- 學位論文
第一型類胰島素生長因子接受器以及胰島素接受器受質-1、2在肺癌細胞中的表現及功能
Differential Expression and function of the IGF-1 receptor, IRS-1 and IRS-2 in Lung Cancer Cell Lines
摘要
肺癌是全世界因癌症死亡最主要的原因，而其高死亡率的主因是由於肺癌轉移率及抗藥性極高所致。IGF-I是一個多功能的生長因子具有促進生長、抗細胞凋亡的作用。當IGF-I結合到IGF-IR，即造成IGF-IR的酪胺酸磷酸化，活化的接受器會吸引IRS及Shc並使其磷酸化。IRS蛋白包含許多酪胺酸殘基，可做為許多訊息分子的結合位，包含PI3K、Grb2、SHP-2以及Nck。適當的IGF-I訊號傳遞調控正常的生理功能，如胎兒發展、組織生長、代謝；然而IGF-I訊號失調時被描述和許多癌症相關，其中包括肺癌。因此我們想去探究IGF-I訊號傳遞在許多肺癌行為中所扮演的角色，我們使用肺腺癌細胞株CL1-0及其高侵入性亞株CL1-5。我們的結果顯示，CL1-0表現較高量的IGF-IR及IRS-2而CL1-5則表現較高量的IRS-1。在IGF-I刺激下，誘發CL1-0 中IGF-IR及IRS-2的酪胺酸磷酸化，CL1-5中IRS-1的酪胺酸磷酸化。由此可知，酪胺酸磷酸化程度之差異主要是因為這些分子的表現量不同所造成。我們想更進一步去探討在CL1-0及 CL1-5中IGF-IR、IRS-1 及IRS-2不同表現量對生長、抗藥性、失巢凋亡敏感性的影響。結果顯示，降低CL1-0細胞株IGF-IR表現量可降低細胞生長，但出乎我們預期卻是降低對doxorubicin的敏感性，對失巢凋亡的抗性則是沒有明顯的影響。降低CL1-5細胞株IRS-1表現量可降低細胞生長，同時降低對抗doxorubicin及破壞細胞黏附所誘發細胞凋亡的能力。降低CL1-0細胞株IRS-2表現量對生長、抗藥性、失巢凋亡敏感性的影響甚微。
並列摘要
Lung cancer is the leading cause of cancer death worldwide. The high mortality of lung cancer is due to metastasis and resistance to chemotherapy. Insulin-like growth factor (IGF-I) is a pleiotropic growth factor with potent mitogenic and anti-apoptotic functions. It initiates cascades of signaling by inducing tyrosine phosphorylation of the IGF-I receptor (IGF-IR). The active receptor then recruits and phosphorylates the IRS and Shc. IRS protein contains multiple tyrosine residues, which serves as docking sites for various signaling molecules including phosphatidylinositol 3-kinase (PI3K), Grb2, SHP-2 and Nck. Proper IGF-I signaling is involved in the normal control of fetal development, tissue growth, and metabolism; however, deregulation of IGF signaling has been described in several cancer types, including lung cancer. To investigate the role of IGF-I signaling in several behavior of lung tumor, the lung adenocarcinoma cell line CL1-0 and its highly invasive subline CL1-5 are used. Our results show that CL1-0 expresses higher levels of IGF-IR and IRS-2, whereas CL1-5 exhibits greater expression of IRS-1. In response to IGF-I stimulation, tyrosine phosphorylation of IGF-IR and IRS-2 is mainly restricted to CL1-0, but phosphorylation of IRS-1 is more pronounced in CL1-5. The extents of tyrosine phosphorylation of these signaling molecules coincide with their expression levels. We then examine whether differential expression of IGF-IR, IRS-1 and IRS-2 in CL1-0 and CL1-5 affects their capacity in proliferation, drug resistance and anoikis resistance. Out results show that knocking down IGF-IR expression in CL1-0 results in a decrease in cell growth, unexpectedly, a decrease in the sensitivity to doxorubicin. There is no obvious effect on 4 anoikis resistance in these cells. Lowering IRS-1 expression in CL1-5 inhibits cell growth and jeopardizes their ability to resist doxorubicin- and detachment-induced apoptosis. Knocking down IRS-2 levels in CL1-0 exerts negligible changes in cell growth, drug resistance and anoikis resistance.
參考文獻
延伸閱讀
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