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標題: HMGB1 對於攝護腺癌細胞上皮間質轉化過程之調控及甘草甜素回復 E-cadherin 之潛力
Regulatory effect of HMGB1 on the process of epithelial-mesenchymal transitionand reversal potential role of glycyrrhizin on E-cadherin in prostate cancer cells
作者: 張珩毓
Heng-Yu Chang
關鍵字: HMGB1;DU145prostate cancer cell,epithelial-mesenchymal transition;Rac1/Cdc42, GSK-3β;cell polarity;E-cadherin, glycyrrhizin;HMGB1;DU145 攝護腺癌細胞;上皮間質轉化現象;Rac1/Cdc42;GSK-3β;細胞極性;E-cadherin;甘草甜素
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Prostate cancer is the first cause of male cancer incidence in the developed countries and is hard to eradicate because of the high metastasis and easy relapse. Therefore, the prevention and therapy of prostate cancer is an important study. Tumor with rapid growth is one of the characteristics in cancer metastasis, resulting from growing environments of hypoxia, starvation and chronic inflammation within the tumor tissue. The stress stimulation during harsh environment not only causes to get nutrients and growing space but also to invade surrounding tissue into the circulatory system. Epithelial-mesenchymal transition (EMT) is the first step in the process of cancer cells with invasion and tumor metastasis, which can help cell adhesion decrease the ability of cell-cell junction and generate cell polarity. The effects result in tumor escape form tumor tissue and migrate, eventually leading to invasion and metastasis. HMGB1plays a role of non-histone chromatin binding nuclear protein and a damage-associated molecular pattern (DAMP), which is released to extracellular by active and passive modes during cell damage. Thus, cancer cells can resist environmental stimuli and injury. The aim of this study was to investigate whether HMGB1 expression can affect its release and regulatory ability of EMT to cause cell invasion. In addition, we also explored the reversal potential effect of phytochemical glycyrrhizin (GR) on E-cadherin of prostate cancer cells was also explored.

The results indicated that knockdown of HMGB1 reduced HMGB1 release in prostate cancer cells, leading to inhibition of phosphorylation of Rac1/Cdc42 to promote GSK-3β activity. The level of GSK-3β activation induced snail degradation and reduced its translocation which increased E-cadherin expression and promoted cell adhesion to down-regulate cell polarity and reduce tumor metastasis. In addition to directly regulate E-cadherin expression, HMGB1 was inhibited to indirectly regulate EMT before being reduced EMT relative inflammatory factor release such as IL-6 and IL-8 to avoid a better condition beneficial for tumor metastasis. To further investigated whether HMGB1-induced Rac1/cdc42 signaling is a major regulatory pathway regarding modulation of EMT ability in prostate cancer cells. The serum-free medium was applied to simulate a starvation environment in tumor growth. The results showed that low expression of HMGB1 in prostate cancer cells exhibited poor ability of tumor migration and low expression of EMT-related inflammatory factors. Based on these finding, HMGB1 is a critical EMT regulator. GR is one of the sweet substances in Liquorice. The recent reports showed that GR is able to bind with HMGB1 to inhibit its cytokine activity. We also found that GR suppressed tumor migration and recovered E-cadherin expression in prostate cancer cells.

In conclusion, HMGB1 could be a hallmark to tumor metastasis. Reduction of prostate cancer metastasis occurred through suppression of HMGB1 releasing and recovering. GR is a phytochemical and has capability to bind HMGB1 and to inhibit tumor metastasis. Therefore, it is suggested that GR may have potential of adjuvant chemotherapy and as an adjuvant therapy.

攝護腺癌於已開發國家男性癌症罹患率位居首位,具有高度轉移性且易復發,導致難以根治,因此攝護腺癌之預防及治療為相當重要之研究。癌細胞轉移主因來自於快速生長之特性,導致腫瘤組織內部呈現缺氧、飢餓及慢性發炎之生長環境,癌細胞由於惡劣環境壓力刺激而導致其為了獲得更多養分及生長空間,侵入到周遭組織並進入循環系統。上皮間質轉化現象 (epithelial-mesenchymal transition, EMT)之過程為癌細胞具有侵入轉移之首要步驟,此步驟幫助癌細胞減弱細胞與細胞間黏附能力,並產生細胞極性,使癌細胞脫離腫瘤組織並具有移行能力,進而促進侵入轉移進行。HMGB1 (High mobility groupbox-1) 為一種核蛋白,正常情況下扮演非組蛋白染色質結合蛋白(non-histone chromatin binding protein)之角色,然而細胞受到傷害或刺激之情況下會透過主動及被動兩種方式釋放至細胞外,作為損傷相關分子 (damage-associated molecular pattern, DAMP),幫助細胞抵抗外來環境之刺激及傷害。本研究目的為探討 HMGB1 於 DU 145 攝護腺癌細胞表現之差異是否會影響其釋放及調控其 EMT 能力 進而調,控癌細胞侵入轉移之特性,並探討天然植物化合物甘草甜素(Glycyrrhizin, GR)回復癌細胞 E-cadherin 表現之潛力。

本研究結果指出,利用基因弱化 (Knockdown) 方式降低攝護腺癌細胞中 HMGB1 (High-mobility group box-1)表現量確實顯著減弱HMGB1 之釋放,此結果導致癌細胞之 Rac1/Cdc42 磷酸化表現減弱,而促進癌細胞 GSK-3β 活性,導致 snail 之降解並減少其轉位,而促使 E-cadherin 表現量顯著提升,進而增加癌細胞間黏附能力,導致癌細胞移行能力減弱而達到抑制侵入轉移之能力。Rac1/Cdc42 之活化除了降低 E-cadherin 外,也可降低癌細胞極性 (cell polarity) 之形成,而使細胞無法脫離腫瘤組織進行移動。除了直接調控訊息傳遞路經促使癌細胞 EMT 能力上升外,抑制 HMGB1 也可減少 EMT 相關發炎因子 IL-6 及 IL-8 之表現量,而避免癌細胞處於有利於侵入轉移之微環境。

此外,以無血清環境方式模擬攝護腺癌細胞處於飢餓環境,進一步探討是否於惡劣生長環境下,HMGB1 所誘導之 Rac1/Cdc42 路徑之活化仍是調控癌細胞 EMT 能力之主要訊息傳遞路徑 結果顯示,。在無血清環境下,HMGB1 釋放確實具有活化前述訊息傳遞路徑之能力,並且經由基因弱化而導致 HMGB1 表現量較低之攝護腺癌細胞株 在無血清環境下之移行能力顯著降低 由此數據顯示 HMGB1 在,,癌細胞 EMT 能力之調控扮演重要之角色 甘草中之主要甜味物質為。甘草甜素,近期文獻指出甘草甜素具有補捉 HMGB1 而抑制其細胞激素功能之用途。本研究發現介入甘草甜素能有效抑制攝護腺癌細胞移 行 之 能 力 , 並 回 復 正 常 HMGB1 表 現 量 之 攝 護 腺 癌 細 胞E-cadherin 表現量。

綜合上述結果 HMGB1 確實可作為癌症侵入轉移能力之指標,,抑制 HMGB1 之釋放或捕捉已釋放 HMGB1 具有抑制攝護腺癌細胞侵入轉移之功能性。天然植物化合物中,甘草甜素可透過螯合HMGB1 而回復攝護腺癌 E-cadherin 表現量,進而降低癌細胞之侵入轉移能力,因此推測甘草甜素具有輔助治療及作為化療藥物佐劑之潛力。
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