Connective Tissue Growth Factor as an Unfavorable Prognostic Marker Promotes the Proliferation, Migration, and Invasion of Gliomas
Glioma, the most common primary central nervous system tumor, presents significant clinical challenges due to its high heterogeneity and aggressive progression. Among gliomas, glioblastoma (GBM) represents the most malignant subtype, characterized by rapid proliferation, angiogenesis, and resistance to therapy. Despite advances in treatment modalities, the median survival for GBM remains dismal at approximately 14.6 months. This underscores the urgent need to identify novel prognostic markers and therapeutic targets. Connective tissue growth factor (CTGF/CCN2), a multifunctional signaling protein involved in tumorigenesis, has been implicated in various cancers. However, its role in glioma progression and prognosis remains incompletely understood. This study comprehensively investigates CTGF expression in glioma, its prognostic significance, and its functional contributions to tumor aggressiveness.
Expression of CTGF in Glioma
The study utilized data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) to analyze CTGF expression across 681 and 301 glioma patients, respectively. Compared to non-tumor brain tissues (n=207), CTGF mRNA levels were significantly elevated in both low-grade gliomas (LGG, n=518) and GBM (n=163) (LGG: t = 2.410, P < 0.05; GBM: t = 2.364, P < 0.05). Validation using clinical samples from Nanfang Hospital (29 gliomas, 11 non-tumor tissues) confirmed these findings. Reverse transcription-polymerase chain reaction (RT-PCR) revealed higher CTGF mRNA expression in 12 glioma tissues versus 10 non-tumor samples (t = 9.117, P < 0.0001). Western blotting of eight paired samples demonstrated elevated CTGF protein levels in gliomas. Immunohistochemistry further localized CTGF overexpression to glioma cells, with 86% (25/29) of tumor samples showing high expression compared to 18% (2/11) of non-tumor tissues (P < 0.001).
Prognostic Significance of CTGF
Survival analysis using TCGA and CGGA datasets revealed a strong correlation between high CTGF expression and poor clinical outcomes. In TCGA, patients with high CTGF expression had a median overall survival (OS) of 35.4 months versus 63.3 months in the low-expression group (χ² = 10.46, P = 0.0012). Similarly, CGGA data showed median OS durations of 27.0 months and 55.1 months for high- and low-expression cohorts, respectively (χ² = 7.596, P = 0.0059). These results position CTGF as an independent unfavorable prognostic marker for glioma patients.
Functional Role of CTGF in Glioma Pathogenesis
To elucidate CTGF’s biological contributions, in vitro experiments were conducted using U87MG and U251MG glioma cell lines. Small-interfering RNA (siRNA)-mediated CTGF knockdown significantly reduced proliferation, as measured by methylthiazoletetrazolium (MTT) assays. Transwell and Boyden assays demonstrated impaired migration and invasiveness in CTGF-silenced cells. For instance, siRNA-transfected U251 cells showed a 75% reduction in migration (P < 0.0001), while U87 cells exhibited an 87% decrease in invasion (P < 0.0001). Flow cytometry revealed cell cycle arrest at the G1 phase in CTGF-deficient cells (U251: 44.87% vs. 34.68% in controls; U87: 72.05% vs. 67.66%), suggesting CTGF promotes DNA synthesis and progression to the S phase.
CTGF in Glioblastoma: Insights from Gene Ontology Analysis
GBM exhibited the highest CTGF expression among gliomas (P < 0.0001). Gene ontology (GO) analysis of 637 CTGF-associated genes in TCGA-GBM data highlighted enrichment in metabolic and energy pathways. Biological processes linked to CTGF included protein metabolism (6.3% of genes) and translation (3.2%), while molecular functions involved catalytic activity (3.7%) and ribosome structure (1.6%). These findings suggest CTGF drives GBM malignancy by modulating cellular metabolism and energy utilization, potentially offering new therapeutic avenues.
Mechanistic Implications and Clinical Relevance
CTGF’s role in glioma aligns with its known functions in other cancers, including angiogenesis, extracellular matrix remodeling, and activation of pathways like Wnt and ERK. In glioma, CTGF likely facilitates tumor progression by enhancing proliferation, suppressing apoptosis, and promoting invasion through integrin-mediated signaling. The study’s demonstration of CTGF’s prognostic value and functional contributions underscores its potential as a therapeutic target. Inhibiting CTGF or its downstream effectors could disrupt critical pathways sustaining glioma growth and resistance.
Conclusion
This study establishes CTGF as a biomarker of poor prognosis in glioma, with elevated expression correlating with aggressive tumor behavior and shorter survival. Functional assays confirm CTGF’s role in driving proliferation, migration, and invasion, while GO analysis links its activity to metabolic reprogramming in GBM. These findings provide a foundation for future research into CTGF-targeted therapies, which may improve outcomes for glioma patients.
DOI: https://doi.org/10.1097/CM9.0000000000000683
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