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ANP32A is a member of the acidic nuclear phosphoprotein 32 (ANP32) family. The biological role of the ANP32 family is extensive, including hormone receptor interactions, enzyme inhibition, cell adhesion, cell transport, gene expression regulation, and apoptotic signaling pathways.
Figure 1. Mammalian ANP32 proteins function in cell-death pathways. (Reilly, et al. 2014)
ANP32A protein is spherical, its amino terminus (N) is rich in leucine repeat domains (LRRs), and LRR is a short-ordered residue of 20-29 in length, arranged in tandem in cytoplasmic, membrane and extracellular proteins. Its presence determines the stable structural and biochemical properties of ANP32A and can mediate interactions between proteins. The carboxy terminus of ANP32A is rich in aspartic acid and threonine, accounting for about 70%, and is strongly acidic. These characteristics allow the ANP32A protein to participate in a variety of biological processes in the cytoplasm and nucleus.
ANP32A is an important component of the acetyltransferase inhibitor complex and is involved in the regulation of chromatin remodeling and transcription. In type I interferon-dependent transcriptional activities, ANP32A is involved in the formation of transcriptional complexes of IFN-activated genes (ISGs), thereby promoting the antiviral activity of cells. ANP32A can also form a multi-subunit complex with HuR protein, regulate the nuclear shuttle of HuR, and ensure the stability and transport process of mRNA. In addition, Sánchez found that a decrease in the expression level of ANP32A can affect the PP2A pathway and play a role in type I spinal cerebellar ataxia.
Negative Regulation of Tumors by ANP32A
Some scholars have performed immunohistochemical staining on ANP32A expression analysis in five pancreatic cancer cell lines and ANP32A in 35 pancreatic cancer tissues. ANP32A was specifically expressed in pancreatic tissue and correlated with the degree of differentiation of pancreatic cancer tissues. This experiment also showed that ANP32A is expressed in the nucleus of pancreatic acinar and ductal. By comparing the expression of ANP32A in five pancreatic cancer cell lines, it was found that ANP32A protein expression was highest in well-differentiated pancreatic cancer HPAC cells. Overexpression of ANP32A in the MaiPaCa2 cell line caused G1 arrest and inhibited cell growth.
In one study, ANP32A was involved in the chromatin remodeling process by immunoblot analysis and genetic assay, confirming that it is a direct target of miR-21. Cell viability was enhanced by knocking out ANP32A in prostate cancer LNCaP cells, whereas overexpression of ANP32A abolished miR-21 mediated effects in the presence of high miR-21 levels. In A172 glioblastoma cells, overexpression of ANP32A compensated for the effects of anti-miR-21 treatment on cell viability and apoptosis. Down-regulation of ANP32A increases the invasiveness of LNCaP cells. These results indicate that down-regulation of ANP32A contributes to the carcinogenic function of miR-21. Conversely, overexpression of ANP32A inhibits the pro-cancer effect of miR-21.
Positive Regulation of ANP32A on Tumor
The researchers used a combination of isotope labeling and two-dimensional liquid chromatography-tandem mass spectrometry to investigate the abnormal protein expression associated with hepatocellular carcinoma in clinical tissues. This method produced a depth-quantitative proteome of 1 360 proteins, of which 267 proteins changed at least 1.5-fold. Proteins that are up-regulated in HCC tissues are involved in regulatory processes such as the granzyme-mediated apoptotic pathway (GzmA pathway). The central component of the GzmA pathway is significantly up-regulated in the SET complex in HCC tissues. Elevated expression of all SET complex components was verified by Western blot. Among them, ANP32A was further studied by immunohistochemical staining using tissue microarrays, which was confirmed to be overexpressed in hepatocellular carcinoma.
ANP32A Promotes Tumor Development through EMT
The progression of most malignancies is accompanied by a loss of epithelial differentiation and a transition to a mesenchymal phenotype. This transformation process is called epithelial-mesenchymal transition (EMT), which exacerbates the viability and invasiveness of many cells and is often considered a prerequisite for tumor invasion and metastasis. During EMT transformation, epithelial markers are reduced and mesenchymal markers are increased. Velmurugan et al. knocked out the expression of endogenous ANP32A in oral squamous cell carcinoma cells and found that the expression levels of Snail, Vimentin, Claudin-1 and other proteins were decreased, while the expression level of E-cadherin protein was increased. The experiment also demonstrated a very significant association between ANP32A and Claudin-1 expression. These results support the notion that ANP32A increases cancer cell invasiveness through the EMT pathway.
ANP32A and Tumor Prognosis
Velmurugan et al. analyzed tissue samples from 259 patients with oral squamous cell carcinoma (OSCC) by tissue microarray and found that ANP32A expression is associated with lymph node metastasis and tumor differentiation. The experiment also showed that the Kaplan-Meier mortality composite curve associated with lymph node staging and ANP32A expression was significantly heterogeneous (P < 0.001 and 0.002, respectively).Similar results were found in the joint mortality curve associated with tumor differentiation and ANP32A expression. Studies to date have shown that overexpression of ANP32A regulates the elevation of COX-2 affecting the prognosis of many tumors, such as pancreatic cancer, oral squamous cell carcinoma. Therefore, indirect suggestion that ANP32A may be an important indicator of poor tumor prognosis, can further track the role of ANP32A in tumor prognosis by in vivo or in vitro experiments.