Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR-196a-5p in bladder cancer cells

Jingjing Pan; Xu Li; Wenjing Wu; Mei Xue; Huilian Hou; Wen Zhai; Wei Chen

doi:10.1016/j.canlet.2016.08.015

Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR-196a-5p in bladder cancer cells

Cancer Lett. 2016 Nov 1;382(1):64-76. doi: 10.1016/j.canlet.2016.08.015. Epub 2016 Aug 31.

Authors

Jingjing Pan¹, Xu Li², Wenjing Wu¹, Mei Xue², Huilian Hou³, Wen Zhai¹, Wei Chen⁴

Affiliations

¹ Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
² Translational Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
³ Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁴ Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].

PMID: 27591936
DOI: 10.1016/j.canlet.2016.08.015

Abstract

Chemoresistance constitutes the major failing of clinical therapy for bladder cancer. However, the molecular mechanisms involved in the chemoresistance of bladder cancer are unclear. Long non-coding RNAs (lncRNAs) have been implicated in chemotherapeutic drug resistance. Urothelial Cancer Associated 1 (UCA1), an lncRNA, is reportedly upregulated in human bladder carcinoma and promotes cancer cell proliferation, migration, invasion, and drug resistance. In the present study, knockdown of UCA1 decreased chemosensitivity to cisplatin/gemcitabine by suppressing cell proliferation and inducing apoptosis, while overexpression of UCA1 increased chemosensitivity in bladder cancer cells. Moreover, UCA1 activated transcription factor CREB which led to miR-196a-5p expression by binding with its promoter. miR-196a-5p induction is involved in UCA1 inhibition of apoptosis induced by cisplatin/gemcitabine via targeting p27^Kip1. These results provide a novel UCA1-CREB-miR-196a-5p paradigm to explain in part how UCA1 functions in cisplatin/gemcitabine resistance, and suggest that UCA1 may be a potential therapeutic target for chemotherapy in bladder cancer.

Keywords: Bladder cancer; CREB; Drug resistance; UCA1; miR-196a-5p.

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Binding Sites
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cisplatin / pharmacology*
Cyclic AMP Response Element-Binding Protein / genetics
Cyclic AMP Response Element-Binding Protein / metabolism*
Cyclin-Dependent Kinase Inhibitor p27 / genetics
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Deoxycytidine / analogs & derivatives*
Deoxycytidine / pharmacology
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm* / genetics
Female
Gemcitabine
Gene Expression Regulation, Neoplastic
Humans
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasm Invasiveness
Promoter Regions, Genetic
RNA Interference
RNA, Long Noncoding / genetics
RNA, Long Noncoding / metabolism*
Signal Transduction / drug effects
Time Factors
Transfection
Tumor Burden / drug effects
Urinary Bladder Neoplasms / drug therapy*
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism
Urinary Bladder Neoplasms / pathology
Xenograft Model Antitumor Assays

Substances

CDKN1B protein, human
CREB1 protein, human
Cyclic AMP Response Element-Binding Protein
MIRN196 microRNA, human
MicroRNAs
RNA, Long Noncoding
UCA1 RNA, human
Deoxycytidine
Cyclin-Dependent Kinase Inhibitor p27
Cisplatin
Gemcitabine