Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma

Authors: Mansi Parasramka, Irene K. Yan, Xue Wang, Phuong Nguyen, Akiko Matsuda, Sayantan Maji, Catherine Foye, Yan Asmann, Tushar Patel

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Background

Genetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies.

Methods

The impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity.

Results

Sensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or bAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine.

Conclusions

NEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.
Appendix
Available only for authorised users
Literature
1.
2.
Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, Niknafs N, Guthrie VB, Maitra A, Argani P, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45(12):1470–3.CrossRefPubMedPubMedCentral
3.
Andrici J, Goeppert B, Sioson L, Clarkson A, Renner M, Stenzinger A, Tayao M, Watson N, Farzin M, Toon CW, et al. Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma. Medicine (Baltimore). 2016;95(2):e2491.CrossRef
4.
Takahashi K, Yan IK, Kogure T, Haga H, Patel T. Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio. 2014;4:458–67.CrossRefPubMedPubMedCentral
5.
Takahashi K, Yan IK, Wood J, Haga H, Patel T. Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Mol Cancer Res. 2014;12(10):1377–87.CrossRefPubMedPubMedCentral
6.
Chakravarty D, Sboner A, Nair SS, Giannopoulou E, Li R, Hennig S, Mosquera JM, Pauwels J, Park K, Kossai M, et al. The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat Commun. 2014;5:5383.CrossRefPubMedPubMedCentral
7.
Ke H, Zhao L, Feng X, Xu H, Zou L, Yang Q, Su X, Peng L, Jiao B. NEAT1 is Required for Survival of Breast Cancer Cells Through FUS and miR-548. Gene Regul Syst Bio. 2016;10 Suppl 1:11–7.PubMedPubMedCentral
8.
Cao J, Zhang Y, Yang J, He S, Li M, Yan S, Chen Y, Qu C, Xu L. NEAT1 regulates pancreatic cancer cell growth, invasion and migration though mircroRNA-335-5p/c-met axis. Am J Cancer Res. 2016;6(10):2361–74.PubMedPubMedCentral
9.
Adriaens C, Marine JC. NEAT1-containing Paraspeckles: central hubs in stress response and tumor formation. Cell Cycle. 2016; [Epub ahead of print].
10.
Sun C, Li S, Zhang F, Xi Y, Wang L, Bi Y, Li D. Long non-coding RNA NEAT1 promotes non-small cell lung cancer progression through regulation of miR-377-3p-E2F3 pathway. Oncotarget. 2016;7(32):51784–814.
11.
Tadlock L, Patel T. Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line. Hepatology. 2001;33(1):43–51.
12.
Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013;45(10):1113–20.CrossRefPubMedPubMedCentral
13.
Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009;25(9):1105–11.
14.
Liao Y, Smyth GK, Shi W. FeatureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923–30.CrossRefPubMed
15.
Hansen KD, Irizarry RA, Wu Z. Removing technical variability in RNA-seq data using conditional quantile normalization. Biostatistics. 2012;13(2):204–16.
16.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.CrossRefPubMed
17.
18.
LaFave LM, Beguelin W, Koche R, Teater M, Spitzer B, Chramiec A, Papalexi E, Keller MD, Hricik T, Konstantinoff K, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21(11):1344–9.CrossRefPubMedPubMedCentral
19.
Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013;13(3):153–9.
20.
Wang A, Papneja A, Hyrcza M, Al-Habeeb A, Ghazarian D. BAP1: gene of the month. J Clin Pathol. 2016;69(9):750–3.
21.
Rai K, Pilarski R, Cebulla CM, Abdel-Rahman MH. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet. 2016;89(3):285–94.CrossRefPubMed
22.
Battaglia A. The Importance of Multidisciplinary Approach in Early Detection of BAP1 Tumor Predisposition Syndrome: Clinical Management and Risk Assessment. Clin Med Insights Oncol. 2014;8:37–47.CrossRefPubMedPubMedCentral
23.
Malouf GG, Zhang J, Yuan Y, Comperat E, Roupret M, Cussenot O, Chen Y, Thompson EJ, Tannir NM, Weinstein JN, et al. Characterization of long non-coding RNA transcriptome in clear-cell renal cell carcinoma by next-generation deep sequencing. Mol Oncol. 2015;9(1):32–43.CrossRefPubMed
24.
Haga H, Yan I, Takahashi K, Matsuda A, Patel T. Extracellular vesicles from bone marrow derived mesenchymal stem cells improve survival from lethal hepatic failure in mice. Stem Cell Translational Med. 2016; (In Press).
25.
Xue X, Yang YA, Zhang A, Fong KW, Kim J, Song B, Li S, Zhao JC, Yu J. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene. 2016;35(21):2746–55.CrossRefPubMed
26.
Wang F, Zhou J, Xie X, Hu J, Chen L, Hu Q, Guo H, Yu C. Involvement of SRPK1 in cisplatin resistance related to long non-coding RNA UCA1 in human ovarian cancer cells. Neoplasma. 2015;62(3):432–8.CrossRefPubMed
27.
Hang Q, Sun R, Jiang C, Li Y. Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating lncRNA AK022798 expression. Anticancer Drugs. 2015;26(6):632–40.PubMed
28.
Fornari F, Ferracin M, Trere D, Milazzo M, Marinelli S, Galassi M, Venerandi L, Pollutri D, Patrizi C, Borghi A, et al. Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, Identify Cirrhotic Patients with HCC. PLoS One. 2015;10(10):e0141448.CrossRefPubMedPubMedCentral
29.
Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, Liu Y. Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. Febs J. 2014;281(7):1750–8.CrossRefPubMed
30.
Jiang M, Huang O, Xie Z, Wu S, Zhang X, Shen A, Liu H, Chen X, Wu J, Lou Y, et al. A novel long non-coding RNA-ARA: adriamycin resistance-associated. Biochem Pharmacol. 2014;87(2):254–83.CrossRefPubMed
31.
Zhu KP, Zhang CL, Shen GQ, Zhu ZS. Long noncoding RNA expression profiles of the doxorubicin-resistant human osteosarcoma cell line MG63/DXR and its parental cell line MG63 as ascertained by microarray analysis. Int J Clin Exp Pathol. 2015;8(8):8754–73.PubMedPubMedCentral
32.
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.CrossRefPubMed
33.
Yu H, Pak H, Hammond-Martel I, Ghram M, Rodrigue A, Daou S, Barbour H, Corbeil L, Hebert J, Drobetsky E, et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc Natl Acad Sci U S A. 2014;111(1):285–90.CrossRefPubMed
34.
Tang B, Du J, Li Y, Tang F, Wang Z, He S. EZH2 elevates the proliferation of human cholangiocarcinoma cells through the downregulation of RUNX3. Med Oncol. 2014;31(11):271.CrossRefPubMed
35.
Nakagawa S, Okabe H, Sakamoto Y, Hayashi H, Hashimoto D, Yokoyama N, Sakamoto K, Kuroki H, Mima K, Nitta H, et al. Enhancer of zeste homolog 2 (EZH2) promotes progression of cholangiocarcinoma cells by regulating cell cycle and apoptosis. Ann Surg Oncol. 2013;20 Suppl 3:S667–675.CrossRefPubMed
36.
Nakagawa S, Sakamoto Y, Okabe H, Hayashi H, Hashimoto D, Yokoyama N, Tokunaga R, Sakamoto K, Kuroki H, Mima K, et al. Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells. Oncol Rep. 2014;31(2):983–8.PubMed
Metadata
Title
BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma
Authors
Mansi Parasramka
Irene K. Yan
Xue Wang
Phuong Nguyen
Akiko Matsuda
Sayantan Maji
Catherine Foye
Yan Asmann
Tushar Patel
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0587-x

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

Reprogramming of stromal fibroblasts by SNAI2 contributes to tumor desmoplasia and ovarian cancer progression

Research

LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-Mediated H3K4me2 demethylation

Letter to the Editor

Profiling, clinicopathological correlation and functional validation of specific long non-coding RNAs for hepatocellular carcinoma

Research

STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4

Review

Cdk5 links with DNA damage response and cancer

Review

Epigenetics in cancer stem cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits