MicroRNA-199a and -214 As Potential Therapeutic Targets in Pancreatic Stellate Cells in Pancreatic Tumor

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Feb 27

PMID 26918939

Citations 47

Authors

Praneeth R Kuninty

Linda Bojmar

Vegard Tjomsland

Marie Larsson

Gert Storm

Arne Ostman

Per Sandstrom

Jai Prakash

Affiliations

Soon will be listed here.

Abstract

Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs and TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a/-214 using hairpin inhibitors significantly inhibited TGFβ-induced differentiation markers (e.g. α-SMA, collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs attained smaller size with hPSCs transfected with anti-miR-199a/-214 compared to control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell growth and endothelial cell tube formation. Interestingly, these inductions were abrogated in hPSCs transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in pancreatic cancer.

Citing Articles

Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies.

Wang H, Qi L, Han H, Li X, Han M, Xing L Acta Pharm Sin B. 2024; 14(11):4756-4775.

PMID: 39664424 PMC: 11628839. DOI: 10.1016/j.apsb.2024.07.007.

Exosomal miR-199a-3p Secreted From Cancer-Associated Adipocytes Promotes Pancreatic Cancer Progression.

Noda K, Sato Y, Okada Y, Nishida K, Kawano Y, Tanahashi T Cancer Med. 2024; 13(20):e70265.

PMID: 39431622 PMC: 11492146. DOI: 10.1002/cam4.70265.

Hsa_circ_0014784-induced YAP1 promoted the progression of pancreatic cancer by sponging miR-214-3p.

Liu B, Gong Y, Jiang Q, Wu S, Han B, Chen F Cell Cycle. 2023; 22(13):1583-1596.

PMID: 37318258 PMC: 10361141. DOI: 10.1080/15384101.2023.2222519.

Epigenetic regulation and therapeutic targets in the tumor microenvironment.

Xie Z, Zhou Z, Yang S, Zhang S, Shao B Mol Biomed. 2023; 4(1):17.

PMID: 37273004 PMC: 10241773. DOI: 10.1186/s43556-023-00126-2.

Correlation Between Endoglin and Malignant Phenotype in Human Melanoma Cells: Analysis of hsa-mir-214 and hsa-mir-370 in Cells and Their Extracellular Vesicles.

Ruiz-Llorente L, Ruiz-Rodriguez M, Savini C, Gonzalez-Munoz T, Riveiro-Falkenbach E, Rodriguez-Peralto J Adv Exp Med Biol. 2023; 1408:253-272.

PMID: 37093432 DOI: 10.1007/978-3-031-26163-3_14.

References

Gore J, Korc M . Pancreatic cancer stroma: friend or foe?. Cancer Cell. 2014; 25(6):711-2. PMC: 4821630. DOI: 10.1016/j.ccr.2014.05.026. View

Azzouzi H, Leptidis S, Dirkx E, Hoeks J, van Bree B, Brand K . The hypoxia-inducible microRNA cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metab. 2013; 18(3):341-54. DOI: 10.1016/j.cmet.2013.08.009. View

Apte M, Wilson J . Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells. J Gastroenterol Hepatol. 2012; 27 Suppl 2:69-74. DOI: 10.1111/j.1440-1746.2011.07000.x. View

Vonlaufen A, Joshi S, Qu C, Phillips P, Xu Z, Parker N . Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 2008; 68(7):2085-93. DOI: 10.1158/0008-5472.CAN-07-2477. View

Schuler M, Maurer U, Goldstein J, Breitenbucher F, Hoffarth S, Waterhouse N . p53 triggers apoptosis in oncogene-expressing fibroblasts by the induction of Noxa and mitochondrial Bax translocation. Cell Death Differ. 2003; 10(4):451-60. DOI: 10.1038/sj.cdd.4401180. View

Omary M, Lugea A, Lowe A, Pandol S . The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest. 2007; 117(1):50-9. PMC: 1716214. DOI: 10.1172/JCI30082. View

Kiaris H, Chatzistamou I, Trimis G, Frangou-Plemmenou M, Pafiti-Kondi A, Kalofoutis A . Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis. Cancer Res. 2005; 65(5):1627-30. DOI: 10.1158/0008-5472.CAN-04-3791. View

Kwon J, Nabinger S, Vega Z, Sahu S, Alluri R, Abdul-Sater Z . Pathophysiological role of microRNA-29 in pancreatic cancer stroma. Sci Rep. 2015; 5:11450. PMC: 4476113. DOI: 10.1038/srep11450. View

Sicard F, Gayral M, Lulka H, Buscail L, Cordelier P . Targeting miR-21 for the therapy of pancreatic cancer. Mol Ther. 2013; 21(5):986-94. PMC: 3666633. DOI: 10.1038/mt.2013.35. View

10.

Bansal R, Post E, Proost J, de Jager-Krikken A, Poelstra K, Prakash J . PEGylation improves pharmacokinetic profile, liver uptake and efficacy of Interferon gamma in liver fibrosis. J Control Release. 2011; 154(3):233-40. DOI: 10.1016/j.jconrel.2011.05.027. View

11.

Zheng H, Ying H, Yan H, Kimmelman A, Hiller D, Chen A . Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol. 2009; 73:427-37. DOI: 10.1101/sqb.2008.73.047. View

12.

Kurose K, Gilley K, Matsumoto S, Watson P, Zhou X, Eng C . Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet. 2002; 32(3):355-7. DOI: 10.1038/ng1013. View

13.

Apte M, Pirola R, Wilson J . Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol. 2012; 3:344. PMC: 3428781. DOI: 10.3389/fphys.2012.00344. View

14.

Bachem M, Schneider E, Gross H, Weidenbach H, Schmid R, Menke A . Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998; 115(2):421-32. DOI: 10.1016/s0016-5085(98)70209-4. View

15.

Giovannetti E, Funel N, Peters G, Del Chiaro M, Erozenci L, Vasile E . MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Res. 2010; 70(11):4528-38. DOI: 10.1158/0008-5472.CAN-09-4467. View

16.

Apte M, Haber P, Applegate T, Norton I, McCaughan G, Korsten M . Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998; 43(1):128-33. PMC: 1727174. DOI: 10.1136/gut.43.1.128. View

17.

Masamune A, Nakano E, Hamada S, Takikawa T, Yoshida N, Shimosegawa T . Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. Scand J Gastroenterol. 2014; 49(3):323-31. DOI: 10.3109/00365521.2013.876447. View

18.

Rhim A, Oberstein P, Thomas D, Mirek E, Palermo C, Sastra S . Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014; 25(6):735-47. PMC: 4096698. DOI: 10.1016/j.ccr.2014.04.021. View

19.

Lino Cardenas C, Henaoui I, Courcot E, Roderburg C, Cauffiez C, Aubert S . miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1. PLoS Genet. 2013; 9(2):e1003291. PMC: 3573122. DOI: 10.1371/journal.pgen.1003291. View

20.

Xu Z, Vonlaufen A, Phillips P, Fiala-Beer E, Zhang X, Yang L . Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol. 2010; 177(5):2585-96. PMC: 2966814. DOI: 10.2353/ajpath.2010.090899. View