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(Landmark Ed)"],"abstract":"<jats:p>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\u2014a highly expressed transcript variant in CRC\u2014remains 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\u2032-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\u2013protein 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 association between LINC00673-V4 and FUS, while co-immunoprecipitation (co-IP) assays revealed that FUS interacted with both YAP and large tumor suppressor 1 (LATS1), suggesting FUS may facilitate LATS1-mediated YAP phosphorylation. FUS was found to promote LATS1-mediated YAP Ser127 phosphorylation, induce YAP cytoplasmic retention, and down-regulate Hippo-YAP target gene expression. Rescue experiments showed that LINC00673-V4 reversed the FUS-induced suppression of Hippo-YAP target gene expression.Conclusions:Our study identified LINC00673-V4 as an isoform-specific oncogenic lncRNA in CRC. By associating with FUS, LINC00673-V4 sequesters FUS away from the LATS1\/YAP complex; thereby inhibiting FUS-mediated YAP phosphorylation and enhancing Hippo-YAP target gene expression. These findings expand the landscape of lncRNA isoform-specific regulation in cancer, highlighting LINC00673-V4 as a potential prognostic biomarker and therapeutic target for CRC.<\/jats:p>","DOI":"10.31083\/fbl52436","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:17:49Z","timestamp":1785413869000},"source":"Crossref","is-referenced-by-count":0,"title":["LINC00673-V4 Promotes Colorectal Cancer Cell Proliferation by Interacting With FUS and Restoring the Expression of Hippo-YAP Target Genes"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3701-0088","authenticated-orcid":true,"given":"Wei","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China"},{"name":"Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, 310009 Hangzhou, Zhejiang, China"},{"name":"Cancer Center, Zhejiang University, 310009 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4475-1606","authenticated-orcid":true,"given":"Jiamin","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1000-0330","authenticated-orcid":true,"given":"Yunxiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3905-7907","authenticated-orcid":true,"given":"Huihui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians. 2024; 74: 229\u2013263.","DOI":"10.3322\/caac.21834"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Nemeth K, Bayraktar R, Ferracin M, Calin GA. Non-coding RNAs in disease: from mechanisms to therapeutics. Nature Reviews. Genetics. 2024; 25: 211\u2013232.","DOI":"10.1038\/s41576-023-00662-1"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Bhan A, Soleimani M, Mandal SS. Long Noncoding RNA and Cancer: A New Paradigm. Cancer Research. 2017; 77: 3965\u20133981.","DOI":"10.1158\/0008-5472.CAN-16-2634"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Swati, Joshi V, Banerjee T, Neve AU, Sengar S, Sen D, et al. LncRNA LASTR promotes TGF-\u03b2 signalling and EMT in HNSCC by enhancing TGF\u03b2R1 expression by suppressing biogenesis of miR-34a and acting as its ceRNA. Cellular Signalling. 2026; 143: 112472.","DOI":"10.1016\/j.cellsig.2026.112472"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Huang B, An H, Qiu Y, Ni Z, Chen L, Lin J, et al. The long noncoding RNA AC093895.1 promotes ovarian cancer formation and metastasis through a positive feedback network dependent on the transcription factor SOX4. Cell Death & Disease. 2026; 17: 202.","DOI":"10.1038\/s41419-026-08429-2"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Su G, Qian J, Wang Y, Zhu Y, Chen Y, Shen J, et al. Platelet-derived exosomal LINC00183 facilitate colorectal cancer malignant progression driven by histone lactylation through stabilizing ENO1. Cell Death & Disease. 2025; 16: 593.","DOI":"10.1038\/s41419-025-07914-4"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Bonnal SC, L\u00f3pez-Oreja I, Valc\u00e1rcel J. Roles and mechanisms of alternative splicing in cancer - implications for care. Nature Reviews. Clinical Oncology. 2020; 17: 457\u2013474.","DOI":"10.1038\/s41571-020-0350-x"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Khan MR, Avino M, Wellinger RJ, Laurent B. Distinct regulatory functions and biological roles of lncRNA splice variants. Molecular Therapy. Nucleic Acids. 2023; 32: 127\u2013143.","DOI":"10.1016\/j.omtn.2023.03.004"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Smith NE, Spencer-Merris P, Fox AH, Petersen J, Michael MZ. The Long and the Short of It: NEAT1 and Cancer Cell Metabolism. Cancers. 2022; 14: 4388.","DOI":"10.3390\/cancers14184388"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Park MK, Zhang L, Min KW, Cho JH, Yeh CC, Moon H, et al. NEAT1 is essential for metabolic changes that promote breast cancer growth and metastasis. 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Cell Reports. 2019; 27: 2493\u20132507.e4.","DOI":"10.1016\/j.celrep.2019.04.101"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Ballester M, Kurilla A, Dai Y, Bergara-Muguruza L, Radke K, Maurer HC, et al. Regulatory elements in the Sox9 locus license the initiation of pancreatic ductal adenocarcinoma. Cell Reports. 2026; 45: 117176.","DOI":"10.1016\/j.celrep.2026.117176"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Lu W, Zhang H, Niu Y, Wu Y, Sun W, Li H, et al. Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p. Molecular Cancer. 2017; 16: 118.","DOI":"10.1186\/s12943-017-0685-9"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Ni H, Tang S, Lu G, Niu Y, Xu J, Zhang H, et al. Linc00673-V3 positively regulates autophagy by promoting Smad3-mediated LC3B transcription in NSCLC. Life Science Alliance. 2024; 7: e202302408.","DOI":"10.26508\/lsa.202302408"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Guan H, Zhu T, Wu S, Liu S, Liu B, Wu J, et al. Long noncoding RNA LINC00673-v4 promotes aggressiveness of lung adenocarcinoma via activating WNT\/\u03b2-catenin signaling. Proceedings of the National Academy of Sciences of the United States of America. 2019; 116: 14019\u201314028.","DOI":"10.1073\/pnas.1900997116"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Ghosh C, Kakar R, Torkamboor S, Sun Y. The Regulation and Function of Hippo\/YAP Pathway in Cancer. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2026; 40: e71744.","DOI":"10.1096\/fj.202504622R"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Ye R, Yin L, Ge Y, Zhu X, Xiao Y, Fang C, et al. Downregulation of SSR2 Enhances Hepatocellular Carcinoma Cisplatin Sensitivity via the Hippo Pathway. Frontiers in Bioscience. 2024; 29.","DOI":"10.31083\/j.fbl2908299"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Zhang L, Zhang F, Liang H, Qin X, Mo Y, Chen S, et al. Hippo\/YAP signaling pathway in colorectal cancer: regulatory mechanisms and potential drug exploration. Frontiers in Oncology. 2025; 15: 1545952.","DOI":"10.3389\/fonc.2025.1545952"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Gao GF, Ruan ZH, Zhang SB, He S, Li YQ, Lyu JL, et al. SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers. Gut. 2026.","DOI":"10.1136\/gutjnl-2025-337606"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Ascen\u00e7\u00e3o K, Lheimeur B, Szabo C. Regulation of CyR61 expression and release by 3-mercaptopyruvate sulfurtransferase in colon cancer cells. Redox Biology. 2022; 56: 102466.","DOI":"10.1016\/j.redox.2022.102466"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483: 603\u2013607.","DOI":"10.1038\/nature11003"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2004; 10: 7252\u20137259.","DOI":"10.1158\/1078-0432.CCR-04-0713"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Cheng L, Yu H, Qin Y, Wang R, Su T, Lyu G, et al. The lncRNA ST18-AS1 suppresses pancreatic cancer progression by enhancing ST18 mRNA stability through anchoring FUS in the cytoplasm. Oncogene. 2025; 44: 2850\u20132863.","DOI":"10.1038\/s41388-025-03455-4"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Cheng R, Li F, Zhang M, Xia X, Wu J, Gao X, et al. A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers. Cell Research. 2023; 33: 30\u201345.","DOI":"10.1038\/s41422-022-00726-7"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Schmidt K, Weidmann CA, Hilimire TA, Yee E, Hatfield BM, Schneekloth JS Jr, et al. Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor. Cell Reports. 2020; 30: 541\u2013554.e5.","DOI":"10.1016\/j.celrep.2019.12.011"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Li N, Cui Z, Huang D, Gao M, Li S, Song M, et al. Association of LINC00673 rs11655237 polymorphism with cancer susceptibility: A meta-analysis based on 23,478 subjects. 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