Chen Luo, Chiang Yiu Chun, Chan Lai Sheung, Chau Wai Yin, Lung Maria Li, Kahn Michael, Lo Kwok Wai, Mak Nai Ki, Lung Hong Lok
Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR, China.
Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR, China.
Cancers (Basel). 2022 Jun 25;14(13):3125. doi: 10.3390/cancers14133125.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy ranking as the 23rd most common cancer globally, while its incidence rate ranked the 9th in southeast Asia. Tumor metastasis is the dominant cause for treatment failure in NPC and metastatic NPC is yet incurable. The Wnt/β-catenin signaling pathway plays an important role in many processes such as cell proliferation, differentiation, epithelial-mesenchymal transition (EMT), and self-renewal of stem cells and cancer stem cells (CSCs). Both the EMT process and CSCs are believed to play a critical role in cancer metastasis. We here investigated whether the specific CBP/β-catenin Wnt antagonist, IGC-001, affects the metastasis of NPC cells. We found that ICG-001 treatment could reduce the adhesion capability of NPC cells to extracellular matrix and to capillary endothelial cells and reduce the tumor cell migration and invasion, events which are closely associated with distant metastasis. Through a screening of EMT and CSC-related microRNAs, it was found that miR-134 was consistently upregulated by ICG-001 treatment in NPC cells. Very few reports have mentioned the functional role of miR-134 in NPC, except that the expression was found to be downregulated in NPC. Transient transfection of miR-134 into NPC cells reduced their cell adhesion, migration, and invasion capability, but did not affect the growth of CSC-enriched tumor spheres. Subsequently, we found that the ICG-001-induced miR-134 expression resulting in downregulation of integrin β1 (). Such downregulation reduced cell adhesion and migration capability, as demonstrated by siRNA-mediated knockdown of . Direct targeting of by miR-134 was confirmed by the 3'-UTR luciferase assay. Lastly, using an in vivo lung metastasis assay, we showed that ICG-001 transient overexpression of miR-134 or stable overexpression of miR-134 could significantly reduce the lung metastasis of NPC cells. Taken together, we present here evidence that modulation of Wnt/β-catenin signaling pathway could inhibit the metastasis of NPC through the miR-134/ axis.
鼻咽癌（NPC）是一种与爱泼斯坦-巴尔病毒（EBV）相关的恶性肿瘤，在全球最常见的癌症中排名第23位，而其发病率在东南亚排名第9位。肿瘤转移是鼻咽癌治疗失败的主要原因，转移性鼻咽癌仍无法治愈。Wnt/β-连环蛋白信号通路在细胞增殖、分化、上皮-间质转化（EMT）以及干细胞和癌症干细胞（CSC）的自我更新等许多过程中发挥重要作用。EMT过程和CSC都被认为在癌症转移中起关键作用。我们在此研究了特异性CBP/β-连环蛋白Wnt拮抗剂IGC-001是否影响鼻咽癌细胞的转移。我们发现IGC-001处理可降低鼻咽癌细胞与细胞外基质和毛细血管内皮细胞的黏附能力，并减少肿瘤细胞的迁移和侵袭，这些事件与远处转移密切相关。通过对EMT和CSC相关微小RNA的筛选，发现miR-134在IGC-001处理的鼻咽癌细胞中持续上调。除了在鼻咽癌中发现其表达下调外，很少有报道提及miR-134在鼻咽癌中的功能作用。将miR-134瞬时转染到鼻咽癌细胞中可降低其细胞黏附、迁移和侵袭能力，但不影响富含CSC的肿瘤球的生长。随后，我们发现IGC-001诱导的miR-134表达导致整合素β1（）下调。这种下调降低了细胞黏附和迁移能力，siRNA介导的敲低证明了这一点。通过3'-UTR荧光素酶测定证实了miR-134对的直接靶向作用。最后，使用体内肺转移试验，我们表明IGC-001瞬时过表达miR-134或稳定过表达miR-134可显著降低鼻咽癌细胞的肺转移。综上所述，我们在此提供证据表明，调节Wnt/β-连环蛋白信号通路可通过miR-134/轴抑制鼻咽癌的转移。
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