Ген PDRG1 активирует онкогенный путь Wnt/β-катенин и ухудшает прогноз при гепатоцеллюлярной карциноме

Hepatocellular carcinoma (HCC) stands as one of the most prevalent and lethal malignancies worldwide, ranking as the third leading cause of cancer-related mortality globally. Despite significant advances in diagnostic techniques and therapeutic modalities, the prognosis for HCC patients remains dismal, particularly for those diagnosed at advanced stages. A considerable proportion of patients present with advanced disease at initial diagnosis due to the lack of prominent clinical symptoms in early-stage HCC, and the propensity for early metastasis and rapid recurrence further contributes to poor outcomes. The pathogenesis of HCC is complex and multifactorial, involving interactions between genetic susceptibility, environmental factors such as chronic viral hepatitis, alcohol consumption, non-alcoholic fatty liver disease, and exposure to aflatoxin. While significant progress has been made in understanding molecular mechanisms, the precise pathogenesis remains incompletely elucidated, and effective therapeutic targets for advanced disease remain limited. Elucidating molecular mechanisms driving HCC pathogenesis and identifying novel therapeutic targets are therefore of paramount importance. P53 and DNA damage-regulated gene 1 (PDRG1), located on chromosome 20q13.12, encodes a small protein of 133 amino acids. PDRG1 was first identified in 2003, with expression regulated by ultraviolet radiation and the tumor suppressor p53, suggesting a role in the cellular DNA damage response. Subsequent research has implicated PDRG1 in various cellular physiological processes including cell proliferation, growth, apoptosis, cell cycle regulation, and DNA damage repair. In recent years, accumulating evidence has revealed that PDRG1 expression is significantly elevated in multiple tumor types including colorectal cancer, ovarian cancer, lung cancer, gastric cancer, breast cancer, and uterine cancer. Consequently, PDRG1 has been proposed as a novel tumor biomarker with potential diagnostic and prognostic value. Mechanistically, PDRG1 has been shown to participate in malignant progression of colorectal cancer by modulating the p21-mediated signaling pathway, and PDRG1 silencing suppresses growth and metastasis of gastric cancer cells via activation of the ATM/p53 pathway. Additionally, PDRG1 silencing inhibits the Wnt signaling pathway in esophageal cancer cells, suggesting a potential link. However, the expression profile of PDRG1 in HCC and its precise mechanistic role remain incompletely understood. The Wnt/β-catenin pathway is a highly conserved developmental signaling pathway regulating diverse biological processes including cell proliferation, apoptosis, migration, invasion, stem cell maintenance, and tissue homeostasis. In the absence of Wnt ligand activation, β-catenin is bound by a destruction complex comprising Axin, APC, and GSK-3β, which phosphorylate β-catenin and target it for ubiquitin-mediated proteasomal degradation. Upon Wnt pathway activation, the destruction complex is inhibited, allowing non-phosphorylated β-catenin to accumulate and translocate to the nucleus, where it associates with TCF/LEF transcription factors to initiate transcription of target genes such as c-Myc and cyclin D1. Aberrant Wnt/β-catenin signaling is prevalent in numerous malignancies including HCC, where mutations in CTNNB1 and AXIN1 occur in approximately 20-40% of cases. Despite the well-established role of Wnt/β-catenin signaling in HCC, upstream regulators modulating this pathway remain incompletely characterized. In this study, the researchers systematically investigated the expression, functional role, and regulatory mechanism of PDRG1 in HCC. They demonstrated that PDRG1 expression is significantly upregulated in HCC tissues at both mRNA and protein levels. Clinicopathological correlation analysis revealed that high PDRG1 expression is significantly associated with advanced tumor stage, higher histological grade, microvascular invasion, and poor overall and disease-free survival, establishing PDRG1 as an independent prognostic factor. Functional studies using gain-of-function and loss-of-function approaches demonstrated that PDRG1 knockdown significantly suppresses HCC cell proliferation, colony formation, migration, and invasion in vitro, and inhibits tumor growth and lung metastasis in xenograft mouse models in vivo. Conversely, PDRG1 overexpression promotes HCC cell proliferation, migration, and invasion, confirming the oncogenic role of PDRG1 in HCC. Mechanistic investigations revealed that PDRG1 activates Wnt/β-catenin signaling, as evidenced by increased levels of total and nuclear β-catenin, elevated expression of downstream target genes including c-Myc and cyclin D1, and increased phosphorylation of GSK-3β at Ser9. Importantly, the Wnt pathway inhibitor XAV939 effectively reversed the oncogenic effects of PDRG1 overexpression, confirming that PDRG1's pro-tumor activity is functionally dependent on Wnt/β-catenin signaling. Further investigation into upstream regulation led to the identification of Specificity Protein 1 (SP1) as a direct transcriptional activator of PDRG1. SP1 is a ubiquitous transcription factor that binds to GC-rich promoter elements and regulates expression of numerous genes involved in cell proliferation, differentiation, apoptosis, and angiogenesis. SP1 is frequently overexpressed and activated in various human cancers including HCC. Using bioinformatic analysis, the researchers identified multiple putative SP1 binding sites within the PDRG1 promoter region.