Analysis of oncogene GLI1 protein expression levels between differing grades of astrocytoma

Abstract

Aberrant expression of oncogene GLI1 has been linked to malignancies in many types of tissues including brain, pancreas, skin and breast. It has been found that GLI1 expression is important for tumor progression and has been linked to tumor grade. In this study, GLI1 expression has been analyzed in different malignancy grade astrocytomas.GLI1 protein expression has been evaluated in 87 clinical tumor samples by using Western blot analysis. Associations between GLI1 expression and tumor grade were analyzed by applying Mann-Whitney or Kruskal-Wallis tests. KaplanMeier survival analysis was performed to evaluate the prognosis of patients.Western blot analysis did not show statistically significant correlation between GLI1 protein expression and astrocytoma tumor grade (P = 0.294). Kaplan-Meier survival also did not show correlation between survival rates and GLI1 expression (P = 0.081). Our results show that GLI1 protein expression levels in astrocytomas have higher variability than previously shown.Our results indicate that GLI1 protein expression is not an absolute requirement for the process of gliomagenesis. Yet, a relatively high (52%) occurrence of GLI1 expression in astrocytomas suggests the need for further analysis on the involvement of GLI1-mediated Hedgehog signaling pathway in glioma tumorogenesis.

Truncated Glioma-Associated Oncogene Homolog 1 (tGLI1) Mediates Mesenchymal Glioblastoma via Transcriptional Activation of CD44

“…The tumor-specific expression pattern of tGLI1 in invasive breast cancer was reported in our previous study (19). Other groups have confirmed our findings that tGLI1 is detectable in triple-negative breast cancer (20) and malignant gliomas (21). Metastatic hepatoma cells also express tGLI1 (22).…”

“…Our present and previous studies uncovered that tGLI1 is expressed in a tumor-specific fashion in GBM and breast cancer (13,15–17,19). Expression of tGLI1 in malignant gliomas (21) and breast cancer (20) has been confirmed by other groups. Interestingly, a recent study detected tGLI1 in metastatic hepatoma cells (22).…”

Hedgehog Signaling and Truncated GLI1 in Cancer

“…The mechanism behind tGLI1′s more potent induction of GLI1 target genes and ability to transcriptionally activate novel target genes remains unclear, but is the subject of active study. tGLI1 expression is tumor-specific: tGLI1 is frequently expressed in cancerous tissues including those of glioblastoma, breast cancer, and hepatocellular carcinoma, but not in normal adult tissues or cell lines [ 24 , 25 , 26 , 27 ]. tGLI1 expression distinctly differs from GLI1 and GLI1ΔN because both of these isoforms are expressed in both normal and cancer cells [ 23 , 24 , 139 ].…”

“…However, the difficulty in separating the two proteins could mean that functions previously ascribed to GLI1 are actually due to tGLI1-specific activity [ 25 , 33 ]. Our laboratory, and others, have shown the tGLI1 variant to be expressed in most GBM specimens and patient-derived xenografts, but undetectable in normal brain cells or tissues [ 24 , 26 , 27 , 29 ]. Interestingly, studies by Stecca et al (2009) did not observe tGLI1 in GBM cell lines and patient-derived neurospheres despite using two antibodies that recognize regions conserved after alternative splicing [ 138 ].…”

“…GLIΔN appears to function similarly to the wild-type GLI1, albeit with weaker gene activation, and is expressed at equal or lower levels in cancers compared to normal tissues [ 23 ]. In stark contrast, the tGLI1 variant has been shown to be frequently expressed in several cancers including glioblastoma, breast, and liver cancer, but not in normal tissues or cells [ 24 , 25 , 26 , 27 ]. Furthermore, tGLI1 is a gain-of-function transcription factor that, in addition to regulating known GLI1 target genes, is able to modulate expression of genes not regulated by GLI1 to induce several oncogenic phenotypes in breast cancer and glioblastoma such as tumor growth, migration and invasion, angiogenesis, maintenance of the cancer stem cell (CSC) population, metastasis, and astrocyte activation [ 24 , 25 , 28 , 29 , 30 , 31 , 32 , 33 ].…”