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ASPHAspartyl/Asparaginyl beta-hydroxylase (ASPH, AAH) is a highly conserved deoxygenase that is present in cells during mammalian embryonic development. Human Aspartyl/Asparaginyl β-hydroxylase (HAAH) is a highly conserved deoxygenase that plays an important role in cell growth, differentiation, migration, adhesion, and movement. Studies have shown that the overexpression of ASPH is closely related to tumorigenesis, proliferation, invasion and metastasis, and it may be an important factor and molecular marker for regulating tumor cell growth in vivo.
ASPH Distribution and Expression Regulation
ASPH is relatively low or absent in most normal tissues and highly expressed in placental trophoblast cells and adrenal cells. And ASPH is overexpressed in liver cancer, intrahepatic cholangiocarcinoma, lung cancer, colorectal cancer, pancreatic cancer, breast cancer and neuroblastoma tissues. HUI YANG et al. confirmed that ASPH is highly expressed in breast cancer MCF-7, liver cancer SMMC-7721, cervical cancer HeLa and ovarian cancer SKOV, but it is lower expressed in renal adenocarcinoma ACHN, bladder cancer BIU-87 and laryngeal cancer Hep-2. No expression was observed in the normal mouse embryonic osteoblast cell line MC3T3.
In addition, overexpressed ASPH can be released from tumor cells and present in the soluble or free form in human serum and body fluids. Insulin or IGF-1 signaling regulates ASPH mRNA expression via Erk protein kinase and PI3 kinase-Akt protein. Overexpression of the ASPH protein inhibits the activity of glycogen synthase kinase-3 (GSK-3), whereas its mRNA does not. Due to the lack of ASPH, the loss of aspartic acid and the asparagine hydroxylated EGF domain protein may affect proteins involved in the pathogenesis of lens ectopic disease. These studies indicate that ASPH is associated with eye diseases.
ASPH and Hepatocellular Carcinoma
Iwagami et al. identified shRNA-mediated knockout and CRISPR/CaS9-mediated ASPH gene knockdown as well as enzymatic inhibition of ASPH-directed human liver cancer cells undergoing cellular senescence. Inhibition of ASPH activity is mediated by GSK3β phosphorylation. In addition, ASPH binds to GSK3β to inhibit its phosphorylation (inactivation), thereby blocking signal transduction of its upstream kinase. The results suggest that ASPH is a potential therapeutic target. The second-generation β-hydroxylase inhibitor is an effective anti-tumor drug that prevents the growth and development of HCC in the liver by inducing cell senescence.
Figure. 1 Hypothesis of how ASPH may mediate senescence of HCC cells. (Iwagami, et al. 2015)
Tomimaru et al. demonstrated that ASPH protein induces antigen-specific CD4+ T cell and CD8+ CTL activation, and ASPH-derived HLA class I and class II restriction peptides can activate CD4+ T cells and CD8+CTLs from Hepatocellular carcinoma (HCC) patients. This study provides a theoretical basis for preventive development (prevention or reduction of micrometastasis after surgical removal of HCC) or peptide-based methods.
The Role of ASPH in Tumor Cell Invasion and Metastasis
The malignant phenotype produced by ASPH overexpression is characterized by promoting cell movement and invasion. Hee-Jung Yoo established four human cholangiocarcinomas (CC) cell lines, including the typical sarcomatoid phenotype SCK, poorly differentiated JCK1, moderately differentiated Cho-CK, and highly differentiated Choi-CK. Furthermore, 260 genes that were significantly overexpressed and 247 genes that were underexpressed were determined in a comparison of expression patterns between SCK sarcoma cells and highly differentiated Choi-CK cells. Four overexpressed genes, including ASPH, were verified by Northern blot and immunohistochemistry.
Kui Wang's research indicates that the expression of ASPH is increased in liver cancer compared with adjacent tissues, which is related to the poor differentiation of liver cancer cells, so ASPH expression is an independent factor affecting recurrence. High expression of ASPH also predicts intrahepatic metastasis, while detection of lower levels of protein is associated with more differentiated tumor phenotypes. Wands et al found that high expression of ASPH in liver cancer significantly increased the invasion of HepG2 and Huh-7 cells. The degree of overexpression exhibited by ASPH correlates with tumor size, invasive growth pattern, histological grade, vascular invasion, and poor survival. ASPH overexpression can promote the malignant transformation of biliary epithelial cells, promote cell movement, and contribute to the invasive growth of cholangiocarcinoma cells. Sturla et al. showed that ASPH has a high expression level in glioblastoma hypoxia and low expression in hypoxic regions. The inhibition of ASPH expression can significantly reduce tumor cell viability and directional motor ability.
ASPH Mediates Anti-tumor Immune Response
The ASPH gene is overexpressed in HCC tumors and its protein is translocated from the endoplasmic reticulum to the plasma membrane. It is an accessible extracellular environment that acts as a tumor-associated antigen (TAA), producing anti-tumor immune responses using ASPH-loaded DCs. A similar anti-tumor response was obtained using the mouse SP2-0 myeloma cell line expressing ASPH as a target cell.
Studies have found that ASPH stimulation can lead to significant growth of antigen-specific CD4+ T cells. Using spleen cells of mice immunized with ASPH-DC, re-stimulation by ASPH protein showed higher levels of IFNc secretion and increased granzyme Bhi CD8+ cells. And in surgically resected liver cancer, ASPH-DC immunotherapy may delay its recurrence. The study also confirmed that the cytotoxicity of ASPH-loaded DC immunization in vitro can counter cholangiocarcinoma cells and significantly inhibit intrahepatic tumor growth and metastasis.