Phosphorylation of galectin-3 contributes to malignant transformation of human epithelial cells via modulation of unique sets of genes
Phosphorylation of galectin-3 contributes to malignant transformation of human epithelial cells via modulation of unique sets of genes
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DOI：
10.1158/0008-5472.can-04-3333
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Bresalier, RS
中科院分区：
文献类型：
--
作者：
Mazurek, N;Sun, YJ;Bresalier, RS
半乳糖凝集素-3是一种多功能β -半乳糖苷结合蛋白，与细胞凋亡、恶性转化和肿瘤进展有关。半乳糖凝集素-3促进恶性进展的机制尚不完全清楚。在这项研究中，我们发现将野生型半乳糖凝集素-3引入到非致瘤性的、半乳糖凝集素-3缺失的BT549人乳腺上皮细胞中，在裸鼠中具有致瘤性和转移潜力，并且该细胞表达的半乳糖凝集素-3被磷酸化。相比之下，表达不能磷酸化（Ser(6)-> Glu Ser6 -> Ala）的半乳糖凝集素-3的BT549细胞是非致瘤性的。通过对1万个人类基因进行微阵列分析，比较了表达野生型和表达半乳糖凝集素-3的BT549转染物，鉴定出188个差异表达基因（>2.5倍）。受野生型磷酸化而非磷酸化半乳糖凝集素-3影响的基因包括那些参与氧化应激、一种新的非半胱天冬酶溶酶体凋亡途径、细胞周期调节、转录激活、细胞骨架重塑、细胞粘附和肿瘤侵袭的基因。通过实时逆转录- pcr （RT-PCR）和Western blot分析验证微阵列数据的可靠性，并通过实时RT-PCR筛选一组匹配的乳腺肿瘤对来评估临床相关性。乳腺癌中被预测与转化BT549细胞中磷酸化半乳糖凝集素-3相关的差异调节基因包括c型凝集素2、胰岛素样生长因子结合蛋白5、组织蛋白酶L2和细胞周期蛋白D1。这些数据显示了半乳糖凝集素-3的功能多样性，并表明该蛋白的磷酸化是调节（直接或间接）在恶性转化中起作用的独特基因组所必需的。[癌症杂志2005；65(23):10767-75]。
Galectin-3 is a multifunctional beta-galactoside-binding protein implicated in apoptosis, malignant transformation, and tumor progression. The mechanisms by which galectin-3 contributes to malignant progression are not fully understood. In this study, we found that the introduction of wild-type galectin-3 into nontumorigenic, galectin-3-null BT549 human breast epithelial cells conferred tumorigenicity and metastatic potential in nude mice, and that galectin-3 expressed by the cells was phosphorylated. In contrast, BT549 cells expressing galectin-3 incapable of being phosphorylated (Ser(6)-> Glu Ser6 -> Ala) were nontumorigenic. A microarray analysis of 10,000 human genes, comparing BT549 transfectants expressing wild-type and those expressing phosphomutant galectin-3, identified 188 genes that were differentially expressed (>2.5fold). Genes affected by introduction of wild-type phosphorylated but not phosphomutant galectin-3 included those involved in oxidative stress, a novel noncaspase lysosomal apoptotic pathway, cell cycle regulation, transcriptional activation, cytoskeleton remodeling, cell adhesion, and tumor invasion. The reliability of the microarray data was validated by real-time reverse transcription-PCR (RT-PCR) and by Western blot analysis, and clinical relevance was evaluated by real-time RT-PCR screening of a panel of matched pairs of breast tumors. Differentially regulated genes in breast cancers that are also predicted to be associated with phospho-galectin-3 in transformed BT549 cells include C-type lectin 2, insulin-like growth factor-binding protein 5, cathepsins L2, and cyclin D1. These data show the functional diversity of galectin-3 and suggest that phosphorylation of the protein is necessary for regulation (directly or indirectly) of unique sets of genes that play a role in malignant transformation. (Cancer Res 2005; 65(23): 10767-75).