ZCCHC4 驱动胶质瘤进展并可作为预后生物标志物

Gliomas are the most prevalent and aggressive primary tumors of the central nervous system, with glioblastoma (GBM) exhibiting rapid progression, high recurrence, and poor prognosis. Therapeutic resistance, particularly to radiotherapy and chemotherapy, remains a major clinical challenge. RNA-binding proteins and RNA methyltransferases have emerged as regulators of tumor progression and immune modulation. ZCCHC4, a zinc finger CCHC domain-containing RNA methyltransferase, has been implicated in cancer, but its biological role and mechanisms in glioma remain largely unexplored.

Gene expression profiles and clinical data from TCGA and CGGA databases were analyzed to assess ZCCHC4 expression and its correlation with clinicopathological features and patient prognosis. Immunohistochemistry, qRT-PCR, and western blotting were performed to evaluate ZCCHC4 expression in glioma tissues and cell lines. Functional assays, including CCK-8, colony formation, wound healing, and transwell migration assays, were conducted to investigate the effects of ZCCHC4 knockdown in vitro. In vivo xenograft models were used to assess tumor growth. RNA sequencing and pathway analyses (GO/KEGG/GSEA) were applied to explore transcriptomic changes, and ssGSEA was used to infer immune-associated signatures.

ZCCHC4 expression was elevated in glioma tissues and cell lines and was associated with higher WHO grade, IDH wild-type status, and unfavorable survival. ZCCHC4 knockdown suppressed glioma cell proliferation and motility in vitro and reduced xenograft growth in vivo. Transcriptomic profiling indicated that ZCCHC4 depletion was accompanied by downregulation of DNA replication/cell-cycle–related programs and upregulation of ER-stress/unfolded protein response–related signatures. ssGSEA-based immune deconvolution suggested that higher ZCCHC4 expression was associated with increased inferred Th2-related and macrophage signatures and decreased inferred cytotoxic T-cell and NK-cell signatures.

ZCCHC4 is upregulated in glioma and associated with adverse clinicopathological features and survival. ZCCHC4 depletion attenuated proliferative and motility-related phenotypes in vitro and reduced xenograft growth in vivo, while transcriptomic analyses suggested links to DNA replication/cell-cycle and ER-stress/UPR programs.