miR-4443 Participates in the Malignancy of Breast Cancer.

Abstract

PURPOSE:

Chemo-resistance is the leading cause of failure in cancer therapy, however, much remains to be understood about the intrinsic mechanisms. In the present study, we discovered the novel miR-4443 that regulated malignancy of breast cancer both in vitro and in vivo.

METHODS:

We examined the expression of miR-4443 in MDA-MB-231/S and MDA-MB-231 Epirubicin-resistant cell lines with 76 breast cancer formalin-fixed paraffin-embedded tissues by real-time PCR. Also, we investigated the loss- and gain-functions of miR-4443 by MTT assay and flow cytometry. Furthermore, we detected miR-4443 mediated tissue inhibitor of metalloproteinase 2 expression in cells by TargetScan, RT-qPCR and western blot.

RESULTS:

We identified the up-regulated expression of miR-4443 in Epi-resistant cell lines versus MDA-MB-231/S cell(Epi versus S) and in post-chemotherapy FFPE tissues, along with statistically differential expressions in PR(partial response) versus SD(stable disease)/PD(progressive disease) patients. Overexpression of miR-4443 increased the IC50 value of Epi for the target cells transfected, while inhibition of miR-4443 could restored sensitivity of the target cells to Epi. Besides, down-regulation of endogenous miR-4443 by miRNA-inhibitors significantly enhanced Epi-induced apoptosis while up-regulation of miR-4443 by miRNA-mimics lead to less Epi-induced apoptotic cells. Consequently, changes in TIMP2 mRNA and protein expression revealed that miR-4443 mimics suppressed expression of TIMP2 and induced migration in breast cancer cells. Furthermore, TIMP2 expression associated with better prognosis(HR = 0.721, 95%CI: 0.529-0.983).

CONCLUSIONS:

We revealed that miR-4443 induced malignancy of breast cancer mainly in chemo-resistance aspect for the very first time, providing a novel biomarker in breast cancer diagnosis and therapy.

• Authors: Xiu Chen, Shan-Liang Zhong, Peng Lu, Dan-Dan Wang, Si-Ying Zhou, Su-Jin Yang, Hong-Yu Shen, Lei Zhang, Xiao-Hui Zhang, Jian-Hua Zhao, Jin-Hai Tang
• Journal: PloS one (PLoS One) Vol. 11 Issue 8 Pg. e0160780 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27504971 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• MIRN-4443 microRNA, human
• MicroRNAs
• TIMP2 protein, human
• Tissue Inhibitor of Metalloproteinase-2

Topics

• Apoptosis
• Biomarkers, Tumor (genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs (genetics)
• Middle Aged
• Retrospective Studies
• Survival Analysis
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)