CCN3/IMP3/HIF1α positive feedback loop enhances malignant progression of triple-negative breast cancer

Abstract

Cancer cells are often exposed to a hypoxic environment due to indiscriminate proliferation and incomplete vasculature formation. Hypoxia-inducible factor-1 (HIF-1), which is induced by a hypoxic environment, promotes tumor malignancy by regulating cancer cell metabolism, metastasis, angiogenesis, and cancer stem cell formation. Previous studies have demonstrated increased activation of HIF-1-induced signaling pathways in triple-negative breast cancer (TNBC). Therefore, a hypoxic environment or hypoxia-induced genes are considered as attractive therapeutic targets for TNBC. We have previously identified CCN3 as a novel player in the cancer progression of TNBC. In this study, using public databases and cell lines with altered CCN3 expression, we found that CCN3 expression and hypoxia gene expression signatures were positively correlated, and that HIF1 alpha and HIF1 alpha target gene expression were regulated by CCN3. Furthermore, the induction of HIF1 alpha by CCN3 was regulated at the post-transcriptional level, mainly by IMP3-mediated modulation of mRNA stability and translation of HIF1 alpha. Additionally, we found that HIF1 alpha directly regulates expression of CCN3 by binding to the promoter region of CCN3. This CCN3-HIF1 alpha positive feedback loop may play an important role in HIF1 alpha-induced tumorigenesis in TNBC and be involved in the metastasis of TNBC cells.