ADAM32 Oncogene in Hepatoblastoma Is Regulated by IGF2BP2

TL;DR

This study shows that ADAM32, an oncogene in liver cancer, is regulated by IGF2BP2 under low-oxygen conditions, suggesting a new target for cancer therapy.

Contribution

The study identifies IGF2BP2 as a novel regulator of ADAM32 in hepatoblastoma under hypoxic conditions.

Findings

ADAM32 expression increases under hypoxic conditions in certain cancer cell lines.

IGF2BP2 regulates ADAM32 expression and its upregulation under hypoxia.

Knockdown of IGF2BP2 reduces ADAM32 levels and oncogenic activity in hepatoblastoma.

Abstract

Since hepatoblastoma (HBL) is a hepatic malignancy, part of which is still resistant to anticancer drug treatment, more effective therapy is desired to be developed. Our previous study showed that ADAM32 is highly expressed in HBL and plays an important role in the oncogenic property. However, the regulatory mechanisms were not determined. In this study, we focused on hypoxia, which is a characteristic of the cancer microenvironment. Then, we demonstrated that the expression levels of ADAM32 increased under hypoxic conditions, and these expressions are regulated by IGF2BP2. Thus, our study suggested that IGF2BP2 could be a molecular target for anticancer therapy of HBL.

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 of ADAM32 under 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 of ADAM32 increased at 48 h in HepG2, MCF7, and MDA-MB-231 but not in HUH-6 or lung cancer lines. However, the promoter activity of the ADAM32 gene in HepG2 remained unchanged under hypoxic conditions, suggesting that the level of ADAM32 in HBL is regulated by factors other than the promoter activity. From the microarray data, we found that the level of IGF2BP2, which is an m6A-related molecule, correlated with that of ADAM32, and these levels were decreased by HIF1A knockdown. And IGF2BP2 knockdown decreased the expression of ADAM32 and attenuated the increased expression of ADAM32 under hypoxic conditions. Conclusions: This study demonstrated that the oncogenic gene ADAM32 is regulated by IGF2BP2 and that IGF2BP2 could be a molecular target for HBL anticancer therapy.

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