture with irisin-induced-brown-like adipocytes. Furthermore, with the injection of radio-isotope-labeled irisin into BALB/c nude mice, we found irisin had significant tumor targeting ability by PET imaging. Our results indicated that irisin could significantly inhibit the cell invasion of U-87 MG in both direct and adipocytes-related indirect way. Cell invasion was important for metastasis and the indicator of aggressive cancers. Therefore, our results proposed irisin play the key role of how exercise delay cancer progression.

並列關鍵字

irisin ； adipocyte browning ； cell migration ； cell invasion ； co-culture

參考文獻

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Irisin對人類神經膠質瘤細胞株U-87 MG之影響

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