Abstract
Introduction
GEO- and TCGA-based data analysis suggested the differential expression of miR-29c in pancreatic cancer. However, limited data are available on the downstream mechanistic actions of miR-29c, which may fuel the in vitro and in vivo studies of pancreatic cancer.
Methods
The downstream target gene of miR-29c and the downstream ERK/MAPK pathway involved in pancreatic cancer were predicted by bioinformatics tools. Next, the expression of miR-29c and MAPK1 was determined in pancreatic cancer tissues and cells. After ectopic expression and depletion experiments in pancreatic cancer cells, oncogenic phenotypes of pancreatic cancer cells were tested by MTS assay, Transwell assay, and flow cytometry. Effects of miR-29c/MAPK1 on tumorigenic ability in vivo were evaluated in pancreatic cancer xenografts in nude mice.
Results
Through differential analysis, five pancreatic cancer-related miRNAs (hsa-miR-29c, hsa-miR-107, hsa-miR-324-3p, hsa-miR-375, and hsa-miR-210) were screened out, among which miR-29c was selected as the key miRNA related to prognosis of pancreatic cancer patients. miR-29c could target and inhibit MAPK1 to suppress the activation of ERK/MAPK pathway. miR-29c was downregulated in pancreatic cancer, and its high expression was related to the good prognosis of pancreatic cancer patients. Both in vitro and in vivo experiments demonstrated that restoration of miR-29c inhibited oncogenic phenotypes of pancreatic cancer cells, as well as repressed tumorigenic ability of pancreatic cancer cells in nude mice.
Conclusions
Taken together, we unveil a novel miR-29c/MAPK1/ERK/MAPK axis that suppresses pancreatic cancer both in vitro and in vivo.
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Availability of data and materials
The data that support the findings of this study are available on request from the corresponding author upon reasonable request.
References
Meng H, Guo K, Zhang Y. Effects of lncRNA LINC01320 on proliferation and migration of pancreatic cancer cells through targeted regulation of miR-324-3p. J Healthc Eng. 2021;2021:4125432.
Torphy RJ, Fujiwara Y, Schulick RD. Pancreatic cancer treatment: better, but a long way to go. Surg Today. 2020;50:1117–25.
Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, et al. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Mol Cancer. 2020;19:50.
Ye Z, Zhuo Q, Hu Q, Xu X, Mengqi L, Zhang Z, et al. FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells. Redox Biol. 2021;38:101807.
Xu X, Yu Y, Zong K, Lv P, Gu Y. Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway. J Exp Clin Cancer Res. 2019;38:497.
Rawat M, Kadian K, Gupta Y, Kumar A, Chain PSG, Kovbasnjuk O, et al. MicroRNA in pancreatic cancer: from biology to therapeutic potential. Genes (Basel). 2019;10(10):752.
Meng Q, Liang C, Hua J, Zhang B, Liu J, Zhang Y, et al. A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: functional validation and clinical significance. Theranostics. 2020;10:3967–79.
Lu Y, Hu J, Sun W, Li S, Deng S, Li M. MiR-29c inhibits cell growth, invasion, and migration of pancreatic cancer by targeting ITGB1. Onco Targets Ther. 2016;9:99–109.
Lu Y, Tang L, Zhang Z, Li S, Liang S, Ji L, et al. Long noncoding RNA TUG1/miR-29c axis affects cell proliferation, invasion, and migration in human pancreatic cancer. Dis Markers. 2018;2018:6857042.
Huang L, Hu C, Cao H, Wu X, Wang R, Lu H, et al. MicroRNA-29c increases the chemosensitivity of pancreatic cancer cells by inhibiting USP22 mediated autophagy. Cell Physiol Biochem. 2018;47:747–58.
Jiang J, Yu C, Chen M, Zhang H, Tian S, Sun C. Reduction of miR-29c enhances pancreatic cancer cell migration and stem cell-like phenotype. Oncotarget. 2015;6:2767–78.
Daoud AZ, Mulholland EJ, Cole G, McCarthy HO. MicroRNAs in pancreatic cancer: biomarkers, prognostic, and therapeutic modulators. BMC Cancer. 2019;19:1130.
Zhang ZY, Gao XH, Ma MY, Zhao CL, Zhang YL, Guo SS. CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis. Sci Rep. 2020;10:9024.
Botta GP, Reginato MJ, Reichert M, Rustgi AK, Lelkes PI. Constitutive K-RasG12D activation of ERK2 specifically regulates 3D invasion of human pancreatic cancer cells via MMP-1. Mol Cancer Res. 2012;10:183–96.
Liu Z, Lu J, Fang H, Sheng J, Cui M, Yang Y, et al. m6A modification-mediated DUXAP8 regulation of malignant phenotype and chemotherapy resistance of hepatocellular carcinoma through miR-584-5p/MAPK1/ERK pathway axis. Front Cell Dev Biol. 2021;9:783385.
Huang L, Chen S, Fan H, Ji D, Chen C, Sheng W. GINS2 promotes EMT in pancreatic cancer via specifically stimulating ERK/MAPK signaling. Cancer Gene Ther. 2021;28:839–49.
Sheng W, Chen C, Dong M, Wang G, Zhou J, Song H, et al. Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway. Cell Death Dis. 2017;8:e3147.
Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–60.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.
Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021;18:493–502.
Lan B, Zeng S, Grutzmann R, Pilarsky C. The role of exosomes in pancreatic cancer. Int J Mol Sci. 2019;20:4332.
Ariston Gabriel AN, Wang F, Jiao Q, Yvette U, Yang X, Al-Ameri SA, et al. The involvement of exosomes in the diagnosis and treatment of pancreatic cancer. Mol Cancer. 2020;19:132.
Abreu FB, Liu X, Tsongalis GJ. miRNA analysis in pancreatic cancer: the dartmouth experience. Clin Chem Lab Med. 2017;55:755–62.
Ye H, Zhou Q, Zheng S, Li G, Lin Q, Ye L, et al. FEZF1-AS1/miR-107/ZNF312B axis facilitates progression and Warburg effect in pancreatic ductal adenocarcinoma. Cell Death Dis. 2018;9:34.
Liu G, Shao C, Li A, Zhang X, Guo X, Li J. Diagnostic value of plasma miR-181b, miR-196a, and miR-210 combination in pancreatic cancer. Gastroenterol Res Pract. 2020;2020:6073150.
Yonemori K, Seki N, Kurahara H, Osako Y, Idichi T, Arai T, et al. ZFP36L2 promotes cancer cell aggressiveness and is regulated by antitumor microRNA-375 in pancreatic ductal adenocarcinoma. Cancer Sci. 2017;108:124–35.
Xu M, Li J, Wang X, Meng S, Shen J, Wang S, et al. MiR-22 suppresses epithelial-mesenchymal transition in bladder cancer by inhibiting snail and MAPK1/Slug/vimentin feedback loop. Cell Death Dis. 2018;9:209.
Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019;25:628–40.
Funding
This work is supported by Health Commission of Hebei Province (20220991).
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HS: conceived and designed research. NZ: performed experiments. CS: interpreted results of experiments. ZL: analyzed data. SH: prepared figures. HS and NZ: drafted paper. CS, ZL and SH: edited and revised manuscript. All authors read and approved final version of manuscript.
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Our study protocol was approved by the Ethics Committee of The Second Hospital of Hebei Medical University, and we collected written informed consent from all participants or their guardians. The animal experiment was also approved by the Ethics Committee of The Second Hospital of Hebei Medical University.
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12094_2022_2991_MOESM1_ESM.jpg
Figure S1 Correlation between 5 differentially expressed miRNAs and the prognosis of pancreatic cancer patients. A, Correlation between miR-29c and prognosis of pancreatic cancer patients. B, Correlation between miR-375 and prognosis of pancreatic cancer patients. C, Correlation between miR-107 and prognosis of pancreatic cancer patients. D, Correlation between miR-324 and prognosis of pancreatic cancer patients. E, Correlation between miR-210 and prognosis of pancreatic cancer patients (JPG 1106 KB)
12094_2022_2991_MOESM2_ESM.jpg
Figure S2 Correlation between MAPK1 expression and the prognosis of pancreatic cancer patients analyzed by TCGA database. A, MAPK1 expression in pancreatic cancer tissues and normal pancreatic tissues. B, Correlation between MAPK1 at different levels and prognosis of pancreatic cancer patients (JPG 247 KB)
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Si, H., Zhang, N., Shi, C. et al. Tumor-suppressive miR-29c binds to MAPK1 inhibiting the ERK/MAPK pathway in pancreatic cancer. Clin Transl Oncol 25, 803–816 (2023). https://doi.org/10.1007/s12094-022-02991-9
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DOI: https://doi.org/10.1007/s12094-022-02991-9