Abstract

Background: Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide; thus, understanding its molecular mechanisms is critical for developing novel therapeutic targets. Long non-coding RNAs (lncRNAs) play crucial isoform-specific roles in cancer. While oncogenic lncRNA LINC00673 is known to be involved in multiple malignancies and possesses five distinct transcript variants, the functional role of LINC00673-V4—a highly expressed transcript variant in CRC—remains largely unexplored. This study investigated how LINC00673-V4 drives CRC proliferation by modulating the Hippo-Yes-associated protein (Hippo-YAP) signaling pathway. Methods: Survival analysis was performed using the GSE39582 dataset to assess the prognostic value of LINC00673 in patients with CRC. The expression of LINC00673 transcript variants in CRC cell lines was detected by quantitative PCR. Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assays were used to assess cell proliferation upon LINC00673-V4 knockdown or overexpression. Western blotting and immunofluorescence staining were utilized to analyze the expression of Hippo-YAP target genes. To confirm the interaction between LINC00673-V4 and fused in sarcoma (FUS), RNA immunoprecipitation (RIP) was performed, while co-IP was used to investigate potential protein–protein interactions. Results: High LINC00673 expression was observed in CRC cell lines and was associated with a poor prognosis in patients with CRC. Among the five LINC00673 transcript variants, LINC00673-V3 and LINC00673-V4 were the predominantly expressed isoforms; however, only LINC00673-V4 significantly promoted CRC cell proliferation. LINC00673-V4 inhibited YAP phosphorylation at Ser127, promoted YAP nuclear translocation, and upregulated the expression of Hippo-YAP target genes (connective tissue growth factor, cysteine-rich angiogenic inducer 61, survivin). RIP assays confirmed an associati