Comparing MicroRNA Profilings of Purified HER-2-Negative and HER-2-Positive Cells Validates MiR-362-5p/Sema3A As Characteristic Molecular Change in Triple-Negative Breast Cancers

Overview

Journal Dis Markers

Publisher Wiley

Specialty Biochemistry

Date 2020 Jan 14

PMID 31929841

Citations 6

Authors

Xiaoqing Zhang

Qi He

Leiqin Sun

Yanfei Zhang

Shengying Qin

Junwei Fan

Jianfeng Wang

Affiliations

Soon will be listed here.

Abstract

Background: HER-2 is a key molecule serving as the therapeutic target, prognostic biomarker, and classification marker in breast cancer. Accurate microRNA profilings had not been conducted in purified tumor cells of HER-2-negative and HER-2-positive tissue specimens obtained from breast cancer patients.

Methods: (i) Differential expression microRNA discovery using laser capture microdissection- (LCM-) assisted specimen preparation and microRNA array chips on HER-2 overexpressing and triple-negative breast carcinoma (TNBC) subtype tissues, (ii) differential expression microRNA validation by quantitative real-time PCR, and (iii) independent validation on tissue microarray.

Results: Five microRNAs (miR-20a-5p, miR-221-3p, miR-362-5p, miR-502-3p, and miR-222-3p) were screened and validated as upregulated microRNAs in TNBC cells comparing to HER-2 overexpressing cells using a microRNA array (5 cases in each group) and quantitative real-time PCR (20 cases in each group). The expression difference of miR-362-5p had the most significant statistical significance ( = 0.0016) among the five microRNAs. The expression of miR-362-5p and its target gene Sema3A was further analyzed using in situ hybridization (ISH) and immunohistochemistry on standard tissue sections ( = 150). 70.8% of HER-2-negative cells showed moderate expression of miR-362-5p whereas 20.4% HER-2-negative cells correlated with strong expression of miR-362-5p ( < 0.0001). The proportion of patients with moderate/strong miR-362-5p expression in luminal, HER-2 overexpressing, and TNBC subtypes were 53.2%, 22.2%, and 74.3%, respectively ( = 0.0002). High miR-362-5p expressers had shorter overall survival in the univariate analysis ( = 0.046). There was a significant negative correlation between miR-362-5p and Sema3A expression ( < 0.0001). The patients with negative/weak Sema3A protein expression had poorer prognosis than those with moderate (HR: 3.723, = 0.021) or strong (HR: 3.966, = 0.013) Sema3A protein expression in the multivariate analysis.

Conclusions: miR-362-5p/Sema3A might provide a promising therapeutic pathway and represents a candidate therapeutic target of the TNBC subtype.

Citing Articles

Roles of miR-20a-5p in breast cancer based on the clinical and multi-omic (CAMO) cohort and in vitro studies.

Tylden E, Delgado A, Lukic M, Moi L, Rasmussen Busund L, Pedersen M Sci Rep. 2024; 14(1):25022.

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ER Negative Breast Cancer and miRNA: There Is More to Decipher Than What the Pathologist Can See!.

Chamandi G, El-Hajjar L, Kurdi A, Le Bras M, Nasr R, Lehmann-Che J Biomedicines. 2023; 11(8).

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Sema3A Alleviates the Malignant Behaviors of Gastric Cancer Cells by Inhibiting NRP-1.

Yang H, Zhou Y, Wang L, Lv M, Sun J, Luo Z Curr Mol Med. 2023; 24(7):931-939.

PMID: 37533240 DOI: 10.2174/1566524023666230801124826.

Role of MicroRNA-502-3p in Human Diseases.

Devara D, Choudhary Y, Kumar S Pharmaceuticals (Basel). 2023; 16(4).

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Alteration of miR-362-5p and miR-454-3p expression elicits diverse responses in breast cancer cell lines.

Aarthy R, Rao A, Patel K, Sridevi V, Rajkumar T, Gowda H Mol Biol Rep. 2021; 49(1):821-826.

PMID: 34727290 DOI: 10.1007/s11033-021-06873-1.

References

Gerson J, Skariah S, Denlinger C, Astsaturov I . Perspectives of HER2-targeting in gastric and esophageal cancer. Expert Opin Investig Drugs. 2017; 26(5):531-540. PMC: 5563845. DOI: 10.1080/13543784.2017.1315406. View

DeSantis C, Bray F, Ferlay J, Lortet-Tieulent J, Anderson B, Jemal A . International Variation in Female Breast Cancer Incidence and Mortality Rates. Cancer Epidemiol Biomarkers Prev. 2015; 24(10):1495-506. DOI: 10.1158/1055-9965.EPI-15-0535. View

Neufeld G, Mumblat Y, Smolkin T, Toledano S, Nir-Zvi I, Ziv K . The semaphorins and their receptors as modulators of tumor progression. Drug Resist Updat. 2016; 29:1-12. DOI: 10.1016/j.drup.2016.08.001. View

Rakha E, Green A . Molecular classification of breast cancer: what the pathologist needs to know. Pathology. 2017; 49(2):111-119. DOI: 10.1016/j.pathol.2016.10.012. View

Pernas S, Barroso-Sousa R, Tolaney S . Optimal treatment of early stage HER2-positive breast cancer. Cancer. 2018; 124(23):4455-4466. DOI: 10.1002/cncr.31657. View

Mohr A, Mott J . Overview of microRNA biology. Semin Liver Dis. 2015; 35(1):3-11. PMC: 4797991. DOI: 10.1055/s-0034-1397344. View

Pinzon N, Li B, Martinez L, Sergeeva A, Presumey J, Apparailly F . microRNA target prediction programs predict many false positives. Genome Res. 2017; 27(2):234-245. PMC: 5287229. DOI: 10.1101/gr.205146.116. View

Petrovic N, Ergun S, Isenovic E . Levels of MicroRNA Heterogeneity in Cancer Biology. Mol Diagn Ther. 2017; 21(5):511-523. DOI: 10.1007/s40291-017-0285-9. View

Fan L, Strasser-Weippl K, Li J, St Louis J, Finkelstein D, Yu K . Breast cancer in China. Lancet Oncol. 2014; 15(7):e279-89. DOI: 10.1016/S1470-2045(13)70567-9. View

10.

Mishra R, Thorat D, Soundararajan G, Pradhan S, Chakraborty G, Lohite K . Semaphorin 3A upregulates FOXO 3a-dependent MelCAM expression leading to attenuation of breast tumor growth and angiogenesis. Oncogene. 2014; 34(12):1584-95. DOI: 10.1038/onc.2014.79. View

11.

Bracken C, Scott H, Goodall G . A network-biology perspective of microRNA function and dysfunction in cancer. Nat Rev Genet. 2016; 17(12):719-732. DOI: 10.1038/nrg.2016.134. View

12.

Curigliano G, Goldhirsch A . The triple-negative subtype: new ideas for the poorest prognosis breast cancer. J Natl Cancer Inst Monogr. 2011; 2011(43):108-10. DOI: 10.1093/jncimonographs/lgr038. View

13.

Ni F, Gui Z, Guo Q, Hu Z, Wang X, Chen D . Downregulation of miR-362-5p inhibits proliferation, migration and invasion of human breast cancer MCF7 cells. Oncol Lett. 2016; 11(2):1155-1160. PMC: 4734047. DOI: 10.3892/ol.2015.3993. View

14.

Staton C, Shaw L, Valluru M, Hoh L, Koay I, Cross S . Expression of class 3 semaphorins and their receptors in human breast neoplasia. Histopathology. 2011; 59(2):274-82. DOI: 10.1111/j.1365-2559.2011.03922.x. View

15.

Guo C, Fu M, Dilimina Y, Liu S, Guo L . microRNA-10b expression and its correlation with molecular subtypes of early invasive ductal carcinoma. Exp Ther Med. 2018; 15(3):2851-2859. PMC: 5867397. DOI: 10.3892/etm.2018.5797. View

16.

Ni F, Zhao H, Cui H, Wu Z, Chen L, Hu Z . MicroRNA-362-5p promotes tumor growth and metastasis by targeting CYLD in hepatocellular carcinoma. Cancer Lett. 2014; 356(2 Pt B):809-18. DOI: 10.1016/j.canlet.2014.10.041. View

17.

Parise C, Caggiano V . Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers. J Cancer Epidemiol. 2014; 2014:469251. PMC: 4058253. DOI: 10.1155/2014/469251. View

18.

Ma H, Ursin G, Xu X, Lee E, Togawa K, Malone K . Body mass index at age 18 years and recent body mass index in relation to risk of breast cancer overall and ER/PR/HER2-defined subtypes in white women and African-American women: a pooled analysis. Breast Cancer Res. 2018; 20(1):5. PMC: 5778748. DOI: 10.1186/s13058-017-0931-5. View

19.

Denkert C, Liedtke C, Tutt A, von Minckwitz G . Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 2016; 389(10087):2430-2442. DOI: 10.1016/S0140-6736(16)32454-0. View

20.

Yang P, Ni F, Deng R, Qiang G, Zhao H, Yang M . MiR-362-5p promotes the malignancy of chronic myelocytic leukaemia via down-regulation of GADD45α. Mol Cancer. 2015; 14:190. PMC: 4636774. DOI: 10.1186/s12943-015-0465-3. View