MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4

Abstract

MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. It is significantly elevated in the majority of human tumors and functionally linked to cellular proliferation, survival and migration. In this study, we used two experimental-based strategies to search for novel miR-21 targets. On the one hand, we performed a proteomic approach using two-dimensional differential gel electrophoresis (2D-DIGE) to identify proteins suppressed upon enhanced miR-21 expression in LNCaP human prostate carcinoma cells. The tumor suppressor acidic nuclear phosphoprotein 32 family, member A (ANP32A) (alias pp32 or LANP) emerged as the most strongly downregulated protein. On the other hand, we applied a mathematical approach to select correlated gene sets that are negatively correlated with primary-miR-21 (pri-miR-21) expression in published transcriptome data from 114 B-cell lymphoma cases. Among these candidates, we found tumor suppressor SMARCA4 (alias BRG1) together with the already validated miR-21 target, PDCD4. ANP32A and SMARCA4, which are both involved in chromatin remodeling processes, were confirmed as direct miR-21 targets by immunoblot analysis and reporter gene assays. Furthermore, knock down of ANP32A mimicked the effect of enforced miR-21 expression by enhancing LNCaP cell viability, whereas overexpression of ANP32A in the presence of high miR-21 levels abrogated the miR-21-mediated effect. In A172 glioblastoma cells, enhanced ANP32A expression compensated for the effects of anti-miR-21 treatment on cell viability and apoptosis. In addition, miR-21 expression clearly increased the invasiveness of LNCaP cells, an effect also seen in part upon downregulation of ANP32A. In conclusion, these results suggest that downregulation of ANP32A contributes to the oncogenic function of miR-21.

Serum miR-21 Expression in Human Esophageal Squamous Cell Carcinomas

“…Conversely, miR-21 overexpression resulted in increased tumor cell proliferation, migration and invasion in hepatocellular carcinoma. These indicate that miR-21 acts as key oncomiR by favouring neoplastic transformation on multiple levels and the network of miR-21-induced gene expression changes needs to be explored (Schramedei et al, 2011).…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…Mir-21 and miR-31 have been identified as TGF-β-dependent positive regulators of tumor cells migration and invasion that act through suppression of T-cell lymphoma invasion and metastasisinducing protein, a guanidine exchange factor of the Rac GTPase [133]. High levels of miR-21 have been found in many cancers, including lung cancer, and its target network includes tumor suppressive components of the p53, TGF-β and mitochondrial apoptosis pathways, as well as several tumor suppressors themselves [134].…”

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

“…In lymphoma cells, ectopic expression of miR-155 is associated with downregulation of IGJ, FAS, SMAD3/5, and BACH1, as well as HLA genes. 45 IGJ, FAS, and genes involved in BMP/SMAD pathways (such as SMAD1, BMP3, and BMP7), as well as SMARCA4 (miR-21 target gene 50 ), were upregulated in MYC-R + GCB-DLBCL (Tables 3 and 5). miR-155 target gene BCL2 showed increased Bcl-2 protein expression in ABC-DLBCL (Figure 3c).…”