MiR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the oxidative stress pathway.

Hui Deng,Yingwei Wang,Daming Zhang,Hongyu Zhang,Youguang Pu,Jun Xiao,Qi Liu,Liting Qian,Jingde Zhu,Yang Li,Cheng Zhang,Weidong Zhao,Yinghua He,Lei Lv,Fang Meng

doi:10.1186/1476-4598-13-234

Abstract

BackgroundChemoresistance is a major obstacle to the curative cancer chemotherapy and presents one of the most formidable challenges in both research and management of cancer.ResultsFrom the detailed studies of a multi-chemosensitive (5637) versus a chemoresistant (H-bc) bladder cancer cell lines, we showed that miR-193a-3p [GenBank: NR_029710.1] promotes the multi-chemoresistance of bladder cancer cells. We further demonstrated that lysyl oxidase-like 4 (LOXL4) gene [GenBank: NM_032211.6] is a direct target of miR-193a-3p and executes the former’s impact on bladder cancer chemoresistance. The Oxidative Stress pathway activity is drastically affected by a forced reversal of miR-193a-3p or LOXL4 levels in cell and may act at the downstream of LOXL4 gene to relay the miR-193a-3p’s impact on the multi-chemoresistance in both cultured cells and the tumor xenografts in nude mice.ConclusionsIn addition to a new mechanistic insight, our results provide a set of the essential genes in this newly identified miR-193a-3p/LOXL4/Oxidative Stress axis as the diagnostic targets for a guided anti-bladder cancer chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-234) contains supplementary material, which is available to authorized users.

Highlights

Chemoresistance is a major obstacle to the curative cancer chemotherapy and presents one of the most formidable challenges in both research and management of cancer
The carcinogenic impact of miR-193a-3p has been attributed to its repression of c-Kit [18] and the PTEN/PI3K signaling pathway in acute myeloid leukemia [19], of KRAS and PLAU in colon cancer [20], of PLAU [21] and EGFR-driven cellcycle network proteins [22] in breast cancer, of ARHGAP19, CCND1, ERBB4, KRAS and Mcl-1 in epithelial ovarian cancer [23], of PLAU in hepatocellular carcinoma (HCC) [24], and of Mcl-1 in non-small cell lung cancer (NSCLC) [25]
The miR-193a-3p level was higher in the chemoresistant (H-bc and UM-UC-3) than the chemosensitive (5637) Bladder cancer (BCa) cell lines The dose required for 50% cells killed (IC50) after a 72 hours drug treatment by Pirarubicin(Pi), Paclitaxel (Pa), Adriamycin(Ad), Cisplatin(Ci) or Epirubicin Hydrochloride(EH) were determined in the following five BCa cell lines: 5637, T24, Biu87, H-bc and UM-UC-3

Summary

Introduction

Chemoresistance is a major obstacle to the curative cancer chemotherapy and presents one of the most formidable challenges in both research and management of cancer. Dysregulation of miR-193a-3p was reported in other types of cancer, such as non-small cell lung cancer (NSCLC) [13], prostate cancer [14], breast cancer [15], Head and Neck Squamous Cell Carcinomas [16], and colorectal cancer [17]. MiR193a-3p was shown to promote in vivo tumorigenesis of metastatic medullary thyroid carcinoma [28], and to enhance both tumor growth in nude mice and chemoresistance of HCC by targeting of the SRSF2 gene [29]

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Results

Conclusion