HNRNPA2/B1 is Upregulated in Endocrine-resistant LCC9 Breast Cancer Cells and Alters the MiRNA Transcriptome when Overexpressed in MCF-7 Cells

Overview

Journal Sci Rep

Specialty Science

Date 2019 Jul 3

PMID 31263129

Citations 61

Authors

Carolyn M Klinge

Kellianne M Piell

Christine Schaner Tooley

Eric C Rouchka

Affiliations

Soon will be listed here.

Abstract

MicroRNAs are dysregulated in breast cancer. Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2/B1) is a reader of the N(6)-methyladenosine (m6A) mark in primary-miRNAs (pri-miRNAs) and promotes DROSHA processing to precursor-miRNAs (pre-miRNAs). We examined the expression of writers, readers, and erasers of m6A and report that HNRNPA2/B1 expression is higher in tamoxifen-resistant LCC9 breast cancer cells as compared to parental, tamoxifen-sensitive MCF-7 cells. To examine how increased expression of HNRNPA2/B1 affects miRNA expression, HNRNPA2/B1 was transiently overexpressed (~5.4-fold) in MCF-7 cells for whole genome miRNA profiling (miRNA-seq). 148 and 88 miRNAs were up- and down-regulated, respectively, 48 h after transfection and 177 and 172 up- and down-regulated, respectively, 72 h after transfection. MetaCore Enrichment analysis identified progesterone receptor action and transforming growth factor β (TGFβ) signaling via miRNA in breast cancer as pathways downstream of the upregulated miRNAs and TGFβ signaling via SMADs and Notch signaling as pathways of the downregulated miRNAs. GO biological processes for mRNA targets of HNRNPA2/B1-regulated miRNAs included response to estradiol and cell-substrate adhesion. qPCR confirmed HNRNPA2B1 downregulation of miR-29a-3p, miR-29b-3p, and miR-222 and upregulation of miR-1266-5p, miR-1268a, miR-671-3p. Transient overexpression of HNRNPA2/B1 reduced MCF-7 sensitivity to 4-hydroxytamoxifen and fulvestrant, suggesting a role for HNRNPA2/B1 in endocrine-resistance.

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References

Sachdeva M, Wu H, Ru P, Hwang L, Trieu V, Mo Y . MicroRNA-101-mediated Akt activation and estrogen-independent growth. Oncogene. 2010; 30(7):822-31. DOI: 10.1038/onc.2010.463. View

Papachristopoulou G, Papadopoulos E, Nonni A, Rassidakis G, Scorilas A . Expression Analysis of miR-29b in Malignant and Benign Breast Tumors: A Promising Prognostic Biomarker for Invasive Ductal Carcinoma With a Possible Histotype-Related Expression Status. Clin Breast Cancer. 2018; 18(4):305-312.e3. DOI: 10.1016/j.clbc.2017.11.007. View

Tribollet V, Barenton B, Kroiss A, Vincent S, Zhang L, Forcet C . miR-135a Inhibits the Invasion of Cancer Cells via Suppression of ERRα. PLoS One. 2016; 11(5):e0156445. PMC: 4881992. DOI: 10.1371/journal.pone.0156445. View

Giulietti M, Occhipinti G, Principato G, Piva F . Identification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis. Cell Oncol (Dordr). 2017; 40(2):181-192. DOI: 10.1007/s13402-017-0315-y. View

Zhang S, Liu X, Liu J, Guo H, Xu H, Zhang G . PGC-1 alpha interacts with microRNA-217 to functionally regulate breast cancer cell proliferation. Biomed Pharmacother. 2016; 85:541-548. DOI: 10.1016/j.biopha.2016.11.062. View

Mangolini A, Ferracin M, Zanzi M, Saccenti E, Ebnaof S, Poma V . Diagnostic and prognostic microRNAs in the serum of breast cancer patients measured by droplet digital PCR. Biomark Res. 2015; 3:12. PMC: 4483205. DOI: 10.1186/s40364-015-0037-0. View

Fu L, Amato N, Wang P, McGowan S, Niedernhofer L, Wang Y . Simultaneous Quantification of Methylated Cytidine and Adenosine in Cellular and Tissue RNA by Nano-Flow Liquid Chromatography-Tandem Mass Spectrometry Coupled with the Stable Isotope-Dilution Method. Anal Chem. 2015; 87(15):7653-9. PMC: 4711271. DOI: 10.1021/acs.analchem.5b00951. View

Yang F, Zhang W, Shen Y, Guan X . Identification of dysregulated microRNAs in triple-negative breast cancer (review). Int J Oncol. 2015; 46(3):927-32. DOI: 10.3892/ijo.2015.2821. View

Yu F, Tu Y, Deng Y, Guo C, Ning J, Zhu Y . MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2. Cancer Biol Ther. 2016; 17(11):1149-1157. PMC: 5137502. DOI: 10.1080/15384047.2016.1235661. View

10.

Pan T . N6-methyl-adenosine modification in messenger and long non-coding RNA. Trends Biochem Sci. 2013; 38(4):204-9. PMC: 3608796. DOI: 10.1016/j.tibs.2012.12.006. View

11.

Nguyen E, Balas M, Griffin A, Roberts J, Johnson A . Global profiling of hnRNP A2/B1-RNA binding on chromatin highlights LncRNA interactions. RNA Biol. 2018; 15(7):901-913. PMC: 6161681. DOI: 10.1080/15476286.2018.1474072. View

12.

Yu S, Liu X, Zhang Y, Li J, Chen S, Zheng H . Circulating microRNA124-3p, microRNA9-3p and microRNA196b-5p may be potential signatures for differential diagnosis of thyroid nodules. Oncotarget. 2016; 7(51):84165-84177. PMC: 5356652. DOI: 10.18632/oncotarget.12389. View

13.

Liu D, Zhang N, Zhang X, Qin M, Dong Y, Jin L . MiR-410 Down-Regulates the Expression of Interleukin-10 by Targeting STAT3 in the Pathogenesis of Systemic Lupus Erythematosus. Cell Physiol Biochem. 2016; 39(1):303-15. DOI: 10.1159/000445625. View

14.

Xiong H, Ni Z, Jiang S, Li X, He J, Gong W . LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells. Oncogene. 2017; 36(25):3528-3540. DOI: 10.1038/onc.2016.521. View

15.

Wang Z, Zhang H, Zhang P, Li J, Shan Z, Teng W . Upregulation of miR-2861 and miR-451 expression in papillary thyroid carcinoma with lymph node metastasis. Med Oncol. 2013; 30(2):577. DOI: 10.1007/s12032-013-0577-9. View

16.

Miller T, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro C . MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 2008; 283(44):29897-903. PMC: 2573063. DOI: 10.1074/jbc.M804612200. View

17.

Mody H, Hung S, Alsaggar M, Griffin J, Govindarajan R . Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p. Mol Cancer Res. 2016; 14(11):1124-1135. PMC: 5107158. DOI: 10.1158/1541-7786.MCR-16-0083. View

18.

Cheng D, He H, Liang B . A three-microRNA signature predicts clinical outcome in breast cancer patients. Eur Rev Med Pharmacol Sci. 2018; 22(19):6386-6395. DOI: 10.26355/eurrev_201810_16051. View

19.

Turashvili G, Lightbody E, Tyryshkin K, SenGupta S, Elliott B, Madarnas Y . Novel prognostic and predictive microRNA targets for triple-negative breast cancer. FASEB J. 2018; :fj201800120R. DOI: 10.1096/fj.201800120R. View

20.

Ahmad A, Zhang W, Wu M, Tan S, Zhu T . Tumor-suppressive miRNA-135a inhibits breast cancer cell proliferation by targeting ELK1 and ELK3 oncogenes. Genes Genomics. 2018; 40(3):243-251. DOI: 10.1007/s13258-017-0624-6. View