Abstract
This study combined with bioinformatics analysis and investigated the expression pattern of miR-181b-5p, as well as explored its role and mechanism in cholangiocarcinoma (CCA or CHOL). Several bioinformatics databases were used to analyze the expression of miR-181b and the enrichment of miR-181b in biological activities and biological pathways in CCA. The RT-qPCR analysis was used to examine the expression levels of miR-181b-5p. A receiver operation characteristics (ROC) curve analysis and the Kaplan–Meier survival assay were conducted to validate the diagnostic and prognostic implication of miR-181b-5p. Cell experiments were used to explore the possible functional role of miR-181b-5p in CCA progression. The bioinformatics assay was used to predict the target gene of miR-181b-5p and Western blot was used to confirm the related signaling pathway. The bioinformatics analysis results suggest that miR-181b-5p was highly expressed in cholangiocarcinoma and its expression was negatively related to PARK2 expression in CCA tissues. miR-181b-5p expression in the serum and tissues was upregulated and associated with lymph node metastasis and TNM stage. Increased expression of miR-181b-5p had relatively high diagnostic accuracy and showed poor prognosis in CCA patients. In addition, miR-181b-5p overexpression enhanced cell proliferation, migration, and invasion by targeting PARK2. Overexpression of miR-181b-5p activated the PI3K/AKT signaling pathway, while knockdown of miR-181b-5p suppressed the signaling pathway. Increased expression of miR-181b-5p in CCA may be a potential diagnostic or/and prognostic indicator for CCA patients. The present data indicated miR-181b-5p acted as an oncogene in CCA through promoting tumor cell proliferation, migration, and invasion of CCA via the PTEN/PI3K/AKT signaling pathway by targeting PARK2, which might be a promising therapeutic target or biomarker for CCA.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF (2008) The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 8:187–198. https://doi.org/10.2174/156800908784293659
Chen H, Chen Q, Fang M, Mi Y (2010) microRNA-181b targets MLK2 in HL-60 cells. Sci China Life Sci 53:101–106. https://doi.org/10.1007/s11427-010-0002-y
Chen S, Liu Y, Wang Y, Xue Z (2019) LncRNA CCAT1 promotes colorectal cancer tumorigenesis via a miR-181b-5p/TUSC3 Axis. Onco Targets Ther 12:9215–9225. https://doi.org/10.2147/ott.s216718
Deng Y, Chen Y (2017) Increased expression of miR-29a and its prognostic significance in patients with cholangiocarcinoma. Oncol Res Treat 40:128–132. https://doi.org/10.1159/000455869
Duan H et al (2019) PARK2 suppresses proliferation and tumorigenicity in non-small cell lung cancer. Front Oncol 9:790. https://doi.org/10.3389/fonc.2019.00790
Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114. https://doi.org/10.1038/nrg2290
Gao J et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling 6:pl1. https://doi.org/10.1126/scisignal.2004088
Gao Y, Xu Z, Yuan F, Li M (2018) Correlation of expression levels of micro ribonucleic Ccid-10b (miR-10b) and micro ribonucleic acid-181b (miR-181b) with gastric cancer and its diagnostic significance. Med Sci Monitor 24:7988–7995. https://doi.org/10.12659/msm.910809
Guo JX, Tao QS, Lou PR, Chen XC, Chen J, Yuan GB (2012) miR-181b as a potential molecular target for anticancer therapy of gastric neoplasms. Asian Pac J Cancer Prev 13:2263–2267. https://doi.org/10.7314/apjcp.2012.13.5.2263
Gupta A et al (2017a) PARK2 depletion connects energy and oxidative stress to PI3K/Akt activation via PTEN S-nitrosylation. Mol Cell 65:999–1013.e1017. https://doi.org/10.1016/j.molcel.2017.02.019
Gupta A, Anjomani-Virmouni S, Koundouros N, Poulogiannis G (2017b) PARK2 loss promotes cancer progression via redox-mediated inactivation of PTEN. Mol Cell Oncol 4:e1329692. https://doi.org/10.1080/23723556.2017.1329692
Kajiwara K et al (2016) Aberrant miR-181b-5p and miR-486–5p expression in serum and tissue of non-small cell lung cancer. PLoS ONE 591:338–343. https://doi.org/10.1016/j.gene.2016.06.014
Khan SA, Tavolari S (2019) Cholangiocarcinoma: epidemiology and risk factors. Linver Int 39(Suppl 1):19–31. https://doi.org/10.1111/liv.14095
Khan SA et al (2012) Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut 61:1657–1669. https://doi.org/10.1136/gutjnl-2011-301748
Labib PL, Goodchild G, Pereira SP (2019) Molecular pathogenesis of cholangiocarcinoma. BMC Cancer 19:185. https://doi.org/10.1186/s12885-019-5391-0
Lei Z et al (2018) PARK2 inhibits osteosarcoma cell growth through the JAK2/STAT3/VEGF signaling pathway. Cell Death Dis 9:375. https://doi.org/10.1038/s41419-018-0401-8
Li C et al (2018) PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism developmental. Cell 46:441–455. https://doi.org/10.1016/j.devcel.2018.07.012
Li JH, Liu S, Zhou H, Qu LH, Yang JH (2014) starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res 42:D92–D97. https://doi.org/10.1093/nar/gkt1248
Mu X, Pradere JP, Affo S, Dapito DH, Friedman R, Lefkovitch JH, Schwabe RF (2016) Epithelial transforming growth factor-beta signaling does not contribute to liver fibrosis but protects mice from cholangiocarcinoma. Gastroenterology 150:720–733. https://doi.org/10.1053/j.gastro.2015.11.039
Nagy A, Lanczky A, Menyhart O, Gyorffy B (2018) Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Reports 8:9227. https://doi.org/10.1038/s41598-018-27521-y
Pan X, Feng J, Zhu Z, Yao L, Ma S, Hao B, Zhang G (2018) A positive feedback loop between miR-181b and STAT3 that affects Warburg effect in colon cancer via regulating PIAS3 expression. J Cell Mol Med 22:5040–5049. https://doi.org/10.1111/jcmm.13786
Panarelli NC, Chen YT, Zhou XK, Kitabayashi N, Yantiss RK (2012) MicroRNA expression aids the preoperative diagnosis of pancreatic ductal adenocarcinoma. Pancreas 41:685–690. https://doi.org/10.1097/MPA.0b013e318243a905
Pathan M et al (2015) FunRich: an open access standalone functional enrichment and interaction network analysis tool. Proteomics 15:2597–2601. https://doi.org/10.1002/pmic.201400515
Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16:203–222. https://doi.org/10.1038/nrd.2016.246
Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z, You Y (2008) hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res 1236:185–193. https://doi.org/10.1016/j.brainres.2008.07.085
Tian F, Shen Y, Chen Z, Li R, Lu J, Ge Q (2016) Aberrant miR-181b-5p and miR-486–5p expression in serum and tissue of non-small cell lung cancer. Gene 591:338–343. https://doi.org/10.1016/j.gene.2016.06.014
Valero V 3rd, Cosgrove D, Herman JM, Pawlik TM (2012) Management of perihilar cholangiocarcinoma in the era of multimodal therapy. Expert Rev Gastroenterol Hepatol 6:481–495. https://doi.org/10.1586/egh.12.20
Vasaikar SV, Straub P, Wang J, Zhang B (2018) LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res 46:D956-d963. https://doi.org/10.1093/nar/gkx1090
Wan P et al (2018) miR-383 promotes cholangiocarcinoma cell proliferation, migration, and invasion through targeting IRF1. J Cell Biochem 119:9720–9729. https://doi.org/10.1002/jcb.27286
Wang JR, Liu B, Zhou L, Huang YX (2019) MicroRNA-124–3p suppresses cell migration and invasion by targeting ITGA3 signaling in bladder cancer. Cancer Biomark 24:159–172. https://doi.org/10.3233/cbm-182000
Xia Y, Gao Y (2014) MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2. Biochem Biophys Res Commun 447:446–451. https://doi.org/10.1016/j.bbrc.2014.04.027
Xia M, Liu CJ, Zhang Q, Guo AY (2019) GEDS: a gene expression display server for mRNAs, miRNAs and proteins. Cells 8:675. https://doi.org/10.3390/cells8070675
Zheng J, Wu C, Xu Z, Xia P, Dong P, Chen B, Yu F (2015) Hepatic stellate cell is activated by microRNA-181b via PTEN/Akt pathway. Mol Cell Biochem 398:1–9. https://doi.org/10.1007/s11010-014-2199-8
Zheng Y et al (2016) MiR-181b promotes chemoresistance in breast cancer by regulating Bim expression. Oncol Reports 35:683–690. https://doi.org/10.3892/or.2015.4417
Zhou GY, Pan CW, Jin LX, Zheng JJ, Yi YX (2016) Neoalbaconol inhibits cell growth of human cholangiocarcinoma cells by up-regulating PTEN. Am J Trans Res 8:496–505
Zhou MH, Zhou HW, Liu M, Sun JZ (2018) The role of miR-92b in cholangiocarcinoma patients. Int J Biol Markers 33:293–300. https://doi.org/10.1177/1724600817751524
Funding
This study was supported by the 900 Hospital Innovation Team Construction Special Funding (No. 2018Q06) for Zhe-long Jiang and (No. 2018J02) for He-jun Yang, The Key Project of Natural Science Foundation of Fujian Province (No. 2019Y0068) for Li-zhi Lv, and the Fujian Natural Science Foundation (Youth Innovation) Project (No. 2020J05299) for Rui-Sheng Ke; Xiamen Medical and Health Guiding Project Fund Project (No. 3502Z20209011) for Rui-Sheng Ke.
Author information
Authors and Affiliations
Contributions
Rui-Sheng Ke and Zhe-Long Jiang wrote the manuscript. Fu-Xing Zhang, He-Jun Yang, Li-Zhi Lv, and Yi Jiang contributed to the final manuscript. Zhe-Long Jiang, Li-Zhi Lv, and Rui-Sheng Ke verified and discussed the studies. Hong-Liang Zhan revised the manuscript. Rui-Sheng Ke, Fu-Xing Zhang, Si-Yu Zhang, Zhao-Hui Liu, and Yi Jiang participated in data analysis and interpretation. Li-Zhi Lv, Rui-Sheng Ke, Zhe-Long Jiang, and Yi Jiang edited and proofread the manuscript. Rui-sheng Ke and Li-zhi Lv supervised the study. All the authors approved final manuscript.
Corresponding authors
Ethics declarations
Competing Interest
The authors claim that they have no competing interest.
Ethical Approval
This study was approved by the Human Research Ethics Committee of 900 Hospital of the Joint Logistics Team (Fuzhou, China).
Consent to Participate
The written informed consent was obtained from all participants.
Consent for Publication
All participants provided written informed consent for publication of the data and any associated images.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Jiang, ZL., Zhang, FX., Zhan, HL. et al. miR-181b-5p Promotes the Progression of Cholangiocarcinoma by Targeting PARK2 via PTEN/PI3K/AKT Signaling Pathway. Biochem Genet 60, 223–240 (2022). https://doi.org/10.1007/s10528-021-10084-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10528-021-10084-5