Background Long non-coding RNAs (lncRNAs) participate in colorectal cancer (CRC) progression and immune regulation. However, the biological functions of lncRNA RP3-380B8.4 (RP3) in CRC and its relationship with the tumor immune microenvironment remain unclear. Methods RP3 expression in CRC was assessed using public datasets and validated by in situ hybridization (ISH). We further examined the expression levels and intracellular localization of RP3 in CRC cells by qRT-PCR. The effect of RP3 on the cell growth, migration, invasion and epithelial-to-mesenchymal transition (EMT) was investigated by in vitro experiments and western blot. In vivo experiments confirmed that RP3 potentiated tumor growth and liver metastasis in CRC. We predicted the mechanism by RNA-seq, and confirmed them by western blot. The impact of RP3 on the tumor immune microenvironment was analyzed by bioinformatics analysis and flow cytometry. Results RP3 was substantially elevated in CRC tissues and associated with poor prognosis. RP3 overexpression increased CRC cell proliferation, migration, invasion, and EMT in vitro. RP3 overexpression accelerated orthotopic colorectal cancer growth and liver metastasis in nude mice. On the contrary, knockdown of RP3 achieved the opposite effect. Mechanistically, gene set enrichment analysis (GSEA) and western blot analysis revealed that RP3 overexpression is associated with enrichment of MYC target gene programs and elevated c-Myc protein levels in colorectal cancer. Furthermore, overexpression of RP3 significantly reduced the infiltration of CD8+ T cells in the tumor, while inhibiting the polarization of macrophages toward the CD86-positive (M1-like) phenotype. Conversely, knockdown of RP3 effectively ameliorated this tumor immunosuppressive microenvironment. Conclusions RP3 facilitates CRC proliferation and metastasis and exerts immunosuppression in the tumor microenvironment. These findings implicate RP3 as a candidate regulator in CRC whose mechanistic and therapeutic potential requires further validation.
Glioblastoma (GBM) is characterized by intensive vascular proliferation that is essential for tumor growth. Recent studies indicate the existence of tumor-derived endothelial-like cells can arise from the differentiation of GBM stem cells (GSCs). The transcription factor brachyury plays a critical role in promoting stem cell identity and vasculogenesis during normal embryonic development. However, its involvement in endothelial-like differentiation of GSCs remains unknown. By integrating clinical bioinformatics from GBM databases with preclinical in vitro and in vivo models, including patient-derived GSC cell lines and xenografts, we found that brachyury is highly expressed in GBM tissues and correlates with angiogenesis genes. Our study demonstrated that brachyury is activated by fibroblast growth factor receptor 1 (FGFR1), which subsequently promotes GSC differentiation into endothelial-like cells via SOX2/ZEB1/YAP1 signaling. GSCs with high brachyury expression display great sensitivity to selective FGFR inhibitors in vascular tube formation assays. In vivo pharmacological targeting of FGFR1 with inhibitor E7090 or brachyury gene editing using Cas9/gRNA suppresses GBM neovascularization and tumor growth. Furthermore, gene signature analysis of GBM patients further demonstrated that a lower FGFR1/brachyury/SOX2/ZEB1/YAP1 signature score significantly correlates with favorable overall survival outcomes. These findings highlight the importance of FGFR1-driven brachyury activation in GSC-derived neovascularization and suggest that targeting the FGFR1-directed brachyury/SOX2/ZEB1/YAP1 signaling represents a promising therapeutic strategy for GBM.
PIWI-interacting RNAs (piRNAs) are a new type of small non-coding RNAs (ncRNAs) that interact with PIWI proteins and exert significant influence over germ cell development and malignant tumor progression. Nevertheless, the precise roles and molecular mechanisms of piRNAs in bladder cancer (BCa) remain unclear. This study first reveals that piR-34379 is profoundly underexpressed in BCa and inversely correlates with advanced pathological staging. Through both cellular and animal models, we identify that piR-34379 exerts strong anti-tumor activity in BCa, as evidenced by restraining proliferation and migration, suppressing xenograft progression, enhancing apoptosis and reversing cisplatin resistance. Mechanistically, we reveal that piR-34379 recruits the GTSF1/PIWIL2 complex to negatively regulate ACAT2 mRNA, which functions as a novel lactylation writer. Downregulation of ACAT2 reduces lactylation modification at the K428 residue of PKM2, thereby decreasing PKM2 protein stability and promoting its degradation via the HSPA8-mediated autophagy-lysosome pathway. Consequently, the oncogenic effect of the PKM2 K428 site in BCa is suppressed. Collectively, our findings establish the tumor-suppressive role of the piR-34379/GTSF1/PIWIL2–ACAT2–PKM2 axis in BCa and underscore its therapeutic promise for reversing cisplatin resistance.
