Background/Objectives: The membrane protein a disintegrin and metalloproteases (ADAMs) are highly expressed in various human carcinomas and play an important role in cancer characteristics. And among these, ADAM32 is highly expressed in hepatoblastoma (HBL) and plays an important role in oncogenic properties. However, the regulatory mechanism has not been determined. Recently, it has been reported that some ADAMs are regulated by HIF, which is an important transcription factor in response to hypoxia. Therefore, we decided to study the regulatory mechanisms ofADAM32under hypoxic conditions by using HBL, breast, and lung cancer cell lines.Methods/Results: When these cells were exposed to 1% O2(hypoxia), it was found that the levels ofADAM32increased at 48 h in HepG2, MCF7, and MDA-MB-231 but not in HUH-6 or lung cancer lines. However, the promoter activity of theADAM32gene in HepG2 remained unchanged under hypoxic conditions, suggesting that the level ofADAM32in HBL is regulated by factors other than the promoter activity. From the microarray data, we found that the level ofIGF2BP2, which is an m6A-related molecule, correlated with that ofADAM32, and these levels were decreased byHIF1Aknockdown. AndIGF2BP2knockdown decreased the expression of ADAM32 and attenuated the increased expression of ADAM32 under hypoxic conditions.Conclusions: This study demonstrated that the oncogenic geneADAM32is regulated by IGF2BP2 and that IGF2BP2 could be a molecular target for HBL anticancer therapy.
背景/目的：膜蛋白解整合素和金属蛋白酶（ADAMs）在多种人类癌症中高表达，并在癌症特性中发挥重要作用。其中，ADAM32在肝母细胞瘤（HBL）中高度表达，并在致癌特性中扮演关键角色。然而，其调控机制尚未明确。近期有报道指出，部分ADAMs受缺氧反应关键转录因子HIF的调控。因此，我们决定利用HBL、乳腺癌及肺癌细胞系，研究缺氧条件下ADAM32的调控机制。 方法/结果：当这些细胞暴露于1% O₂（缺氧）环境时，发现HepG2、MCF7和MDA-MB-231细胞中ADAM32水平在48小时后升高，而HUH-6及肺癌细胞系中未见此现象。然而，在缺氧条件下HepG2细胞中ADAM32基因的启动子活性保持不变，提示HBL中ADAM32水平受启动子活性以外的因素调控。通过微阵列数据分析，我们发现m6A相关分子IGF2BP2的水平与ADAM32水平呈正相关，且两者水平均因HIF1A敲低而降低。IGF2BP2敲低不仅降低了ADAM32的表达，还减弱了缺氧条件下ADAM32表达的上调。 结论：本研究证实致癌基因ADAM32受IGF2BP2调控，且IGF2BP2可能成为HBL抗癌治疗的分子靶点。
肿瘤(癌症)患者之家