- 學位論文
瘦體素對內分泌相關腫瘤細胞生長與凋亡之作用機轉
Mechanisms of Leptin Effects on Growth and Apoptosis of Endocrine-Related Cancer Cells
摘要
摘要 瘦體素為脂肪細胞主要分泌的內泌素之一，可能參與肥胖相關的癌生成與進展，也被視為許多類型癌細胞的生長因子，除了內分泌方式，也可能以旁分泌方式作用於標的組織。較少文獻探討瘦體素於乳癌、卵巢癌與肝癌細胞的作用，本研究乃針對此三類型的癌細胞，研究瘦體素的作用與其傳訊途徑與機制。在所有測試的三類型癌細胞，瘦體素都促進細胞的增生與抗凋亡作用。在促進細胞增生上，瘦體素普遍刺激cyclin D1的表現、進而加速細胞週期的運轉；而在兩種婦癌細胞，一種cyclin D1的轉錄因子c-Myc其表現也被瘦體素刺激。此外，在乳癌細胞中，抑癌因子p53與細胞素依賴性激酶抑制因子p21WAF/CIP1的表現則被瘦體素所減弱，顯示瘦體素也能藉由減弱p53與p21WAF/CIP1的表現以推促細胞週期的運轉。在兩種婦癌細胞細的抗凋亡上，瘦體素主要刺激抗凋亡因子Mcl-1的表現，而在肝癌細胞，則減少凋亡因子Bax的表現；顯然瘦體素抗凋亡的作用機制有細胞類型的差別。在所有測試的三類型癌細胞中，瘦體素的作用皆由JAK2所連接的訊息途徑所傳達，而在JAK2下游必有MEK1/2與ERK1/2（一般構成所謂MEK/ERK1/2的傳訊單位）的參與，形成JAK2-MEK/ERK1/2的傳訊路徑。在肝癌細胞，於JAK2-MEK/ERK1/2的傳訊路徑間另有PI3K與Akt（一般構成所謂PI3K/Akt的傳訊單位）的參與，形成JAK2-PI3K/Akt-MEK/ERK1/2的傳訊途徑；而在乳癌細胞，瘦體素作用的傳訊途徑則為JAK2-PI3K-EK/ERK1/2，瘦體素並不活化Akt。有趣的是，瘦體素分別活化卵巢癌細胞中JAK2-MEK/ERK1/2與PI3K/Akt兩條分明的路徑，雖然PI3K/Akt與JAK2-MEK/ERK1/2之間有訊息交接，彼此卻不為上下游的關係。本研究顯示活化cyclin D1以加速細胞週期運轉為瘦體素促進乳癌、卵巢癌與肝癌細胞增生作用的共同機制，而瘦體素抗凋亡的作用機制則因細胞類型略有不同。在乳癌、卵巢癌與肝癌細胞中，瘦體素作用的的傳訊途徑明顯呈現細胞類型的特異性。
並列摘要
Abstract Leptin, one of the major hormones synthesized by adipocytes, is involved in the development of obesity associated cancers. It plays as a paracrine/ autocrine regulator mediating growth of various types of cancer cells. Effects of leptin in breast, ovarian and liver cancer cells were less studied, therefore in the present study, we used the three cancer cells to investigate leptin effects and its signaling pathways and mechanisms. In all three examined cancer cells, we found leptin induced cell proliferation and anti-apoptosis. Leptin-stimulated cell proliferation was achieved by provoking expression of cyclin D1 that speeds up cell-cycle progression. In breast and ovarian cancer calls, the expression of c-Myc, one of the transcription factors of cyclin D1 promoter, was enhanced by leptin. In addition, we observed leptin also down-regulated tumor suppressor p53 and cyclin-depedent kinase (CDK) inhibitor p21WAF1/CIP1 to promote cell-cycle progression. In both gynaecological cancer cells, leptin attenuated cell apoptosis by up-regulating expression of antiapoptotic MCL-1. In hepatocellular carcinoma (HCC) cells, the anti-apoptotic effects of leptin were mediated by decreasing expression of proapoptotic Bax. The results indicated the mechanism of leptin-inhibited anti-apoptosis is cell type-specific. In all three cancer cells, the intracellular signals of leptin were transduced by a Janus kinase 2 (JAK2)-linked pathways and at the downstream of JAK2, MEK1/2 and ERK1/2 are involved in the signaling cascade. Besides of JAK2, MEK1/2 and ERK1/2, in HCC cells, PI3K and Akt were participated in the leptin activated signaling pathway. We define that the signaling cascade of leptin in HCC is a JAK2-PI3K/Akt-MEK/ERK1/2. In breast cancer cells, not like in HCC, leptin has no influence on phosphorylation of Akt and leptin-induced signaling pathway is JAK2-PI3K-MEK/ERK1/2. Interestingly, in ovarian cancer cells, crosstalk between two signaling pathways, JAK2-MEK/ERK1/2 and PI3K/Akt, were activated by leptin. Our study demonstrated that in the three examined cancer cells, leptin promotes cell proliferation is generally mediated by stimulating the expression of cyclin D1 to accelerate cell-cycle progression. However the mechanism of leptin on inhibiting apoptosis is cell-specific. The signaling pathways activated by leptin are cell type-dependent.