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 α3β1 and α6β1, 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.

中文翻译：

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层粘连蛋白521通过STAT3激活增强自我更新，并促进结直肠癌中的肿瘤进展。

基底膜蛋白的重塑有助于肿瘤发展到转移阶段。这些蛋白之一是层粘连蛋白521（LN521），可维持胚胎干细胞和诱导性多能干细胞的自我更新，但其在癌症中的假定作用却鲜有描述。在本研究中，我们发现LN521可以促进结直肠癌（CRC）细胞的自我更新和侵袭。siRNA介导的内源性层粘连蛋白α5的敲低，以及用抗整联蛋白α3β1和α6β1的中和抗体处理，能够逆转LN521对自我更新的作用。将CRC细胞暴露于LN521会增强STAT3磷酸化，与STAT3抑制剂那巴布沙星和Stattic一起孵育足以阻止LN521驱动的自我更新。在从CRC患者收集的7/10肝转移组织切片以及小鼠肝转移异种移植物中，在大多数情况下，在表达转移癌干细胞标志物（例如c-KIT和CD44v6）的区域中检测到层粘连蛋白α5的强健表达。最后，对多个CRC数据集的回顾性分析突出了大肠癌患者LN521 mRNA高表达与不良临床结局之间的显着关联。总的来说，我们的结果表明层粘连蛋白521的高表达是CRC转移扩散的常见特征，它促进细胞侵袭和自我更新，后者通过整合素同工型的激活和STAT3信号的激活而得以实现。在大多数情况下，在表达癌干细胞标记（例如c-KIT和CD44v6）的区域内。最后，对多个CRC数据集的回顾性分析突出了大肠癌患者LN521 mRNA高表达与不良临床结局之间的显着关联。总的来说，我们的结果表明层粘连蛋白521的高表达是CRC转移扩散的常见特征，它促进细胞侵袭和自我更新，后者通过整合素同工型的激活和STAT3信号的激活而得以实现。在大多数情况下，在表达癌干细胞标记（例如c-KIT和CD44v6）的区域内。最后，对多个CRC数据集的回顾性分析突出了大肠癌患者LN521 mRNA高表达与不良临床结局之间的显着关联。总的来说，我们的结果表明层粘连蛋白521的高表达是CRC转移扩散的常见特征，它促进细胞侵袭和自我更新，后者通过整合素同工型的激活和STAT3信号的激活而得以实现。