Laminin 521 enhances self-renewal via STAT3 activation and promotes tumor progression in colorectal cancer
Laminin 521 enhances self-renewal via STAT3 activation and promotes tumor progression in colorectal cancer
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DOI：
10.1016/j.canlet.2020.02.026
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发表时间：
2020-04-28
期刊：
影响因子：
9.7
通讯作者：
Hollande, Frederic
中科院分区：
文献类型：
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作者：
Qin, Yan;Shembrey, Carolyn;Hollande, Frederic
基底膜蛋白的重构有助于肿瘤向转移阶段的进展。这些蛋白质之一，层粘连蛋白521（LN 521），维持胚胎和诱导多能干细胞自我更新，但其在癌症中的假定作用描述甚少。在本研究中，我们发现LN 521促进结直肠癌（CRC）细胞的自我更新和侵袭。siRNA介导的内源性层粘连蛋白α 5的敲除，以及用针对整合素α 3 β 1和α 6 β 1的中和抗体治疗，能够逆转LN 521对自我更新的作用。将CRC细胞暴露于LN 521增强了STAT 3磷酸化，并且与STAT 3抑制剂Napabucasin和Stattic孵育足以阻断LN 521驱动的自我更新增加。在从CRC患者收集的7/10个肝转移组织切片中以及在小鼠肝转移异种移植物中检测到层粘连蛋白α 5的稳健表达，在大多数情况下在表达转移癌干细胞标志物如c-KIT和CD 44 v6的区域内。最后，对多个CRC数据集的回顾性分析强调了LN 521 mRNA高表达与结直肠癌患者临床预后不良之间的显著相关性。总的来说，我们的结果表明，高层粘连蛋白521表达是CRC转移性播散的常见特征，并且它促进细胞侵袭和自我更新，后者通过整合素同种型的参与和STAT 3信号传导的激活。
Remodeling of basement membrane proteins contributes to tumor progression towards the metastatic stage. One of these proteins, laminin 521 (LN521), sustains embryonic and induced pluripotent stem cell self-renewal, but its putative role in cancer is poorly described. In the present study we found that LN521 promotes colorectal cancer (CRC) cell self-renewal and invasion. siRNA-mediated knockdown of endogenously-produced laminin alpha 5, as well as treatment with neutralizing antibodies against integrin alpha 3 beta 1 and alpha 6 beta 1, were able to reverse the effect of LN521 on self-renewal. Exposure of CRC cells to LN521 enhanced STAT3 phosphorylation, and incubation with STAT3 inhibitors Napabucasin and Stattic was sufficient to block the LN521-driven self-renewal increase. Robust expression of laminin alpha 5 was detected in 7/10 liver metastases tissue sections collected from CRC patients as well as in mouse liver metastasis xenografts, in most cases within areas expressing metastasis cancer stem cell markers such as c-KIT and CD44v6. Finally, retrospective analysis of multiple CRC datasets highlighted the significant association between high LN521 mRNA expression and poor clinical outcome in colorectal cancer patients. Collectively our results indicate that high Laminin 521 expression is a frequent feature of metastatic dissemination in CRC and that it promotes cell invasion and self-renewal, the latter through engagement of integrin isoforms and activation of STAT3 signaling.