橘皮素抑制子宮頸癌細胞移動和侵襲之分子機制

橘皮素（Tangeretin）是一種具有多酚結構的黃酮類化合物，廣泛存在於芸香科柑橘類中。過去研究指出橘皮素具有抗氧化、抗發炎、神經保護及抗癌等效果。然而橘皮素在對抗子宮頸癌的效果尚屬未知。本研究主要探討橘皮素對於子宮頸癌細胞抑制效果及其訊息傳遞路徑機制。利用MTT和細胞群落實驗結果證實橘皮素（0、5、10及20 μM）抑制子宮頸癌細胞（SiHa、Caski）生長，但不影響HeLa細胞和子宮平滑肌細胞生長能力。橘皮素也顯著抑制子宮頸癌細胞（SiHa、Caski）細胞移動及侵襲，同時橘皮素抑制p-p38/MAPK活化、基質蛋白水解酵素（MMP9和MMP12）、上皮間質轉換蛋白（Snail和N-cadherin）蛋白及轉錄因子（NF-κB和c-Jun）蛋白表現。另外我們也發現橘皮素抑制LCN2轉錄和轉譯作用但不影響LCN2接受器（24P3R）表現。為了釐清橘皮素是否影響子宮頸癌病毒（HPV16 E6/E7）的表現，我們證實橘皮素明顯抑制HPV16 E6/E7 mRNA表現。5-氟尿嘧啶（5-FU）及順鉑（cisplatin）是目前子宮頸癌有效的化療藥物，實驗結果說明橘皮素合併5-Fu具有顯著抑制子宮頸癌SiHa細胞的生長能力及誘導細胞凋亡作用。此項研究說明橘皮素具有抑制子宮頸癌細胞生長和侵襲能力可能透過抑制p-p38活化及脂質運載蛋白-2（LCN2）的訊息傳遞路徑，同時也發現橘皮素具有輔助5-Fu的抗子宮頸癌生長之功效。本研究未來期望橘皮素能夠當作具有抗子宮頸癌增生及轉移之天然藥物，同時也具有輔助化療藥物之功效，進而提升子宮頸癌患者的存活率及改善化療藥物造成不良副作用的能力。

Tangeretin is a flavonoid compound with a polyphenolic structure, widely found in citrus plants of the Rutaceae family. Previous studies have demonstrated various functions of Tangeretin, including antioxidant, anti-inflammatory, neuroprotective, and anticancer. However, the bioactivity of Tangeretin on cervical cancer remains unclear. Our study investigates the inhibitory effects of Tangeretin on cervical cancer cells and its underlying signaling mechanisms. The results of MTT and colony formation assays show that Tangeretin (0, 5, 10, and 20 μM) inhibited the growth rate of SiHa and Caski cervical cancer cell lines, but had no effect on HeLa cells and uterine smooth muscle cells. Tangeretin also significantly inhibited the cell migration and invasion on SiHa and Caski cervical cancer cell lines. Additionally, Tangeretin suppressed the activation of p-p38MAPK, the expression of matrix metalloproteinases (MMP9, MMP12), epithelial-mesenchymal transition proteins (Snail and N-cadherin), and transcription factors (NF-κB, c-Jun). On the other hand, we also found that Tangeretin inhibited the transcription and translation of lipocalin-2(LCN2) but did not affect the expression of 24P3R. To determine whether Tangeretin affects the expression of human papillomavirus (HPV16 E6/E7), we demonstrated that Tangeretin significantly inhibits HPV16 E6/E7 mRNA expression. 5-Fluorouracil (5-FU) and cisplatin are currently effective chemotherapy drugs for cervical cancer. The results show that the combination of Tangeretin with 5-FU significantly inhibited the growth rate on SiHa cell line and induced the cell apoptosis. This study suggests that Tangeretin may inhibit the cell growth and invasion of cervical cancer cells by suppressing p-p38 activation and LCN2 signaling pathways and enhances the anticancer effects of 5-FU. This study anticipates that Tangeretin could serve as a natural compound with anti-proliferative and anti-metastatic properties for cervical cancer. It could also act as an adjuvant to chemotherapy, improving the survival rate of cervical cancer patients while reducing the adverse side effects of chemotherapy.