Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signaling.
Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signaling.
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胰腺癌中过表达的乳肠蛋白3通过结合Ras并激活RAS信号传导诱导细胞增殖和侵袭。
DOI：
10.1371/journal.pone.0042699
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bresalier RS
中科院分区：
文献类型：
--
作者：
Song S;Ji B;Ramachandran V;Wang H;Hafley M;Logsdon C;Bresalier RS
胰腺癌（PDAC）是一种致命的疾病，5年生存率为3-5%。K-Ras突变几乎在所有病例中都有发现，但K-Ras突变本身并不足以导致PDAC的发展。其他因素有助于Ras信号的激活并导致肿瘤的形成。半乳糖凝集素-3 （Gal-3）是一种多功能β-半乳糖苷结合蛋白，在PDAC中高表达。因此，我们研究了Gal-3在胰腺癌进展中的功能作用及其与Ras信号的关系。采用免疫组织化学、Q-PCR和免疫印迹法检测Gal-3的表达。功能研究使用基因工程胰腺细胞系表达高或低水平的Gal-3。采用Raf下拉法检测Ras活性。免疫共沉淀法和免疫荧光法用于评估蛋白相互作用。在这项研究中，我们证明了Gal-3在人类肿瘤和突变的K-Ras小鼠PDAC模型中被高度上调。慢病毒shRNA下调Gal-3可降低PDAC细胞的体外增殖和侵袭，减少原位小鼠模型中肿瘤的体积和大小。Gal-3结合Ras并维持Ras活性；Gal-3的下调降低了Ras活性以及Ras下游信号传导，包括ERK和AKT的磷酸化以及Ral A活性。转染Gal-3 cDNA到低水平Gal-3增强Ras活性及其下游信号传导的PDAC细胞。这些结果表明，在一定程度上，Gal-3通过结合Ras和激活Ras信号通路促进了胰腺癌的进展。因此，Gal-3可能是这种致命疾病的潜在新靶点。
Pancreatic cancer (PDAC) is a lethal disease with a five-year survival of 3–5%. Mutations in K-Ras are found in nearly all cases, but K-Ras mutations alone are not sufficient for the development of PDAC. Additional factors contribute to activation of Ras signaling and lead to tumor formation. Galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in PDAC. We therefore investigated the functional role of Gal-3 in pancreatic cancer progression and its relationship to Ras signaling. Expression of Gal-3 was determined by immunohistochemistry, Q-PCR and immunoblot. Functional studies were performed using pancreatic cell lines genetically engineered to express high or low levels of Gal-3. Ras activity was examined by Raf pull-down assays. Co-immunoprecipitation and immunofluorescence were used to assess protein-protein interactions. In this study, we demonstrate that Gal-3 was highly up-regulated in human tumors and in a mutant K-Ras mouse model of PDAC. Down-regulation of Gal-3 by lentivirus shRNA decreased PDAC cell proliferation and invasion in vitro and reduced tumor volume and size in an orthotopic mouse model. Gal-3 bound Ras and maintained Ras activity; down-regulation of Gal-3 decreased Ras activity as well as Ras down-stream signaling including phosphorylation of ERK and AKT and Ral A activity. Transfection of Gal-3 cDNA into PDAC cells with low-level Gal-3 augmented Ras activity and its down-stream signaling. These results suggest that Gal-3 contributes to pancreatic cancer progression, in part, by binding Ras and activating Ras signaling. Gal-3 may therefore be a potential novel target for this deadly disease.
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影响因子：
7.5
作者：
Khayyata, S;Basturk, O;Adsay, NV
通讯作者：
Adsay, NV
影响因子：
11.2
作者：
Shalom-Feuerstein, R;Cooks, T;Kloog, Y
通讯作者：
Kloog, Y
影响因子：
2.9
作者：
Takaori, K;Hruban, RH;Tanigawa, N
通讯作者：
Tanigawa, N
影响因子：
4.8
作者：
Elad-Sfadia, G;Haklai, R;Kloog, Y
通讯作者：
Kloog, Y
前梯度2在胰腺癌的发展过程中表达和分泌，并促进癌细胞的存活。
影响因子：
11.2
作者：
Ramachandran V;Arumugam T;Wang H;Logsdon CD
通讯作者：
Logsdon CD