Transient gene silencing of galectin-3 suppresses pancreatic cancer cell migration and invasion through degradation of β-catenin.
Transient gene silencing of galectin-3 suppresses pancreatic cancer cell migration and invasion through degradation of β-catenin.
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DOI：
10.1002/ijc.25946
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发表时间：
2011-12-15
影响因子：
6.4
通讯作者：
Raz, Avraham
中科院分区：
文献类型：
--
作者：
Kobayashi, Tsutomu;Shimura, Tatsuo;Yajima, Toshiki;Kubo, Norio;Araki, Kenichiro;Tsutsumi, Soichi;Suzuki, Hideki;Kuwano, Hiroyuki;Raz, Avraham
胰腺癌是癌症相关死亡的主要原因，由于其诊断晚、局部侵袭性强、转移早、化疗反应差，预后往往较差。化疗药物吉西他滨治疗晚期胰腺癌有效，但其疗效仍不令人满意。我们希望进一步研究胰腺癌细胞的侵袭并开发阻断这一过程的策略，以改善疾病的预后。在这项研究中，我们验证了我们的假设，即半乳糖凝集素-3 (gal-3)， β-半乳糖苷结合蛋白家族的多功能成员，可能调节胰腺癌细胞的运动，而沉默它会抑制细胞的运动。先前的研究表明，该蛋白与肿瘤细胞的粘附、增殖、分化、血管生成、凋亡和转移有关。在此，我们利用gal-3小干扰RNA （siRNA）沉默其在各种胰腺癌细胞系中的表达，以确定gal-3是否在体外调节细胞增殖、迁移和侵袭。我们发现沉默gal-3可以减少细胞迁移和侵袭，但不能影响细胞增殖。在转染gal-3 sirna的细胞中，我们检测到癌细胞侵袭的重要信号β-catenin的表达减少，这是由于磷酸化Akt和GSK-3β的下调引起的。我们还发现，基质金属蛋白酶(MMP)-2的表达因gal-3沉默而降低。这些结果表明，在胰腺癌细胞中，β-catenin降解调控的MMP-2介导的gal-3侵袭是由Akt磷酸化引发的。我们的研究结果表明，gal-3可能是胰腺癌的一个新的治疗靶点。
Pancreatic cancer is a leading cause of cancer-related mortality and often has a poor prognosis because of its late diagnosis, aggressive local invasion, early metastasis, and poor response to chemotherapy. The chemotherapeutic agent gemcitabine is effective for treating advanced pancreatic cancer, but its efficacy remains less than satisfactory. It is expected that further investigation of pancreatic cancer cell invasion and development of strategies to block this process should improve the disease prognosis. In this study, we tested our hypothesis that galectin-3 (gal-3), a multifunctional member of the β-galactoside-binding protein family, may regulate pancreatic cancer cell motility, and silencing of it inhibit cell motility. Previous studies demonstrated that this protein is associated with tumor cell adhesion, proliferation, differentiation, angiogenesis, apoptosis, and metastasis. Here, we used gal-3 small interfering RNA (siRNA) to silence its expression in various pancreatic cancer cell lines to determine whether gal-3 regulates cell proliferation, migration and invasion in vitro. We found that silencing gal-3 reduced cellular migration and invasion, but failed to affect proliferation. In gal-3 siRNA-transfected cells, we detected a decrease in β-catenin expression, an important signal for cancer cell invasion, which was caused by down-regulation of phosphorylated Akt and GSK-3β. We also found that matrix metalloproteinase (MMP)-2 expression was reduced by gal-3 silencing. These results indicate that gal-3-mediated invasion via MMP-2 regulated by β-catenin degradation is initiated by Akt phosphorylation in pancreatic cancer cells. Our results suggest that gal-3 can be a novel therapeutic target in pancreatic cancer.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
DOI：
10.1016/j.bbrc.2008.12.153
发表时间：
2009-02-06
影响因子：
3.1
作者：
Lin, Chi-Iou;Whang, Edward E.;Ruan, Daniel T.
通讯作者：
Ruan, Daniel T.
DOI：
10.1083/jcb.200709019
发表时间：
2008-03-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goetz JG;Joshi B;Lajoie P;Strugnell SS;Scudamore T;Kojic LD;Nabi IR
通讯作者：
Nabi IR
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
3.3
作者：
Fukushi, J;Makagiansar, IT;Stallcup, WB
通讯作者：
Stallcup, WB