Identification of tyrosine-phosphorylated proteins associated with metastasis and functional analysis of FER in human hepatocellular carcinoma cells.
Identification of tyrosine-phosphorylated proteins associated with metastasis and functional analysis of FER in human hepatocellular carcinoma cells.
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人肝癌细胞转移相关酪氨酸磷酸化蛋白的鉴定及 FER 功能分析
DOI：
10.1186/1471-2407-9-366
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发表时间：
2009-10-16
期刊：
影响因子：
3.8
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Li H;Ren Z;Kang X;Zhang L;Li X;Wang Y;Xue T;Shen Y;Liu Y
酪氨酸磷酸化蛋白的异常活性通常与肝细胞癌的转移有关。由这些蛋白质驱动的细胞信号事件与改变癌细胞行为的许多过程有关。探索这些蛋白在肝细胞癌转移中的活性和信号通路可能有助于寻找新的肝细胞癌靶向治疗候选分子。本研究以非转移性肝癌细胞系Hep3B和高转移性肝癌细胞系MHCC97H为研究对象，采用基于LC-MS/MS的磷酸化蛋白质组学技术，通过蛋白质-蛋白质相互作用和功能聚类分析，确定与肝癌转移密切相关的蛋白质活性和信号转导途径。在这两个细胞系中，在没有任何刺激的情况下，总共鉴定出247个含有281个pTyr位点的磷酸酪氨酸(PTyr)蛋白。其中近30%与肝癌或肝癌有关的报道以前从未报道过。生物过程聚类分析表明，参与细胞运动、迁移、蛋白自磷酸化、细胞间通讯和抗凋亡功能的pTyr蛋白在转移过程中过表达。路径聚类分析表明，参与EGFR信号转导、细胞因子和趋化因子介导的信号转导以及PI3K和JAK-STAT等信号通路在肝细胞癌转移过程中显著激活。此外，JNK级联的非规范调控也可能为肝细胞癌转移提供新的靶点。在比较了在肝癌细胞转移过程中差异表达的pTyr蛋白后，我们选择了非受体酪氨酸激酶FER，并验证了它在表达和功能方面的作用。结果证实FER在肝细胞癌的侵袭和转移过程中可能起重要作用。PTyr蛋白和与肝癌转移相关的信号通路的发现为选择新的分子干预靶点提供了有用的信息。此外，FER可能成为未来肝癌治疗的一个新的药物靶点。
Aberrant activity of tyrosine-phosphorylated proteins is commonly associated with HCC metastasis. Cell signaling events driven by these proteins are implicated in numerous processes that alter cancer cell behavior. Exploring the activities and signaling pathways of these proteins in HCC metastasis may help in identifying new candidate molecules for HCC-targeted therapy. Hep3B (a nonmetastatic HCC cell line) and MHCC97H (a highly metastatic HCC cell line) were used in this study, and the tyrosine-phosphorylated proteins expressed in these cell lines were profiled by a phosphoproteomics technique based on LC-MS/MS. Protein-protein interaction and functional clustering analyses were performed to determine the activities of the identified proteins and the signaling pathways closely related to HCC metastasis. In both cell lines, a total of 247 phosphotyrosine (pTyr) proteins containing 281 pTyr sites were identified without any stimulation. The involvement of almost 30% of these in liver or liver cancer has not been reported previously. Biological process clustering analysis indicated that pTyr proteins involved in cell motility, migration, protein autophosphorylation, cell-cell communication, and antiapoptosis functions were overexpressed during metastasis. Pathway clustering analysis revealed that signaling pathways such as those involved in EGFR signaling, cytokine- and chemokine-mediated signal transduction, and the PI3K and JAK-STAT cascades were significantly activated during HCC metastasis. Moreover, noncanonical regulation of the JNK cascade might also provide new targets for HCC metastasis. After comparing the pTyr proteins that were differentially expressed during HCC cell metastasis, we selected FER, a nonreceptor tyrosine kinase, and validated its role in terms of both expression and function. The data confirmed that FER might play a critical role in the invasion and metastasis of HCC. The identification of pTyr proteins and signaling pathways associated with HCC metastasis could provide useful information for selecting new molecular intervention targets. Moreover, FER might serve as a novel drug target in future HCC therapy.
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影响因子：
3
作者：
Berger SI;Posner JM;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
5.3
作者：
Grandal MV;Madshus IH
通讯作者：
Madshus IH
SILAC对不同转移潜能HCC细胞系的定量蛋白质组分析
影响因子：
3.4
作者：
Chen, Ning;Sun, Wei;He, Fuchu
通讯作者：
He, Fuchu
影响因子：
5.8
作者：
Birzele, Fabian;Gewehr, Jan E.;Zimmer, Ralf
通讯作者：
Zimmer, Ralf
影响因子：
3.4
作者：
Hatakeyama, Hiromitsu;Kondo, Tadashi;Hirohashi, Setsuo
通讯作者：
Hirohashi, Setsuo