{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:16:17Z","timestamp":1788441377763,"version":"build-2803163510"},"reference-count":22,"publisher":"IMR Press","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82270495"],"award-info":[{"award-number":["82270495"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:PDE4DIP encodes a scaffold protein that has been implicated in compartmentalized signaling and cytoskeletal organization, but the role of its myomegalin variant 8 (MMG8) isoform in hepatocellular carcinoma (HCC) remains unclear. To address this gap, we examined PDE4DIP expression in public HCC datasets and investigated the functional role of MMG8 in HCC models.Methods:PDE4DIP expression was analyzed in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and two Gene Expression Omnibus (GEO) cohorts (GSE14520, GSE36376). MMG8 function was assessed in Huh7 cells using siRNA-mediated knockdown and in Hepa1-6 cells using lentiviral Clustered Regularly Interspaced Short Palindromic Repeats - CRISPR-associated protein 9 (CRISPR-Cas9)-mediated knockout. Cell proliferation in MMG8-KD Huh7 cells and MMG8-KO Hepa1-6 cells was assessed using Cell Counting Kit-8 (CCK-8) assays, while Huh7 cell migration was evaluated using Transwell assays. Tumor growth was assessed using a murine subcutaneous tumor model. Immunohistochemical staining for Ki67 and cleaved caspase-3 was employed to assess tumor cell proliferation and apoptosis-associated changes, respectively. Gene set enrichment analysis was performed in TCGA-LIHC tumors stratified based on PDE4DIP expression.Results:PDE4DIP expression differed between tumor and non-tumor tissues across HCC cohorts, although the directionality of this difference was not uniform. MMG8 knockdown in Huh7 cells reduced proliferation and migratory activity. A single-cell-derived MMG8-KO Hepa1-6 clone exhibited reduced proliferation in vitro and formed smaller tumors in vivo, with lower Ki67 positivity but no significant difference in cleaved caspase-3 positivity between groups. In tumors from the TCGA-LIHC cohort, PDE4DIP expression was associated with distinct transcriptional programs. Specifically, PDE4DIP-high tumors presented with positive normalized enrichment score (NES) values for several metabolic pathways, whereas adhesion\/extracellular matrix (ECM), cell cycle\/proliferation, and translation\/ribosome-related pathways exhibited negative NES values.Conclusions:These findings support a functional contribution of MMG8 to proliferative, migratory, and tumor-growth phenotypes in the tested HCC models. Bulk gene-level PDE4DIP expression in human tumors was associated with context-dependent transcriptional states and should not be interpreted as a direct surrogate for MMG8 function.<\/jats:p>","DOI":"10.31083\/fbl54109","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["PDE4DIP-Derived MMG8 Supports Proliferation, Migration, and Tumor Growth in Hepatocellular Carcinoma Models"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1349-9935","authenticated-orcid":true,"given":"Cong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8283-1200","authenticated-orcid":true,"given":"Chunjing","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7777-0853","authenticated-orcid":true,"given":"Tao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China"},{"name":"National Clinical Research Center for Geriatric Diseases, 100053 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Villanueva A. Hepatocellular Carcinoma. The New England Journal of Medicine. 2019; 380: 1450\u20131462.","DOI":"10.1056\/NEJMra1713263"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nature Reviews. Disease Primers. 2021; 7: 6.","DOI":"10.1038\/s41572-020-00240-3"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017; 169: 1327\u20131341.e23.","DOI":"10.1016\/j.cell.2017.05.046"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Hoshida Y, Nijman SMB, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Research. 2009; 69: 7385\u20137392.","DOI":"10.1158\/0008-5472.CAN-09-1089"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, et al. Myomegalin is a novel protein of the golgi\/centrosome that interacts with a cyclic nucleotide phosphodiesterase. The Journal of Biological Chemistry. 2001; 276: 11189\u201311198.","DOI":"10.1074\/jbc.M006546200"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Roubin R, Acquaviva C, Chevrier V, Sedja\u00ef F, Zyss D, Birnbaum D, et al. Myomegalin is necessary for the formation of centrosomal and Golgi-derived microtubules. Biology Open. 2013; 2: 238\u2013250.","DOI":"10.1242\/bio.20123392"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Wang Z, Zhang C, Qi RZ. A newly identified myomegalin isoform functions in Golgi microtubule organization and ER-Golgi transport. Journal of Cell Science. 2014; 127: 4904\u20134917.","DOI":"10.1242\/jcs.155408"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Esseltine JL, Scott JD. AKAP signaling complexes: pointing towards the next generation of therapeutic targets? Trends in Pharmacological Sciences. 2013; 34: 648\u2013655.","DOI":"10.1016\/j.tips.2013.10.005"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Reggi E, Diviani D. The role of A-kinase anchoring proteins in cancer development. Cellular Signalling. 2017; 40: 143\u2013155.","DOI":"10.1016\/j.cellsig.2017.09.011"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Heath AP, Ferretti V, Agrawal S, An M, Angelakos JC, Arya R, et al. The NCI Genomic Data Commons. Nature Genetics. 2021; 53: 257\u2013262.","DOI":"10.1038\/s41588-021-00791-5"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Research. 2002; 30: 207\u2013210.","DOI":"10.1093\/nar\/30.1.207"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102: 15545\u201315550.","DOI":"10.1073\/pnas.0506580102"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Liberzon A, Birger C, Thorvaldsd\u00f3ttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Systems. 2015; 1: 417\u2013425.","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer. 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Cellular Signalling. 2022; 94: 110322.","DOI":"10.1016\/j.cellsig.2022.110322"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Safri F, Nguyen R, Zerehpooshnesfchi S, George J, Qiao L. Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications. Cancer Gene Therapy. 2024; 31: 1105\u20131112.","DOI":"10.1038\/s41417-024-00764-w"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2023; 77: 1773\u20131796.","DOI":"10.1002\/hep.32740"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Alvarez M, Benhammou JN, Darci-Maher N, French SW, Han SB, Sinsheimer JS, et al. Human liver single nucleus and single cell RNA sequencing identify a hepatocellular carcinoma-associated cell-type affecting survival. Genome Medicine. 2022; 14: 50.","DOI":"10.1186\/s13073-022-01055-5"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Guo DZ, Zhang X, Zhang SQ, Zhang SY, Zhang XY, Yan JY, et al. Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts. Molecular Cancer. 2024; 23: 157.","DOI":"10.1186\/s12943-024-02062-3"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Yoshihara K, Shahmoradgoli M, Mart\u00ednez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. 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