Loss of Inhibitor of Growth (ING‐4) is Implicated in the Pathogenesis and Progression of Human Astrocytomas

Abstract

Inhibitor of growth 4 (ING-4) is a tumor suppressor gene that interacts with nuclear factor-kappaB (NF-kappaB) and represses its transcriptional activity. Several lines of evidence suggest that the tumor suppressor gene ING-4, the transcription factor NF-kappaB and its target genes matrix metalloproteases MMP-2, MMP-9 and urokinase plasminogen activator (u-PA) are critically involved in tumor invasion. The aim of the present study was to investigate immunohistochemically the expression pattern of ING-4, NF-kappaB and the NF-kappaB downstream targets MMP-2, MMP-9 and u-PA in human astrocytomas from 101 patients. We found that ING-4 expression was significantly decreased in astrocytomas, and ING-4 loss was associated with tumor grade progression. Expression of p65, a NF-kappaB subunit, was significantly higher in grade IV than in grade III and grade I/II tumors, and a statistical significant negative correlation between expression of ING-4 and expression of nuclear p65 was noticed. MMP-9, MMP-2 and u-PA were overexpressed in human astrocytomas. Of note, astrocytomas of advanced histologic grades (grade III, IV) displayed significantly higher expression levels of these proteins compared to tumors of lower grades (grade I, II). Collectively, our data suggest an essential role for ING-4 in human astrocytoma development and progression possibly through regulation of the NF-kappaB-dependent expression of genes involved in tumor invasion.

Reduced expression and prognostic implication of inhibitor of growth 4 in human osteosarcoma

“…To the best of our knowledge, no study has investigated the level of expression of ING4 in human osteosarcoma tissue as compared with normal bone tissue, or the prognostic value of ING4 expression in patients diagnosed with osteosarcoma. Similar to the results of previous studies regarding other malignant tumors (11,18,20,(28)(29)(30)(31), the results of the present study demonstrated that the osteosarcoma tissues had significantly decreased expression of ING4 when compared with the normal bone tissues (P<0.001). The majority of the osteosarcoma specimens had a score of (-) or (+), whilst no normal bone specimens had a score of (-) or (+).…”

“…Previous studies have demonstrated that ING4 expression is suppressed or reduced in a number of malignancies, and the degree of expression is associated with the tumor grade (11,18,20,(28)(29)(30)(31). To the best of our knowledge, no study has investigated the level of expression of ING4 in human osteosarcoma tissue as compared with normal bone tissue, or the prognostic value of ING4 expression in patients diagnosed with osteosarcoma.…”

“…ING4 expression is decreased in a number of tumor tissues and the degree of low expression corresponds with tumor grade (11,18,20,(28)(29)(30)(31). Allelic loss and mutation of ING4 have also been observed in various cancer cell lines (26,32,33), thus suggesting that ING4 is a promising tumor suppressor.…”

“…Instead, it was noted that the degree of reduction in ING4 expression correlated with the progression from low to high grades of osteosarcoma, according to the Enneking classification system for malignant bone tumors (P=0.002). ING4, a novel tumor suppressor of the ING family, has potential tumor-suppressing effects that are exerted through various signaling pathways, including tumorigenesis, cell cycle regulation, angiogenesis, cell apoptosis, DNA repair, migration and transcriptional regulation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(37)(38)(39)(40)(41)(42)(43). These functions of ING4, which acts as an oncogene suppressor in numerous tumor types, have been identified repeatedly in vitro and in vivo (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(37)(38)…”

“…The inhibition of NF-κB negatively regulates various target genes, including matrix metalloproteinase (MMP)-2, MMP-9, interleukin (IL)-6, IL-8, cyclooxygenase-2 and colony stimulating factor-3. The downregulation of these cytokines inhibits angiogenesis and tumor cell growth (11)(12)(13)(14)(15). In RKO colorectal cancer cells, ING4 expression was able to decrease the cell population in the S-phase of the cell cycle in a p53-dependent manner, as well as upregulate p21 expression (16).…”