研究β-mangostin抑制人類肝癌細胞的侵襲機制

肝癌不僅是常見的癌症之一，由於其疾病特性與臨床治療的困難，也是死亡率很高的疾病，尤其在亞洲，肝癌因慢性肝炎的盛行，增加了罹病機率。肝癌目前在臨床上能夠治療的藥物相當有限，隨著癌細胞的侵襲與轉移，大大增加肝癌致死的機率，因此一個有效抑制肝癌生長的藥物，成為重要的研究領域。β-mangostin是山竹果中山酮素之一，目前許多研究發現山酮素可用來抗腫瘤、抗發炎。過去許多文獻指出α-mangostin具有抗腫瘤的功效，但β-mangostin抗腫瘤的相關研究仍是非常少，本研究計畫目的是深入探討β-mangostin對人類肝癌細胞所抑制細胞轉移機轉以及相關訊息傳遞機制。肝癌的侵襲與轉移大大減少了病患的存活，也是疾病惡化和致死的原因，因此本實驗想了解β-mangostin是否能降低肝癌的侵襲與轉移現象。首先，我們利用MTT assay來觀察β-mangostin對於人類肝癌細胞株(SK-Hep-1、Huh-7和HA22T/VGH)是否影響細胞生長。從實驗結果可以發現肝癌細胞在β-mangostin處理不同濃度(0、2.5、5、7.5和10 μM)，並不會造成細胞毒性。接著在以相同劑量處理發現β-mangostin也不影響細胞週期分佈。進一步利用細胞爬行試驗證明隨著β-mangostin劑量增加，會抑制三株肝癌細胞的移動及侵襲的能力。我們透過西方墨點法分析發現，β-mangostin會透過抑制MMP9及MMP2來抑制肝癌細胞的侵襲與轉移，此外我們也證明β-mangostin會誘導ERK和JNK的磷酸化，因此推測β-mangostin是透過MAPK路徑來調控MMP9/MMP2蛋白，進而抑制肝癌細胞的侵襲與轉移。接著本實驗預先處理ERK磷酸化抑制劑(PD98059)或JNK磷酸化抑制劑(JNKII)，發現β-mangostin所抑制肝癌細胞侵襲與轉移的現象有回復情形。綜合以上結果，β-mangostin藉由誘導ERK和JNK磷酸化進一步抑制MMP9和MMP2，來達到抑制肝癌細胞的侵襲與轉移的效果。藉由本研究的初步結果，未來β-mangostin可以投入更多研究，發展成臨床上治療肝癌和對抗癌細胞侵襲藥物。

β-mangostin, a xanthones compound, is isolated from Garcinia mangostana Linn. It was being investigated for its anti-cancer effect in various cancers, including breast cancer and colon cancer. The aim of this study was to investigate the anti-metastasis effect and the mechanisms of β-mangostin on human hepatocellular carcinoma (HCC) cells. We observed that β-mangostin inhibite the cell migration and invasion activity of HCC cells under non-cytotoxic concentrations. We next identify the protein expression of MMP2/MMP9 were down-regulates after β-mangostin treatment. Our results showed β-mangostin inhibit metastasis on HCC cells were associated with phosphorylation of ERK1/2 and JNK MAPK pathways. Moreover, inhibition of ERK1/2 or JNK by phospho-inhibitor were significantly reversed that β-mangostin attenuated HCC cells migration and invasion ability. In conclusion, the results of this study showed that β-mangostin might potentially could be developed as an anti-cancer agent to inhibit HCC cells metastasis based on its capacity to activate ERK1/2 and JNK and to suppress MMP2/MMP9 expression.