結締組織生長因子經由ERK1/2途徑促進Bcl-xl/cIAP1表現的機轉及其臨床應用

乳癌對於全世界是主要的健康威脅，它不論是在已開發或是開發中國家都是婦女癌症的第一位，佔全部婦女癌症的百分之十六。乳癌手術後接受適當的全身性治療，如輔助性化學治療，在降低乳癌死亡率具有非常重要的地位。然而仍有一部份的病人在接受化學治療後，產生轉移性的病灶，只對於傳統化學治療產生暫時性的反應，最終造成死亡。所以了解產生抗藥性的機轉，終將幫助我們治療這些病患並增進其預後。結締組織生長因子(CTGF)在晚期的乳癌有較高的表現，也會促進乳癌細胞的轉移。在本研究我們探討CTGF是否會影響乳癌細胞對於化學治療的敏感度。在接受術前化學治療的乳癌病人中，我們使用免疫組織化學染色，發現在高表現的病人族群中，化學治療的反應較差。在細胞實驗中，我們使用CTGF plasmid將其過度表現於MCF7細胞株 (MCF7/CTGF)，及使用antisense CTGF抑制MDA231細胞株之CTGF表現。MCF7/CTGF接受化學藥物doxorubicin及paclitaxel後，癌細胞之形成聚落(clonogenic)及存活能力都上升；CTGF表現受到阻斷時(MDA231/AS)則導致相反之結果。在MCF7/CTGF中，我們發現Bcl-xL和cIAP1的表現增加，相對的MDA231/AS則是下降。在MCF7/CTGF中使用siRNA抑制Bcl-xL或cIAP1會阻斷CTGF表現所產生的抗藥性，而使用plasmid轉殖使MDA231/AS中Bcl-xL或cIAP1恢復表現，可使因CTGF表現下降而喪失的抗藥性恢復。在CTGF四個區域(domain)中，我們發現CT domain和CTGF對於活化ERK1/2，增加Bcl-xl和cIAP1的表現及增加MCF7抗藥性的能力，具有相似的生物性質。在臨床標本中，我們可以發現Bcl-xL表現和CTGF的表現有正相關。本研究證明CTGF對於乳癌細胞之抗藥性之重要性，也找出其中調控Bcl-xL/cIAP1之機制。同時也指出CT domain可能是CTGF產生抗藥性的主要功能部分。藉此研究我們發現了一個可以影響乳癌細胞對於藥物敏感性的因子，對於乳癌治療找到ㄧ個可能的標的，作為將來增進乳癌治療成效的研究方向。

關鍵字

結締組織生長因子；乳癌； ERK1/2 ； Integrin ；抗藥性； Bcl-xL ； cIAP1

並列摘要

Breast cancer is a major health threat world wide. It is the top cancer in women both in the developed and the developing world, comprising 16% of all female cancers. Optimal systemic treatment (adjuvant therapy) after breast cancer surgery is a crucial factor in reducing mortality in women with breast cancer, however a significant number of them still develop metastatic diseases and respond only transiently to conventional treatments leading to eventual mortality. So understanding the mechanism of drug resistance would help us to manage these patients and improved their prognosis. Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes breast cancer metastasis. In the present study, we examined whether CTGF expression could confer drug resistance in human breast cancer. In breast cancer patients who received neoadjuvant chemotherapy, CTGF expression inversely correlated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability and resistance to apoptosis upon exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) decreased these effects. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cIAP1. Furthermore, CTGF overexpression resulted in activation of the ERK1/2 pathway. Inhibition of ERK1/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAP1 in MCF7/CTGF cells. We also found that a C-terminal domain peptide from CTGF could exert similar activities to full-length CTGF in activation of ERK1/2, up-regulation of Bcl-xL/cIAP1 and resistance to apoptosis. We conclude that CTGF expression could confer resistance to chemotherapeutic agents through ERK1/2-mediated Bcl-xL/cIAP1 up-regulation of a survival pathway.

並列關鍵字

Connective tissue growth factor ； Breast cancer ； ERK1/2 ； Integrin ； drug resistance ； Bcl-xL ； cIAP1

參考文獻

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結締組織生長因子經由ERK1/2途徑促進Bcl-xl/cIAP1表現的機轉及其臨床應用

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