KSRP 在人類肺癌轉移浸襲之角色探討

Abstract

肺癌高居世界十大癌症死因之首，導致肺癌死亡率居高不下、治癒率低的主要 元凶為癌細胞遠端轉移所造成的治療失敗。因此研究抑制癌細胞轉移之機轉在癌 症治療領域中占有極重要的角色。癌細胞轉移的病理機制包括細胞移動、浸襲、 血管新生、及細胞增生。不同型態的細胞轉移會受到不同的機轉調控。找出抑制 腫瘤浸襲基因並釐清其機制，可作為病理診斷上的新方法，及提供未來治療癌症 的方向。 KSRP 在過去研究中已知可以藉由促進訊息核糖核酸降解及促進微型核糖核酸 成熟調控基因表現，並參與許多生物性功能如細胞增生、分化、凋亡等。因此， 我們試圖探討KSRP 在肺癌發展及轉移浸襲中的重要性及其調控機轉。在本篇研 究中，我們發現KSRP 在肺腫瘤周邊的正常組織的表現量遠高於腫瘤組織，臨床 上分析KSRP 表現量較高的病人，與較長存活時間有正相關性。在體外細胞株實 驗當中，KSRP 的核糖核酸及蛋白質表現量和轉移浸襲能力有高度負相關性。在 KSRP 過度表現之轉殖細胞株中發現顯著降低細胞的轉移及浸襲能力;相反的在 KSRP 表現降低的轉殖細胞株中則促進癌細胞轉移能力。動物實驗結果也證明，持 續抑制KSRP 表現導致腫瘤快速生長並且轉移浸襲致其他肺葉，證明KSRP 無論 是在體外及活體內實驗都能有抑制腫瘤轉移浸襲的能力。 進一步探討KSRP 所調控之浸襲能力之機轉則發現，KSRP 可藉由調控let-7a、 miR-23a 及miR-25*等抑癌微型核糖核酸成熟，導致標的基因蛋白表現量下降，進而抑制其所調控之轉移浸襲能力。因此，KSRP 為一個新發現之抑癌基因並可作為將來治療癌症轉移的標的因子。

Lung cancer is the most common cause of cancer-related death worldwide, and metastasis is the major cause of treatment failure and mortality in cancer patients. The pathogenesis of cancer metastasis involves cell migration, invasion, angiogenesis, and cell proliferation. Different types of cell migration are regulated by different mechanisms. Identification of novel tumor metastasis-associated genes and elucidation of their mechanism of action may provide new insights into the pathogenesis and management of cancer metastasis. KH-type splicing regulatory protein (KSRP) has been shown to be an essential factor for the rapid decay of mRNAs containing AU-rich elements and involved in the biogenesis of a subset of miRNAs, to regulate a variety of biological processes, including cell cycle, differentiation, development, and metabolism. The purpose of this study is to investigate the regulatory role of KSRP in lung cancer metastasis and invasion. In the present study, we found that KSRP was expressed higher in non-tumor part than matched tumor part of lung cancer patients and inversely correlated with the patient’s survival, as well as migration and invasion abilities in lung cancer cell lines. By using transwell migration and invasion assay, we found that KSRP inhibited lung cancer cell-induced migratory and invasive abilities. In addition, in vivo orthotopic mouse model showed that KSRP inhibited tumor growth, intrapulmonary metastasis and distal organ metastasis. We further demonstrated that KSRP depletion results in down regulation of several tumor suppressive miRNAs including let-7a, miR-23a and miR-25*. KSRP may suppressed cancer cell invasion and metastasis through promoting the maturation of these miRNAs, which may result in reduction of downstream genes. In conclusion, we considered KSRP as a tumor suppressor gene and it inhibited cancer cell invasion and metastasis. Therefore, KSRP may be a potential target for cancer treatment.