Ying Xu, Jing Li, Ma Shijie, Li Qianjun, Luo Xiaoling, Pan Zhenguo, Feng Yanling, Feng Pan
Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300 People's Republic of China.
Department of Hepatology, Huai'an Fourth People's Hospital, No.128, Yan an East Road, Qing pu District, Huai'an, Jiangsu 223300 People's Republic of China.
Cancer Cell Int. 2015 Jul 5;15:70. doi: 10.1186/s12935-015-0216-y. eCollection 2015.
Glycogen synthase kinase-3β (GSK3β) expression and activity are upregulated in pancreatic cancer tissues. In our previous study, we found that stromal cell-derived factor-1/ chemokine receptor C-X-C motif chemokine receptor 4 (SDF-1α/CXCR4) upregulated matrix metalloproteinase 2 (MMP-2) and promoted invasion in PANC1 and SW-1990 pancreatic cancer cells by activating p38 mitogen-activated protein kinase (p38 MAPK). Additionally, inhibition of GSK3β reduced MMP-2 secretion.
To investigate the molecular mechanism of GSK3β in pancreatic cancer tissues, we created stable PANC1 cells up-regulation of GSK3β by transfecting GSK3β overexpression plasmid, and down-regulation of GSK3β using two different types of RNA interference.
Western blotting showed that overexpression of GSK3β up-regulated CXCR4 and MMP-2 expression; suppression of GSK3β down-regulated CXCR4 and MMP-2 protein expression. Up-regulation of MMP2 induced by overexpression of GSK3β was blocked by inhibition of CXCR4. Overexpression of GSK3β promoted PANC1 cell invasion, and down-regulation of GSK3β suppressed PANC1 cell invasion in the transwell invasion assays. However, inhibition of CXCR4 using shRNA attenuated the ability of GSK3β to promote PANC1 cell invasion.
This study demonstrated that GSK3β promotes PANC1 cell invasion via the CXCR4/MMP-2 pathway.
糖原合酶激酶-3β（GSK3β）的表达和活性在胰腺癌组织中上调。在我们之前的研究中，我们发现基质细胞衍生因子-1/趋化因子C-X-C基序趋化因子受体4（SDF-1α/CXCR4）通过激活p38丝裂原活化蛋白激酶（p38 MAPK）上调基质金属蛋白酶2（MMP-2）并促进PANC1和SW-1990胰腺癌细胞的侵袭。此外，抑制GSK3β可减少MMP-2的分泌。
为了研究GSK3β在胰腺癌组织中的分子机制，我们通过转染GSK3β过表达质粒建立了稳定上调GSK3β的PANC1细胞，并使用两种不同类型的RNA干扰下调GSK3β。
蛋白质印迹显示，GSK3β的过表达上调了CXCR4和MMP-2的表达；抑制GSK3β可下调CXCR4和MMP-2蛋白的表达。GSK3β过表达诱导的MMP2上调被CXCR4抑制所阻断。在Transwell侵袭实验中，GSK3β的过表达促进了PANC1细胞的侵袭，而GSK3β的下调则抑制了PANC1细胞的侵袭。然而，使用短发夹RNA抑制CXCR4减弱了GSK3β促进PANC1细胞侵袭的能力。
本研究表明，GSK3β通过CXCR4/MMP-2途径促进PANC1细胞侵袭。
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