||Effect and possible mechanism of fibroblast growth factor 9 on cell proliferation in mouse Leydig cell lines
||Institute of Cell Biology and Anatomy
Fibroblast growth factor 9 (FGF9)
cell cycle progression
纖維母細胞生長因子能夠與其接受器交互作用以調控大部分的生物功能:像是細胞增生、抗凋亡、細胞移行以及細胞分化。之前的研究顯示：纖維母細胞生長因子9在胚胎發育中扮演非常重要的角色但是其蛋白質表現在人體器官中非常低。纖維母細胞生長因子9亦被報導可參與性別決定。在本實驗室之前的研究已經證實纖維母細胞生長因子9能夠在小鼠萊氏細胞中透過MAPK、PI3K及PKA訊號傳遞路徑以刺激固醇類荷爾蒙的生成。另一方面，之前研究已經指出異常表現的纖維母細胞生長因子9能夠造成人類大腸癌、卵巢癌以及前列腺癌的發生。此外纖維母細胞生長因子9能夠增加卵巢癌的細胞增生速率和細胞移動能力。這些現象說明著過度表現纖維母細胞生長因子9能夠導致癌症的發生。在此，我們想要探討纖維母細胞生長因子9對於小鼠萊氏細胞與小鼠萊氏腫瘤細胞的效果。結果顯示纖維母細胞生長因子9能夠明顯的增加TM3細胞存活率以及在MA-10細胞中有增加的趨勢產生。細胞增生相關標準蛋白增殖细胞核抗原(PCNA and Ki67)經過纖維母細胞生長因子9處理後在TM3細胞中顯著增加，但在MA-10中卻沒有看到此現象。另外，我們發現纖維母細胞生長因子9能夠增加5-乙炔基-2'-脫氧尿苷(EdU)的表現在這兩株細胞中。在訊息傳遞的機制探討中，纖維母細胞生長因子9 在這兩株細胞中沒有活化AKT/mTOR 路徑。然而纖維母細胞生長因子9在TM3細胞中能夠活化磷酸化的JNK以及ERK1/2；在MA-10則是活化ERK1/2。甚至纖維母細胞生長因子9在TM3細胞中能夠活化PLCγ1的表現，但在MA-10中則是沒有活化。碘化丙啶(PI)染色研究更能偵測纖維母細胞生長因子9在細胞週期進展的效果。我們發現纖維母細胞生長因子9在TM3細胞中能夠促進細胞週期的進展，而在MA-10中則沒有看到此現象。另外，細胞週期的相關蛋白質週期蛋白依赖性激酶1、2、4 (CDK1、2、4)以及細胞週期調節蛋白A、B、D1(Cyclin A、B、D1)都在TM3中明顯的增加，而MA-10則沒有增加的現象。此外纖維母細胞生長因子9在TM3細胞中能夠抑制細胞週期抑制蛋白p27而在MA-10則沒有看到此現象。除此之外，藉由細胞刮傷試驗發現，纖維母細胞生長因子9在加入到TM3細胞後3、6、9小時以及加入MA-10細胞後的48小時能夠明顯促進細胞移動。另外，在轉移盤試驗中顯示，纖維母細胞生長因子9明顯促進這兩株細胞的細胞移動和細胞侵襲能力。總結來說，纖維母細胞生長因子9能夠促進細胞增生在TM3細胞透過活化訊息傳遞和加速細胞週期進展。然而，纖維母細胞生長因子9只能透過活化ERK1/2的表現來產生些許效果幫助MA-10細胞增生。除此之外，我們也證實纖維母細胞生長因子9能夠增強細胞移動和侵襲的能力在TM3和MA-10細胞中。
Fibroblast growth factors (FGFs) interacts with its receptor, fibroblast growth factor receptor (FGFR), to control a wide range of biological functions, such as cell proliferation, anti-apoptosis, migration and differentiation. Previous studies have shown that fibroblast growth factors 9 (FGF9) has an important role in embryo development, and FGF9 protein level is low and the expression of FGF9 is restricted in few adult organs. FGF9 is found to be involved in sex-determination. In our lab, we have demonstrated that FGF9 stimulated steroidogenesis in mouse Leydig cells through MAPK, PI3K and PKA signal transduction pathways. On the other hand, studies have reported that abnormal expression of FGF9 usually results in colon, ovarian and prostate cancers in human. Also, study indicated that FGF9 could increase proliferation rate and cell mobility in ovarian cancer. These phenomena illustrated that over-expression of FGF9 could contribute to the cancer occurrence. Here, we sought to investigate the roles of FGF9 on mouse Leydig normal and tumor cell line. The results showed that FGF9 could increase cell viability in TM3 with an increased trend in MA-10. The proliferation related marker proteins PCNA and Ki67 were significantly increased after FGF9 treatment in TM3 not in MA-10. However, we found that FGF9 could increase EDU positive cell in these cell lines. In mechanistic study, AKT/mTOR pathway was not activated upon FGF9 treatment in both of cell lines, whereas FGF9 could active phosphor-JNK and -ERK1/2 in TM3 and phosphor-ERK1/2 in MA-10. FGF9 could also activate the expression of PLCγ1 in TM3 cells, but not in MA-10 cells. PI staining study further detected the effect of FGF9 on cell cycle regulation. We found that FGF9 promoted cell cycle progression in TM3 but not in MA-10 cells. The cell cycle related proteins CDK1, CDK2, CDK4, cyclin A, cyclin B, cyclin D1 were increased in TM3 but not in MA-10. Besides, the cell cycle inhinitory proteins p27 was decreased in TM3 but not in MA-10. In addition, FGF9 significantly increased cell migration in TM3 after 3, 9 and 12 hr and MA-10 after 48 hr treatments, respectively, in wound-healing assay. Also, the transwell assay showed that both migration and invasion were increased in both TM3 and MA-10 cell lines. In conclusion, FGF9 induces cell proliferation on TM3 cells through the activation of signal transduction and speed up cell cycle progression, whereas, FGF9 only activates ERK to have a minor effect on cell proliferation in MA-10 cells. Besides, FGF9 could enhance on cell migration and invasion in TM3 and MA-10 cells.
TABLE OF CONTENTS
TABLE OF CONTENTS........VI
LIST OF FIGURES........VIII
MATERIALS AND METHODS
Cell Cycle Analysis.........8
Protein Collection and Western Blotting ………......8
EdU Cell Incorporation assay……………………………….…………………………..10
Effects of FGF9 on cell proliferation in mouse Leydig cell lines…………..11
Effects of FGF9 on cell proliferation with EdU incorporation assay in mouse Leydig cell line…..………………………………………………….....11
Effects of FGF9 on the protein levels of cell proliferation-related proteins, proliferating cell nuclear antigen (PCNA) and Ki67, in mouse Leydig cell lines….………………………………………………………………………….……...11
Effects of FGF9 on the distribution of cell cycle in mouse Leydig cell lines…….12
Effects of FGF9 on the protein levels of cell cycle-related proteins in mouse Leydig cell lines……………………………………………………………………………..…..13
Effects of FGF9 on the p53 pathway in mouse Leydig cell lines...14
Effects of FGF9 on cell mobility in mouse Leydig cell lines...15
Effects of FGF9 on the protein levels of AKT/mTOR pathway in mouse Leydig cell lines..........16
Effects of FGF9 on the protein levels of MAPK pathway in mouse Leydig cell lines..........17
Effects of FGF9 on the protein levels of PLC pathway in mouse Leydig cell lines..........17
Effects of FGF9 on the protein levels of FGFRs in mouse Leydig cell lines..........18
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