{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T11:01:41Z","timestamp":1774868501966,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["15H04920"],"award-info":[{"award-number":["15H04920"]}]},{"name":"JSPS KAKENHI","award":["24H00642"],"award-info":[{"award-number":["24H00642"]}]},{"name":"Kagoshima Shinsangyo Sousei Investment Limited Partnership"},{"name":"METI Monozukuri R&D Support Grant Program for SMEs","award":["JPJ005698"],"award-info":[{"award-number":["JPJ005698"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Aim: Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and an extremely poor prognosis. MicroRNAs (miRNAs), which regulate gene expression at the post-transcriptional level, have emerged as promising candidates for next-generation cancer therapeutics. The purpose of this study is to clarify the feasibility of miR-4711 as a potential therapeutic option against pancreatic cancer. Materials and Methods: The effects of miR-4711-5p were examined in pancreatic cancer cell lines with respect to cell proliferation, apoptosis, cancer stemness, cell cycle progression, and invasive capacity. RNA sequencing and in silico analyses were performed to identify potential target genes of miR-4711-5p. For in vivo safety evaluation, miR-4711-5p was formulated with super carbonate apatite, a delivery vehicle that is already amenable to large-scale production, and administered to cynomolgus monkeys. A nucleic acid dose equivalent to 10 times the effective dose observed in prior mouse efficacy studies was used. General clinical conditions, body weight, food consumption, ophthalmologic findings, electrocardiography, blood pressure, hematological and biochemical parameters, and histopathological changes were systematically assessed. Results: miR-4711-5p significantly suppressed cancer stemness, cell proliferation, and invasion, while inducing apoptosis and delaying cell cycle progression in pancreatic cancer cells. RNA sequencing and bioinformatic analyses identified MET, CTSA, and ANO1 as potential target genes of miR-4711-5p. In the cynomolgus monkey study, administration of miR-4711-5p formulated with super carbonate apatite resulted in no apparent differences compared with the control group in body weight, clinical observations, laboratory parameters, or histopathological findings, indicating the absence of treatment-related adverse effects even at a supra-therapeutic dose. Conclusions: These findings demonstrate that miR-4711-5p exerts potent antitumor effects against pancreatic cancer cells while exhibiting a favorable safety profile in a non-human primate model. Collectively, this study provides strong preclinical evidence supporting miR-4711-5p as a novel and safe therapeutic strategy for pancreatic cancer and represents an important step toward clinical application.<\/jats:p>","DOI":"10.3390\/cancers18071104","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T09:57:24Z","timestamp":1774864644000},"page":"1104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Potential of miR-4711-5p in Pancreatic Cancer: Antitumor Activity and Mechanistic Insights"],"prefix":"10.3390","volume":"18","author":[{"given":"Yuhki","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2687-9933","authenticated-orcid":false,"given":"Yoshihiro","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Osaka General Medical Center, 3-1-56 Bandaihigashi, Osaka 558-8558, Osaka, Japan"},{"name":"Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, 2-2, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shihori","family":"Kouda","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiho","family":"Kawanami","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruijia","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manami","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanami","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Shimomura","sequence":"additional","affiliation":[{"name":"Nanobeyond Inc., 7-7-15 Saito-Asagi, Ibaraki 567-0085, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kana","family":"Nishida","sequence":"additional","affiliation":[{"name":"Nanobeyond Inc., 7-7-15 Saito-Asagi, Ibaraki 567-0085, Osaka, Japan"},{"name":"Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, 2-2, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5000-9084","authenticated-orcid":false,"given":"Akira","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Ikeda City Hospital, 3-1-18 Jyonan, Ikeda 563-8510, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, The University of Osaka, 1-7, Yamadaoka, Suita 565-0871, Osaka, Japan"},{"name":"Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, 2-2, Yamadaoka, Suita 565-0871, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Mori","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115652","DOI":"10.1016\/j.addr.2025.115652","article-title":"Navigating the complexities of pancreatic ductal adenocarcinoma: A review on therapeutic models and RAS inhibitors","volume":"224","author":"Barrambana","year":"2025","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc1590","article-title":"Tumour stem cells and drug resistance","volume":"5","author":"Dean","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1093\/carcin\/bgh293","article-title":"Will cancer stem cells provide new therapeutic targets?","volume":"26","author":"Behbod","year":"2005","journal-title":"Carcinogenesis"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jbior.2014.05.001","article-title":"Pancreatic cancer stem cells: Association with cell surface markers, prognosis, resistance, metastasis and treatment","volume":"56","author":"Fitzgerald","year":"2014","journal-title":"Adv. Biol. Regul."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1152\/physrev.00058.2009","article-title":"Mammalian Kr\u00fcppel-like factors in health and diseases","volume":"90","author":"McConnell","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.stem.2008.09.003","article-title":"Kr\u00fcppel-like factor 5 is essential for blastocyst development and the normal self-renewal of mouse ESCs","volume":"3","author":"Ema","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/bies.20581","article-title":"The diverse functions of Kr\u00fcppel-like factors 4 and 5 in epithelial biology and pathobiology","volume":"29","author":"McConnell","year":"2007","journal-title":"Bioessays"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1111\/cas.14411","article-title":"High expression of Kr\u00fcppel-like factor 5 is associated with poor prognosis in patients with colorectal cancer","volume":"111","author":"Takagi","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1158\/0008-5472.CAN-13-2574","article-title":"KLF5 regulates the integrity and oncogenicity of intestinal stem cells","volume":"74","author":"Nakaya","year":"2014","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5035","DOI":"10.18632\/aging.102096","article-title":"Overexpression of KLF5 is associated with poor survival and G1\/S progression in pancreatic cancer","volume":"11","author":"Li","year":"2019","journal-title":"Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1053\/j.gastro.2017.12.005","article-title":"Kr\u00fcppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice","volume":"154","author":"He","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/s41416-020-0758-1","article-title":"miR-4711-5p regulates cancer stemness and cell cycle progression via KLF5, MDM2 and TFDP1 in colon cancer cells","volume":"122","author":"Morimoto","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"619","DOI":"10.21873\/anticanres.17974","article-title":"The miR-29b Byproduct MIRTX Shows Superior Anti-tumor Activity, Compared to miR-29b-3p, in Pancreatic Cancer Cells","volume":"46","author":"Yokoyama","year":"2026","journal-title":"Anticancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3892\/ijo.2022.5303","article-title":"Functional assessment of miR-1291 in colon cancer cells","volume":"60","author":"Wang","year":"2022","journal-title":"Int. J. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.omtn.2018.07.007","article-title":"The Supercarbonate Apatite-MicroRNA Complex Inhibits Dextran Sodium Sulfate-Induced Colitis","volume":"12","author":"Fukata","year":"2018","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wu, X., Yamamoto, H., Nakanishi, H., Yamamoto, Y., Inoue, A., Tei, M., Hirose, H., Uemura, M., Nishimura, J., and Hata, T. (2015). Innovative delivery of siRNA to solid tumours by super carbonate apatite. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116022"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.cell.2009.01.035","article-title":"Origins and mechanisms of miRNAs and siRNAs","volume":"136","author":"Carthew","year":"2009","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.biopha.2016.09.099","article-title":"The role of microRNAs in colorectal cancer","volume":"84","author":"Mohammadi","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrd.2016.246","article-title":"MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases","volume":"16","author":"Rupaimoole","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nrd4359","article-title":"Therapeutic targeting of microRNAs: Current status and future challenges","volume":"13","author":"Li","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"368","DOI":"10.5732\/cjc.011.10186","article-title":"MicroRNA therapeutics: Principles, expectations, and challenges","volume":"30","author":"Rupaimoole","year":"2011","journal-title":"Chin. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1158\/1535-7163.MCT-17-0788","article-title":"Photodynamic Therapy Using Indocyanine Green Loaded on Super Carbonate Apatite as Minimally Invasive Cancer Treatment","volume":"17","author":"Tamai","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1158\/1535-7163.MCT-17-0850","article-title":"A miR-29b Byproduct Sequence Exhibits Potent Tumor-Suppressive Activities via Inhibition of NF-\u03baB Signaling in KRAS-Mutant Colon Cancer Cells","volume":"17","author":"Inoue","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Forterre, A., Komuro, H., Aminova, S., and Harada, M. (2020). A comprehensive review of cancer microRNA therapeutic delivery strategies. Cancers, 12.","DOI":"10.3390\/cancers12071852"},{"key":"ref_28","first-page":"8029721","article-title":"Development of microRNAs as potential therapeutics against cancer","volume":"2020","author":"Kamaruzman","year":"2020","journal-title":"J. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Merhautova, J., Demlova, R., and Slaby, O. (2016). MicroRNA-based therapy in animal models of selected gastrointestinal cancers. Front. Pharmacol., 7.","DOI":"10.3389\/fphar.2016.00329"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1111\/cas.13965","article-title":"Development of miRNA-based therapeutic approaches for cancer patients","volume":"110","author":"Takahashi","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1080\/10408363.2019.1653821","article-title":"HGF\/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers","volume":"56","author":"Moosavi","year":"2019","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrc3205","article-title":"Targeting MET in cancer: Rationale and progress","volume":"12","author":"Gherardi","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41568-018-0002-y","article-title":"Known and novel roles of the MET oncogene in cancer","volume":"18","author":"Comoglio","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1007\/s00424-014-1598-8","article-title":"ANO1 (THEM16A) in pancreatic ductal adenocarcinoma (PDAC)","volume":"467","author":"Sauter","year":"2015","journal-title":"Pflug. Arch."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13026","DOI":"10.1073\/pnas.1900703116","article-title":"THEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis","volume":"116","author":"Lin","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Guo, S., Zhang, L., and Li, N. (2022). ANO1: More Than Just Calcium-Activated Chloride Channel in Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.922838"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E1026","DOI":"10.1073\/pnas.1217072110","article-title":"Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling","volume":"110","author":"Britschgi","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"108407","DOI":"10.1016\/j.abb.2020.108407","article-title":"Suppression of cathepsin a inhibits growth, migration, and invasion by inhibiting the p38 MAPK signaling pathway in prostate cancer","volume":"688","author":"Park","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2152\/jmi.52.1","article-title":"Involvement of cathepsins in the invasion, metastasis and proliferation of cancer cells","volume":"52","author":"Nomura","year":"2005","journal-title":"J. Med. Investig."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/7\/1104\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T10:10:22Z","timestamp":1774865422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/7\/1104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,29]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cancers18071104"],"URL":"https:\/\/doi.org\/10.3390\/cancers18071104","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,29]]}}}