從基因及藥物治療觀點探討癌症轉移

Abstract

癌症目前是全世界最受矚目的公眾健康議題，在美國每四人死亡就有一人是因為罹癌。無論在台灣或全世界，肺癌是占癌症死亡的首位，而大腸直腸癌的發生率及死亡率在台灣與已開發國家皆不斷逐年上升。縱使近年來癌症偵測有顯著的進步，但多數的癌症仍於晚期方被診斷出，同時治療的結果尚未臻滿意。癌症轉移乃因癌細胞擴散及遠端器官腫瘤生長，此乃導致癌症致死最主要的原因。因此，為了降低腫瘤復發及轉移所造成的癌症死亡，深入地研究及探討癌轉移機制實為刻不容緩之事。近年伴隨著轉譯醫學的蓬勃發展，癌症個人化醫療更備受重視。對於癌症分子標靶治療而言，發展新的癌症生物標記、標靶基因和治療藥物對病人亦是極為重要。然而，抗藥性的產生為目前癌症分子標靶治療所遇到的最大困境，尤其是肺癌。本實驗室之前的研究發現，不論在活體內或體外，中草藥薑黃的主要成分薑黃素(curcumin)對艾瑞莎(Iressa®, Gefitinib)具抗藥性的肺癌細胞株具有明顯的抑制生長能力並且會增強艾瑞莎對抗藥性細胞株的抑癌活性。本研究主要利用兩種不同觀點，分別從基因及藥物治療層面各別探討抑制兩種具代表性的癌症(肺癌及大腸直腸癌)腫瘤轉移之機制。首先，我們利用array CGH以及expression microarrays兩種不同實驗平台來分析兩種不同侵犯程度的肺癌細胞株，發現在染色體位置4p13的區域有一新穎且和腫瘤侵犯相關的基因，名為shisa3。我們發現在高度侵襲的肺癌細胞株中，shisa3基因的DNA拷貝數及mRNA和蛋白質的表現量皆非常低。本研究更指出此基因不但可以在活體外抑制肺腺癌細胞株的侵犯能力、移動能力以及生長能力，還可在活體內抑制腫瘤的生長及轉移。此外，shisa3基因會透過WNT/β-catenin傳導路徑來調控EMT現象，並從非小細胞肺癌的病人身上可發現當shisa3基因低度表現時與癌轉移有高度相關性，且存活率較差。再者，我們利用薑黃素來處理大腸直腸癌細胞株探討其影響癌轉移之機制。結果指出薑黃素不但在活體外可抑制大腸直腸癌細胞株的移動能力、侵犯能力以及生長能力，還可在活體內抑制腫瘤生長及肝轉移。總結以上，我們發現薑黃素會透過抑制Sp1, FAK, CD24以及促進E-cadherin的表現量，來抑制大腸直腸癌細胞株的癌轉移能力。

Cancer is a most important and popular issue of public health globally and which causes about 25% death in the United States. Lung cancer is the leading cause of cancer death in Taiwan and worldwide. The incidence and mortality of colorectal cancer (CRC) is increasing in Taiwan and many developed countries. Although the development of cancer detection is greatly progressed recently, the majority of cancers are diagnosed at late stages and the therapeutic outcome is still not satisfied. Metastasis causes the major death of all cancers due to dissemination and outgrowth of tumors at distant organs. To reduce cancer mortality caused by recurrence and metastasis the understanding of mechanisms involved in cancer progression in depth is urgently needed. Recent years, personalized medicine has become the most important issue globally which is due to the advanced development of translational medicine. Hence, how to identify potential genes as cancer biomarkers and druggable targets and to develop therapeutic drugs for molecular-targeted therapy are helpful to cancer patients. However, the challenge confronted by targeted cancer therapies is the development of drug resistance. Our previous report indicated that a component of Chinese herbal medicine, curcumin, could inhibit cell proliferation and improve the efficiency of gefitinib in the gefitinib-resistant lung cells in vitro and in vivo. Here, we investigate the underlying anti-metastasis mechanism with different views from genetic and pharmacotherapeutic aspects in two representative cancers, lung cancer and CRC. First, we identify a novel invasion-associated gene, shisa3, which is located on chromosome 4p13 by using array CGH (comparative genomic hybridization) and expression microarrays with two lung adenocarcinoma cell lines among varied invasive ability. The gene copy number, mRNA and protein expression of shisa3 is decreased in highly invasive cells significantly. Here, we report that shisa3 is a potential tumor suppressor, which inhibits the cell invasion, migration, proliferation and anchorage-independent growth of lung adenocarcinoma cells in vitro and it also inhibits metastasis and tumorigenesis in vivo. We not only explore that shisa3 may reverse the EMT through WNT/β-catenin signaling pathway but also find that low shisa3 expression are associated with lung metastasis and poor survival in non-small-cell lung cancer (NSCLC) patients. Moreover, we explore the underlying molecular mechanisms of curcumin on metastasis of CRC cells in vitro and in vivo. The results indicate that curcumin not only significantly inhibits cell migration, invasion and colony formation in vitro, but also reduces tumor growth and liver metastasis in vivo. Together all, we suggest that curcumin executes its anti-metastasis function through down-regulation of Sp1, FAK, CD24, and by promoting E-cadherin expression in CRC cells.