Fukazawa Takahiro, Tanimoto Keiji, Yamaoka Emi, Kojima Masato, Kanawa Masami, Hirohashi Nobuyuki, Hiyama Eiso
Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima 734-8553, Japan.
Department of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Cancers (Basel). 2022 Sep 28;14(19):4732. doi: 10.3390/cancers14194732.
Outcomes of pediatric hepatoblastoma (HBL) have improved, but refractory cases still occur. More effective and safer drugs are needed that are based on molecular mechanisms. A disintegrin and metalloproteases (ADAMs) are expressed with high frequency in various human carcinomas and play an important role in cancer progression. In this study, we analyzed expression of in HBL with a cDNA microarray dataset and found that the expression level of is particularly high. To investigate the role of ADAM32 in cancer, forced expression or knockdown experiments were conducted with HepG2 and HBL primary cells. Colony formation, cell migration and invasion, and cell viability were increased in HepG2 expressing ADAM32, whereas knockdown of ADAM32 induced a decrease in these cellular functions. Quantitative RT-PCR demonstrated an association between expression and the expression of genes related to cancer stem cells and epithelial-mesenchymal transition (EMT), suggesting a role of ADAM32 in cancer stemness and EMT. Furthermore, knockdown of ADAM32 increased cisplatin-induced apoptosis, and this effect was attenuated by a caspase-8 inhibitor, suggesting that ADAM32 plays a role in extrinsic apoptosis signaling. We conclude that ADAM32 plays a crucial role in progression of HBL, so it might be a promising molecular target in anticancer therapy.
小儿肝母细胞瘤（HBL）的治疗效果已有改善，但仍有难治性病例出现。需要基于分子机制研发更有效、更安全的药物。解整合素和金属蛋白酶（ADAMs）在多种人类癌症中高频率表达，在癌症进展中起重要作用。在本研究中，我们利用cDNA微阵列数据集分析了ADAM在HBL中的表达，发现ADAM32的表达水平特别高。为研究ADAM32在癌症中的作用，我们对HepG2细胞和HBL原代细胞进行了过表达或敲低实验。在过表达ADAM32的HepG2细胞中，集落形成、细胞迁移和侵袭以及细胞活力均增加，而敲低ADAM32则导致这些细胞功能下降。定量逆转录聚合酶链反应（qRT-PCR）表明，ADAM32表达与癌症干细胞及上皮-间质转化（EMT）相关基因的表达有关，提示ADAM32在癌症干性和EMT中发挥作用。此外，敲低ADAM32可增加顺铂诱导的细胞凋亡，且这种作用被半胱天冬酶-8抑制剂减弱，提示ADAM32在外源性凋亡信号传导中发挥作用。我们得出结论，ADAM32在HBL进展中起关键作用，因此它可能是抗癌治疗中有前景的分子靶点。
