{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:29:40Z","timestamp":1785421780137,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","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":"publisher","award":["82472662"],"award-info":[{"award-number":["82472662"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82472662"],"award-info":[{"award-number":["82472662"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Noncommunicable Chronic Diseases","award":["2023ZD0502003"],"award-info":[{"award-number":["2023ZD0502003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background:\u00a0PPP1R1B has been implicated in tumor progression in several malignancies; however, population-level genetic evidence supporting its role in intrahepatic cholangiocarcinoma (ICC) remains limited. This study aimed to investigate the association between PPP1R1B and ICC risk and prognosis using genetic and multi-omics analyses. Methods: Multiple public datasets were integrated, including finn-b-C3_LIVER_INTRAHEPATIC_BILE_DUCTS, ebi-a-GCST90018583, eqtl-a-ENSG00000131771, GSE138709, The Cancer Genome Atlas (TCGA)-ICC, and FU-iCCA. Two-sample Mendelian randomization (MR) was performed to evaluate the genetic association between PPP1R1B expression and ICC risk. PPP1R1B expression patterns were further characterized using single-cell and bulk transcriptomic analyses. Expression validation was conducted using TCGA-ICC data and tissue microarray immunohistochemistry. Survival analyses were performed using the FU-iCCA cohort and institutional clinical samples. Results: MR analysis identified PPP1R1B as significantly associated with increased ICC risk (p &lt; 0.05, OR &gt; 1), and sensitivity analyses supported the robustness of the results. Single-cell analysis demonstrated enrichment of PPP1R1B expression in malignant cell populations. Bulk transcriptomic datasets and immunohistochemical validation confirmed elevated PPP1R1B expression in tumor tissues. High PPP1R1B expression was significantly associated with poorer overall survival. Conclusions: Genetic and multi-omics evidence supports PPP1R1B as a risk-associated and potential prognostic biomarker in ICC, providing a translational genomics framework for future biomarker development. These findings complement previously reported functional studies and strengthen the biological relevance of PPP1R1B in ICC.<\/jats:p>","DOI":"10.3390\/genes17080868","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T16:11:56Z","timestamp":1785168716000},"page":"868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mendelian Randomization and Single-Cell Transcriptomic Analyses Implicate PPP1R1B as a Risk Factor of Intrahepatic Cholangiocarcinoma"],"prefix":"10.3390","volume":"17","author":[{"given":"Zhuomiaoyu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumei","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/j.jhep.2022.07.022","article-title":"Current epidemiology of cholangiocarcinoma in Western countries","volume":"77","author":"Vithayathil","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_2","first-page":"198","article-title":"Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians","volume":"73","author":"Moris","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1111\/liv.15392","article-title":"Bcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma","volume":"42","author":"Mock","year":"2022","journal-title":"Liver Int."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2023). EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J. Hepatol., 79, 181\u2013208.","DOI":"10.1016\/j.jhep.2023.09.006"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/301069a0","article-title":"A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions","volume":"301","author":"Walaas","year":"1983","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1053\/j.gastro.2020.07.046","article-title":"Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis","volume":"159","author":"Tiwari","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/45251","article-title":"Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons","volume":"402","author":"Bibb","year":"1999","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.bcp.2018.12.008","article-title":"Darpp-32 and t-Darpp protein products of PPP1R1B: Old dogs with new tricks","volume":"160","author":"Avanes","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.neubiorev.2018.02.007","article-title":"Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations","volume":"87","author":"Heckman","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_11","first-page":"4061","article-title":"Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP","volume":"62","author":"Smith","year":"2002","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"a040501","DOI":"10.1101\/cshperspect.a040501","article-title":"Mendelian Randomization: Concepts and Scope","volume":"12","author":"Richmond","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1038\/s41588-021-00945-5","article-title":"An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci","volume":"53","author":"Mountjoy","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chen, L., Fan, Z., Sun, X., Qiu, W., Mu, W., Chai, K., Cao, Y., Wang, G., and Lv, G. (2022). Examination on the risk factors of cholangiocarcinoma: A Mendelian randomization study. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.900424"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1111\/liv.16015","article-title":"Integrative analysis reveals different feature of intrahepatic cholangiocarcinoma subtypes","volume":"44","author":"Chen","year":"2024","journal-title":"Liver Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ccell.2021.12.006","article-title":"Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma","volume":"40","author":"Dong","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/gepi.22295","article-title":"A comparison of robust Mendelian randomization methods using summary data","volume":"44","author":"Slob","year":"2020","journal-title":"Genet. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s43586-021-00092-5","article-title":"Mendelian randomization","volume":"2","author":"Sanderson","year":"2022","journal-title":"Nat. Rev. Methods Primers"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells","volume":"32","author":"Trapnell","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100226","DOI":"10.1016\/j.jhepr.2021.100226","article-title":"Cell of origin in biliary tract cancers and clinical implications","volume":"3","author":"Moeini","year":"2021","journal-title":"JHEP Rep. Innov. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.molmed.2025.01.008","article-title":"Molecular subtypes of intrahepatic cholangiocarcinoma","volume":"31","author":"Zhu","year":"2025","journal-title":"Trends Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1158\/1078-0432.CCR-17-0824","article-title":"t-Darpp Activates IGF-1R Signaling to Regulate Glucose Metabolism in Trastuzumab-Resistant Breast Cancer Cells","volume":"24","author":"Lenz","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1038\/onc.2013.472","article-title":"PPP1R1B-STARD3 chimeric fusion transcript in human gastric cancer promotes tumorigenesis through activation of PI3K\/AKT signaling","volume":"33","author":"Yun","year":"2014","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1158\/1541-7786.MCR-12-0243-T","article-title":"Regulation of CXCR4-mediated invasion by DARPP-32 in gastric cancer cells","volume":"11","author":"Zhu","year":"2013","journal-title":"Mol. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13599","DOI":"10.1002\/cam4.6057","article-title":"Inflammatory bowel disease increases the risk of hepatobiliary pancreatic cancer: A two-sample Mendelian randomization analysis of European and East Asian populations","volume":"12","author":"Huang","year":"2023","journal-title":"Cancer Med."},{"key":"ref_31","first-page":"221","article-title":"Association of gut microbiome and primary liver cancer: A two-sample Mendelian randomization and case-control study","volume":"43","author":"Ma","year":"2023","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"213","DOI":"10.9738\/INTSURG-D-14-00022.1","article-title":"High Expression of DARPP-32 in Colorectal Cancer Is Associated With Liver Metastases and Predicts Survival for Dukes A and B Patients: Results of a Pilot Study","volume":"100","author":"Kopljar","year":"2015","journal-title":"Int. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.canlet.2018.11.014","article-title":"The PEAK1-PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2\/PI3K\/Akt signalling in colorectal cancer","volume":"442","author":"Ding","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.18632\/oncotarget.3465","article-title":"MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN","volume":"6","author":"Wang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17631","DOI":"10.18632\/oncotarget.7268","article-title":"DARPP-32: From neurotransmission to cancer","volume":"7","author":"Belkhiri","year":"2016","journal-title":"Oncotarget"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/868\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T16:19:09Z","timestamp":1785169149000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/868"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,25]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080868"],"URL":"https:\/\/doi.org\/10.3390\/genes17080868","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,25]]}}}