{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:18:54Z","timestamp":1785403134217,"version":"3.56.0"},"reference-count":70,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["JP21H02366"],"award-info":[{"award-number":["JP21H02366"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["JP20K21375"],"award-info":[{"award-number":["JP20K21375"]}]},{"award":["JP21H02366"],"award-info":[{"award-number":["JP21H02366"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP20K21375"],"award-info":[{"award-number":["JP20K21375"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hypoxia-driven regulatory mechanisms play a critical role in tumor progression and therapeutic resistance in hepatocellular carcinoma (HCC), yet hypoxia-responsive microRNAs (HRMs) remain incompletely characterized. This study aimed to identify HRMs in canine HCC to evaluate their diagnostic potential and translational relevance to human disease. Next-generation sequencing of two canine HCC cell lines under normoxic and hypoxic conditions identified 332 and 321 differentially expressed miRNAs, respectively. Integrating these with tumor tissue data revealed 11 HRMs, featuring consistent upregulation of cfa-miR-210 and cfa-miR-34a, which was validated via RT-qPCR in hypoxic cells and clinical tissues. Both miRNAs were significantly elevated in plasma-derived extracellular vesicles (EVs), highlighting their value as promising circulating biomarkers (AUC 1.00 for miR-210; 0.98 for miR-34a). Target gene and pathway analyses identified shared regulatory nodes, including TGIF2 and SPRED1; and enrichment of MAPK, Ras, PI3K-Akt, and Rap1 signaling, broadly linked to hypoxia adaptation, cellular metabolism, and stress-response signaling. Cross-species comparison with human HCC datasets showed that, while miR-210 associates with poor prognosis in human HCC, miR-34a exhibits tumor-suppressive features. These findings define complementary HRM programs in canine HCC, reflecting conserved adaptive and stress-limiting regulatory mechanisms with potential diagnostic and translational relevance to human HCC.<\/jats:p>","DOI":"10.3390\/cells15151341","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:26:23Z","timestamp":1785115583000},"page":"1341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conserved Hypoxia-Responsive miRNA Programs Define Adaptive and Stress-Limiting Regulatory Axes in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-756X","authenticated-orcid":false,"given":"Most Shumi Akhter","family":"Shathi","sequence":"first","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3432-7696","authenticated-orcid":false,"given":"Mohammad","family":"Arif","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7261-3193","authenticated-orcid":false,"given":"Nobuhiro","family":"Nozaki","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8666-972X","authenticated-orcid":false,"given":"MD Nazmul","family":"Hasan","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4256-1407","authenticated-orcid":false,"given":"Yutaro","family":"Ide","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2048-2508","authenticated-orcid":false,"given":"Yoshiyuki","family":"Akiyama","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7808-777X","authenticated-orcid":false,"given":"Shaohsu","family":"Wang","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3583-0605","authenticated-orcid":false,"given":"Sirazul","family":"Islam","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Department of Livestock Services (DLS), Farmgate, Dhaka 1215, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7436-9069","authenticated-orcid":false,"given":"Tanjila","family":"Rahman","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Department of Anatomy, Histology & Physiology, Sher-e-Bangla Agricultural University, Dhaka 1207, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohide","family":"Kuramoto","sequence":"additional","affiliation":[{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Furusawa","sequence":"additional","affiliation":[{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6467-490X","authenticated-orcid":false,"given":"Takeshi","family":"Sogawa","sequence":"additional","affiliation":[{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aki","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7511-0767","authenticated-orcid":false,"given":"Tatsuro","family":"Hifumi","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Department of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Hirano","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Department of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriaki","family":"Miyoshi","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Department of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4430-5645","authenticated-orcid":false,"given":"Osamu","family":"Yamato","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4603-5594","authenticated-orcid":false,"given":"Masashi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4625-5231","authenticated-orcid":false,"given":"Naoki","family":"Miura","sequence":"additional","affiliation":[{"name":"Joint Graduate School of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"},{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.rvsc.2014.01.004","article-title":"Identification of Tumor-Initiating Cells in a Canine Hepatocellular Carcinoma Cell Line","volume":"96","author":"Michishita","year":"2014","journal-title":"Res. Vet. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Gibson, E.A., Goldman, R.E., and Culp, W.T.N. (2022). Comparative Oncology: Management of Hepatic Neoplasia in Humans and Dogs. Vet. Sci., 9.","DOI":"10.3390\/vetsci9090489"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Maniscalco, L., Varello, K., Morello, E., Montemurro, V., Olimpo, M., Giacobino, D., Abbamonte, G., Gola, C., Iussich, S., and Bozzetta, E. (2022). Investigating a Prognostic Factor for Canine Hepatocellular Carcinoma: Analysis of Different Histological Grading Systems and the Role of PIVKA-II. Vet. Sci., 9.","DOI":"10.3390\/vetsci9120689"},{"key":"ref_4","first-page":"811","article-title":"Comparative Analysis of Hepatocellular Carcinoma in Men and Dogs","volume":"33","author":"Seiwerth","year":"2009","journal-title":"Coll. Antropol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1177\/030098588101800402","article-title":"Canine Hepatocellular Carcinoma","volume":"18","author":"Patnaik","year":"1981","journal-title":"Vet. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s12276-023-00977-3","article-title":"Comparative Oncology: Overcoming Human Cancer through Companion Animal Studies","volume":"55","author":"Oh","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1111\/liv.12818","article-title":"Global Patterns of Hepatocellular Carcinoma Management from Diagnosis to Death: The BRIDGE Study","volume":"35","author":"Park","year":"2015","journal-title":"Liver Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/nrc2540","article-title":"The Impact of O2 Availability on Human Cancer","volume":"8","author":"Bertout","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Moriondo, G., Scioscia, G., Soccio, P., Tondo, P., De Pace, C.C., Sabato, R., Barbaro, M.P.F., and Lacedonia, D. (2022). Effect of Hypoxia-Induced Micro-RNAs Expression on Oncogenesis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116294"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bui, B.P., Nguyen, P.L., Lee, K., and Cho, J. (2022). Hypoxia-Inducible Factor-1: A Novel Therapeutic Target for the Management of Cancer, Drug Resistance, and Cancer-Related Pain. Cancers, 14.","DOI":"10.3390\/cancers14246054"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Miranda-Galvis, M., and Teng, Y. (2020). Targeting Hypoxia-Driven Metabolic Reprogramming to Constrain Tumor Progression and Metastasis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155487"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wu, S., Anand, N., Guo, Z., Li, M., Figueroa, M.S., Jung, L., Kelly, S., and Franses, J.W. (2025). Bridging Immune Evasion and Vascular Dynamics for Novel Therapeutic Frontiers in Hepatocellular Carcinoma. Cancers, 17.","DOI":"10.3390\/cancers17111860"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Liu, F., Qian, Y., Zhang, Q., Tian, Q., and Rao, W. (2026). Understanding How Hypoxia Contributes to Liver Cancer Stem Cells Maintenance. Clin. Transl. Oncol.","DOI":"10.1007\/s12094-026-04414-5"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1053\/j.gastro.2017.04.017","article-title":"Antagonistic Effects of P53 and HIF1A on MicroRNA-34a Regulation of PPP1R11 and STAT3 and Hypoxia-Induced Epithelial to Mesenchymal Transition in Colorectal Cancer Cells","volume":"153","author":"Li","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.freeradbiomed.2013.05.022","article-title":"Hypoxia: A Master Regulator of MicroRNA Biogenesis and Activity","volume":"64","author":"Nallamshetty","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/aps.2012.195","article-title":"Hypoxia-Regulated MicroRNAs in Human Cancer","volume":"34","author":"Shen","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1111\/vco.12379","article-title":"Aberrant Expression of MicroRNAs and the MiR-1\/MET Pathway in Canine Hepatocellular Carcinoma","volume":"16","author":"Lai","year":"2018","journal-title":"Vet. Comp. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105903","DOI":"10.1016\/j.rvsc.2025.105903","article-title":"Identification of Dysregulated Mirna Transcriptomic Profile in Canine Hepatocellular Carcinoma and Comparison to Human Hcc","volume":"196","author":"Hashimoto","year":"2025","journal-title":"Res. Vet. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/hepr.12606","article-title":"Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review","volume":"46","author":"Mizuguchi","year":"2016","journal-title":"Hepatol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1128\/MCB.01395-06","article-title":"A MicroRNA Signature of Hypoxia","volume":"27","author":"Kulshreshtha","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7752277","DOI":"10.1155\/2022\/7752277","article-title":"Hypoxia-Induced MiR-210 Promotes Endothelial Cell Permeability and Angiogenesis via Exosomes in Pancreatic Ductal Adenocarcinoma","volume":"2022","author":"Wu","year":"2022","journal-title":"Biochem. Res. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41419-021-03713-9","article-title":"Hypoxia-Induced MiR-210 Modulates the Inflammatory Response and Fibrosis upon Acute Ischemia","volume":"12","author":"Zaccagnini","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Liu, H., Chen, C., Zeng, J., Zhao, Z., and Hu, Q. (2021). MicroRNA-210-3p Is Transcriptionally Upregulated by Hypoxia Induction and Thus Promoting EMT and Chemoresistance in Glioma Cells. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253522"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13578-023-01045-z","article-title":"MiR-210-3p Enriched Extracellular Vesicles from Hypoxic Neuroblastoma Cells Stimulate Migration and Invasion of Target Cells","volume":"13","author":"Fusco","year":"2023","journal-title":"Cell Biosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"33161","DOI":"10.1074\/jbc.M109.020925","article-title":"Ischemic Preconditioning Augments Survival of Stem Cells via MiR-210 Expression by Targeting Caspase-8-Associated Protein 2","volume":"284","author":"Kim","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cmet.2009.08.015","article-title":"MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1\/2","volume":"10","author":"Chan","year":"2009","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1177\/15353702211011576","article-title":"Hypoxic Colorectal Cancer-Secreted Exosomes Deliver MiR-210-3p to Normoxic Tumor Cells to Elicit a Protumoral Effect","volume":"246","author":"Ge","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1089\/ars.2013.5206","article-title":"Hypoxia-Induced MiR-210 Modulates Tissue Response to Acute Peripheral Ischemia","volume":"21","author":"Zaccagnini","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1128\/MCB.01242-10","article-title":"A Hypoxia-Induced Positive Feedback Loop Promotes Hypoxia-Inducible Factor 1\u03b1 Stability through MiR-210 Suppression of Glycerol-3-Phosphate Dehydrogenase 1-Like","volume":"31","author":"Kelly","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4318","DOI":"10.1111\/febs.12021","article-title":"DNA Demethylation Regulates the Expression of MiR-210 in Neural Progenitor Cells Subjected to Hypoxia","volume":"279","author":"Xiong","year":"2012","journal-title":"FEBS J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/35106009","article-title":"Assessing TP53 Status in Human Tumours to Evaluate Clinical Outcome","volume":"1","author":"Soussi","year":"2001","journal-title":"Nat. Rev. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/cdd.2009.56","article-title":"The MiR-34 Family in Cancer and Apoptosis","volume":"17","author":"Hermeking","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.molcel.2007.05.017","article-title":"Transcriptional Activation of MiR-34a Contributes to P53-Mediated Apoptosis","volume":"26","author":"Marciano","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1038\/cddis.2011.48","article-title":"Reciprocal Influence of the P53 and the Hypoxic Pathways","volume":"2","author":"Sermeus","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.yexcr.2012.03.018","article-title":"MiR-34a Inhibits Lipopolysaccharide-Induced Inflammatory Response Through Targeting Notch1 in Murine Macrophages","volume":"318","author":"Jiang","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5189138","DOI":"10.1155\/2017\/5189138","article-title":"Identification of Four Oxidative Stress-Responsive MicroRNAs, MiR-34a-5p, MiR-1915-3p, MiR-638, and MiR-150-3p, in Hepatocellular Carcinoma","volume":"2017","author":"Wan","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"152876","DOI":"10.1016\/j.prp.2020.152876","article-title":"MiR-34a Promotes Liver Fibrosis in Patients with Chronic Hepatitis via Mediating Sirt1\/P53 Signaling Pathway","volume":"216","author":"Li","year":"2020","journal-title":"Pathol. Res. Pract."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1016\/j.bpj.2014.02.032","article-title":"Involvement of MiR-605 and MiR-34a in the DNA Damage Response Promotes Apoptosis Induction","volume":"106","author":"Zhou","year":"2014","journal-title":"Biophys. J."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Shathi, M.S.A., Arif, M., Nozaki, N., Ide, Y., Akiyama, Y., Wang, S., Takahashi, M., and Miura, N. (2025). Divergent Tissue and Circulatory Expression of MiR-10a in Canine Hepatocellular Carcinoma: Comparative Insights from Human HCC. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47110950"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1292\/jvms.12-0549","article-title":"Identification of Cell Surface Antigen Expression in Canine Hepatocellular Carcinoma Cell Lines","volume":"75","author":"Fujimoto","year":"2013","journal-title":"J. Vet. Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"108815","DOI":"10.1016\/j.isci.2024.108815","article-title":"Comprehensive Characterization of Small Noncoding RNA Profiles in Hypoxia-Induced Pulmonary Hypertension (HPH) Rat Tissues","volume":"27","author":"Wang","year":"2024","journal-title":"iScience"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Koenig, E.M., Fisher, C., Bernard, H., Wolenski, F.S., Gerrein, J., Carsillo, M., Gallacher, M., Tse, A., Peters, R., and Smith, A. (2016). The Beagle Dog MicroRNA Tissue Atlas: Identifying Translatable Biomarkers of Organ Toxicity. BMC Genom., 17.","DOI":"10.1186\/s12864-016-2958-x"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Koehler, J., Sandey, M., Prasad, N., Levy, S.A., Wang, X., and Wang, X. (2020). Differential Expression of MiRNAs in Hypoxia (\u201cHypoxamiRs\u201d) in Three Canine High-Grade Glioma Cell Lines. Front. Vet. Sci., 7.","DOI":"10.3389\/fvets.2020.00104"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"145552","DOI":"10.1016\/j.gene.2021.145552","article-title":"Hypoxic MiRNAs Expression Are Different between Primary and Metastatic Melanoma Cells","volume":"782","author":"Hino","year":"2021","journal-title":"Gene"},{"key":"ref_45","first-page":"148597","article-title":"Malignancy Associated MicroRNA Expression Changes in Canine Mammary Cancer of Different Malignancies","volume":"2014","author":"Schmeck","year":"2014","journal-title":"Int. Sch. Res. Not."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1111\/pcmr.13000","article-title":"Identification of Melanoma-Specific Exosomal MiRNAs as the Potential Biomarker for Canine Oral Melanoma","volume":"34","author":"Husna","year":"2021","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1002\/hep.24614","article-title":"Hypoxia-Inducible MicroRNA-210 Augments the Metastatic Potential of Tumor Cells by Targeting Vacuole Membrane Protein 1 in Hepatocellular Carcinoma","volume":"54","author":"Ying","year":"2011","journal-title":"Hepatology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/1756-9966-33-50","article-title":"Multiple Functions of Hypoxia-Regulated MiR-210 in Cancer","volume":"33","author":"Qin","year":"2014","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Alegre, F., Ormonde, A.R., Snider, K.M., Woolard, K., Yu, A.M., and Wittenburg, L.A. (2018). A Genetically Engineered MicroRNA-34a Prodrug Demonstrates Anti-Tumor Activity in a Canine Model of Osteosarcoma. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0209941"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12935-017-0431-9","article-title":"MiR-34a and MiR-206 Act as Novel Prognostic and Therapy Biomarkers in Cervical Cancer","volume":"17","author":"Chen","year":"2017","journal-title":"Cancer Cell Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1093\/carcin\/bgp219","article-title":"MiR-34a as a Prognostic Marker of Relapse in Surgically Resected Non-Small-Cell Lung Cancer","volume":"30","author":"Gallardo","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s10238-012-0186-5","article-title":"MiR-34a Inhibits Proliferation and Migration of Breast Cancer through down-Regulation of Bcl-2 and SIRT1","volume":"13","author":"Li","year":"2013","journal-title":"Clin. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lopez, C.M., Yu, P.Y., Zhang, X., Yilmaz, A.S., London, C.A., and Fenger, J.M. (2018). MiR-34a Regulates the Invasive Capacity of Canine Osteosarcoma Cell Lines. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0190086"},{"key":"ref_54","first-page":"103","article-title":"MiR-34a Regulates HDAC1 Expression to Affect the Proliferation and Apoptosis of Hepatocellular Carcinoma","volume":"9","author":"Sun","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.cellsig.2014.12.003","article-title":"Tumor Suppressor MiR-34a Targets PD-L1 and Functions as a Potential Immunotherapeutic Target in Acute Myeloid Leukemia","volume":"27","author":"Wang","year":"2015","journal-title":"Cell. Signal."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1177\/0300985820967902","article-title":"MicroRNA Biomarkers in Canine Diffuse Large B-Cell Lymphoma","volume":"58","author":"Elshafie","year":"2021","journal-title":"Vet. Pathol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Du, R., Sun, W., Xia, L., Zhao, A., Yu, Y., Zhao, L., Wang, H., Huang, C., and Sun, S. (2012). Hypoxia-Induced down-Regulation of MicroRNA-34a Promotes EMT by Targeting the Notch Signaling Pathway in Tubular Epithelial Cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030771"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1093\/jmcb\/mju003","article-title":"The p53\/miR-34 Axis in Development and Disease","volume":"6","author":"Rokavec","year":"2014","journal-title":"J. Mol. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.gene.2014.03.059","article-title":"Methylation-Associated Silencing of MicroRNA-34b in Hepatocellular Carcinoma Cancer","volume":"543","author":"Xie","year":"2014","journal-title":"Gene"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Bouznad, N., Rokavec, M., \u00d6ner, M.G., and Hermeking, H. (2023). MiR-34a and IRE1A\/XBP-1(S) Form a Double-Negative Feedback Loop to Regulate Hypoxia-Induced EMT, Metastasis, Chemo-Resistance and Autophagy. Cancers, 15.","DOI":"10.3390\/cancers15041143"},{"key":"ref_61","first-page":"467","article-title":"Differentially Expressed MiRNAs in Hepatocellular Carcinoma Cells under Hypoxic Conditions Are Associated with Transcription and Phosphorylation","volume":"15","author":"Hu","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"bio033290","DOI":"10.1242\/bio.033290","article-title":"Inhibition of MiR-34a-5p Alleviates Hypoxia-Reoxygenation Injury by Enhancing Autophagy in Steatotic Hepatocytes","volume":"7","author":"Li","year":"2018","journal-title":"Biol. Open"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Sharma, P., Dando, I., Strippoli, R., Kumar, S., Somoza, A., Cordani, M., and Tafani, M. (2020). Nanomaterials for Autophagy-Related MiRNA-34a Delivery in Cancer Treatment. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01141"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Zhao, M., Qi, Q., Liu, S., Huang, R., Shen, J., Zhu, Y., Chai, J., Zheng, H., Wu, H., and Liu, H. (2022). MicroRNA-34a: A Novel Therapeutic Target in Fibrosis. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.895242"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1093\/bib\/bbz046","article-title":"A Comprehensive Overview of Oncogenic Pathways in Human Cancer","volume":"21","author":"Li","year":"2020","journal-title":"Brief. Bioinform."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Qiao, J., Peng, Q., Qian, F., You, Q., Feng, L., Hu, S., Liu, W., Huang, L., Shu, X., and Sun, B. (2021). HIV-1 Vpr Protein Upregulates MicroRNA-210-5p Expression to Induce G2 Arrest by Targeting TGIF2. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0261971"},{"key":"ref_67","first-page":"8921","article-title":"MicroRNA-34a Inhibits Tumor Invasion and Metastasis in Gastric Cancer by Targeting Tgif2","volume":"8","author":"Hu","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/s40478-025-02073-1","article-title":"NSC-Derived Extracellular Vesicles-Mediates Neuronal Plasticity Enhancement in Vascular Dementia via Transferring MiR-210","volume":"13","author":"Pan","year":"2025","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1126\/science.1086432","article-title":"The Dog Genome: Survey Sequencing and Comparative Analysis","volume":"301","author":"Kirkness","year":"2003","journal-title":"Science"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Tawa, G.J., Braisted, J., Gerhold, D., Grewal, G., Mazcko, C., Breen, M., Sittampalam, G., and LeBlanc, A.K. (2021). Transcriptomic Profiling in Canines and Humans Reveals Cancer Specific Gene Modules and Biological Mechanisms Common to Both Species. PLoS Comput. Biol., 17.","DOI":"10.1371\/journal.pcbi.1009450"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1341\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:31:24Z","timestamp":1785115884000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,26]]},"references-count":70,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15151341"],"URL":"https:\/\/doi.org\/10.3390\/cells15151341","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,26]]}}}