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PMID: 30728036 Published · epublish English Journal Article

Long non-coding RNA LINC00346 promotes pancreatic cancer growth and gemcitabine resistance by sponging miR-188-3p to derepress BRD4 expression.

Journal of experimental & clinical cancer research : CR ·Vol. 38 ·No. 1 ·2019-02-06 ·Pages 60

Shi W, Zhang C, Ning Z, Hua Y, Li Y, Chen L, Liu L, Chen Z, Meng Z

Abstract

Long non-coding RNA LINC00346 has been recently suggested as a prognostic marker in pancreatic cancer. However, its biological function in pancreatic cancer has not yet been determined. In this study, we attempted to ascertain the role of LINC00346 in regulating the aggressiveness of pancreatic cancer. The effects of overexpression and knockdown of LINC00346 on the proliferation, cell cycle progression, apoptosis, and gemcitabine resistance were investigated. Bioinformatic analysis, luciferase reporter assay, and RNA immunoprecipitation assay were performed to search for potential microRNAs (miRs) that can interact with LINC00346. Overexpression of LINC00346 significantly enhanced the proliferation, colony formation, and tumorigenesis of pancreatic cancer cells. Conversely, knockdown of LINC00346 suppressed pancreatic cancer cell proliferation and caused a cell-cycle arrest at the G2/M-phase. Depletion of LINC00346 also enhanced gemcitabine sensitivity in pancreatic cancer cells both in vitro and in vivo. Mechanistic investigation revealed that LINC00346 acted as a sponge for miR-188-3p and blocked the repression of BRD4 by miR-188-3p in pancreatic cancer cells. Clinical evidence indicated a negative correlation between LINC00346 and miR-188-3p in pancreatic cancer specimens. Rescue experiments showed that LINC00346 attenuated the growth-suppressing and chemosensitizing effects of miR-188-3p on pancreatic cancer cells. In addition, silencing of BRD4 significantly inhibited LINC00346-induced pancreatic cancer cell proliferation and colony formation. LINC00346 shows the ability to promote pancreatic cancer growth and gemcitabine resistance, which is in part mediated by antagonization of miR-188-3p and induction of BRD4. Targeting LINC00346 may improve gemcitabine-based therapeutic efficacy.

Keywords
Gemcitabine Growth LINC00346 Pancreatic cancer miR-188-3p
MeSH Terms
Animals Antimetabolites, Antineoplastic/therapeutic use Carcinogenesis Cell Cycle Proteins Cell Line, Tumor Deoxycytidine/analogs & derivatives,therapeutic use Drug Resistance, Neoplasm Female Humans Male Mice MicroRNAs/metabolism Middle Aged Molecular Targeted Therapy Nuclear Proteins/biosynthesis,metabolism Pancreatic Neoplasms/drug therapy,metabolism,pathology RNA, Long Noncoding/metabolism Transcription Factors/biosynthesis,metabolism
Chemicals
Antimetabolites, Antineoplastic BRD4 protein, human Cell Cycle Proteins MIRN188 microRNA, human MicroRNAs Nuclear Proteins RNA, Long Noncoding Transcription Factors Deoxycytidine gemcitabine
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Shi Weidong
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Zhang Chenyue
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Ning Zhouyu
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Hua Yongqiang
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Li Ye
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Chen Lianyu
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Liu Luming
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Chen Zhen
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Meng Zhiqiang
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. mengzhq@yeah.net. | Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. mengzhq@yeah.net. | Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China. mengzhq@yeah.net.
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Article Info
Journal
Journal of experimental & clinical cancer research : CR
Abbr.
J Exp Clin Cancer Res
ISSN
1756-9966
DOI
10.1186/s13046-019-1055-9
Email
mengzhq@yeah.net
Published
2019-02-06
Epub
2019-00-06
Pages
60
Language
English
Region
England
NLM ID
8308647
PMCID
PMC6366022
Subset
IM
Grants
National Natural Science Foundation of China · 81673746
National Natural Science Foundation of China · 81774063
National Natural Science Foundation of China · 81673749
External Links
PubMed source DOI: 10.1186/s13046-019-1055-9 PMC Full Text View journal details
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