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 2023 EHA Congress 2023 ASCO Annual Meeting
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 1/2014

Open Access 01-12-2014 | Research

miR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the Oxidative Stress pathway

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

Published in: Molecular Cancer | Issue 1/2014

Login to get access

Abstract

Background

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.

Results

From 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.

Conclusions

In 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.
Appendix
Available only for authorised users
Literature
1.
Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, Kassouf W, Kiemeney LA, La Vecchia C, Shariat S: Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013, 63 (2): 234-241. 10.1016/j.eururo.2012.07.033CrossRefPubMed
2.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M: Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005, 23: 4602-4608. 10.1200/JCO.2005.07.757CrossRefPubMed
3.
4.
5.
Di Leva G, Garofalo M, Croce CM: MicroRNAs in cancer. Annu Rev Pathol Mech Dis. 2014, 9: 287-314. 10.1146/annurev-pathol-012513-104715.CrossRef
6.
Cheng CJ, Slack FJ: The duality of oncomiR addiction in the maintenance and treatment of cancer. Cancer J (Sudbury, Mass). 2012, 18: 232-10.1097/PPO.0b013e318258b75b.CrossRef
7.
Blandino G, Fazi F, Donzelli S, Kedmi M, Sas-Chen A, Muti P, Strano S, Yarden Y: Tumor suppressor microRNAs: a novel non-coding alliance against cancer. FEBS Lett. 2014, 588 (16): 2639-2652. 10.1016/j.febslet.2014.03.033CrossRefPubMed
8.
Ling H, Fabbri M, Calin GA: MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013, 12: 847-865. 10.1038/nrd4140PubMedCentralCrossRefPubMed
9.
Sethi S, Ali S, Philip PA, Sarkar FH: Clinical advances in molecular biomarkers for cancer diagnosis and therapy. Int J Mol Sci. 2013, 14: 14771-14784. 10.3390/ijms140714771PubMedCentralCrossRefPubMed
10.
Haenisch S, Cascorbi I: miRNAs as mediators of drug resistance. Epigenomics. 2012, 4: 369-381. 10.2217/epi.12.39CrossRefPubMed
11.
Su S, Chang Y, Andreu-Vieyra C, Fang J, Yang Z, Han B, Lee A, Liang G: miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene. 2013, 32 (39): 4694-4701. 10.1038/onc.2012.483PubMedCentralCrossRefPubMed
12.
K-i K, Imoto I, Mogi S, Omura K, Inazawa J: Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 2008, 68: 2094-2105. 10.1158/0008-5472.CAN-07-5194CrossRef
13.
Heller G, Weinzierl M, Noll C, Babinsky V, Ziegler B, Altenberger C, Minichsdorfer C, Lang G, Döme B, End-Pfützenreuter A: Genome-wide miRNA expression profiling identifies miR-9-3 and miR-193a as targets for DNA Methylation in non–small cell lung cancers. Clin Cancer Res. 2012, 18: 1619-1629. 10.1158/1078-0432.CCR-11-2450CrossRefPubMed
14.
Avci CB, Harman E, Dodurga Y, Susluer SY, Gunduz C: Therapeutic potential of an anti-diabetic drug, metformin: alteration of miRNA expression in prostate cancer cells. Asian Pac J Cancer Prev. 2013, 14: 765-768. 10.7314/APJCP.2013.14.2.765CrossRefPubMed
15.
Tahiri A, Leivonen SK, Luders T, Steinfeld I, Ragle Aure M, Geisler J, Makela R, Nord S, Riis ML, Yakhini Z, Kleivi Sahlberg K, Børresen-Dale AL, Perälä M, Bukholm IR, Kristensen VN: Deregulation of cancer-related miRNAs is a common event in both benign and malignant human breast tumors. Carcinogenesis. 2014, 35: 76-85. 10.1093/carcin/bgt333CrossRefPubMed
16.
Chen D, Cabay RJ, Jin Y, Wang A, Lu Y, Shah-Khan M, Zhou X: MicroRNA deregulations in head and neck squamous cell carcinomas. J Oral Maxillofac Res. 2013, 4: e2-PubMedCentralCrossRefPubMed
17.
Yong FL, Law CW, Wang CW: Potentiality of a triple microRNA classifier: miR-193a-3p, miR-23a and miR-338-5p for early detection of colorectal cancer. BMC Cancer. 2013, 13: 280- 10.1186/1471-2407-13-280PubMedCentralCrossRefPubMed
18.
Gao X, Lin J, Li Y, Gao L, Wang X, Wang W, Kang H, Yan G, Wang L, Yu L: MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia. Oncogene. 2011, 30: 3416-3428. 10.1038/onc.2011.62CrossRefPubMed
19.
Li Y, Gao L, Luo X, Wang L, Gao X, Wang W, Sun J, Dou L, Li J, Xu C: Epigenetic silencing of microRNA-193a contributes to leukemogenesis in t (8; 21) acute myeloid leukemia by activating the PTEN/PI3K signal pathway. Blood. 2013, 121: 499-509. 10.1182/blood-2012-07-444729CrossRefPubMed
20.
Iliopoulos D, Rotem A, Struhl K: Inhibition of miR-193a expression by Max and RXRα activates K-Ras and PLAU to mediate distinct aspects of cellular transformation. Cancer Res. 2011, 71: 5144-5153. 10.1158/0008-5472.CAN-11-0425PubMedCentralCrossRefPubMed
21.
Noh H, Hong S, Dong Z, Pan ZK, Jing Q, Huang S: Impaired microRNA processing facilitates breast cancer cell invasion by upregulating urokinase-type plasminogen activator expression. Genes Cancer. 2011, 2: 140-150. 10.1177/1947601911408888PubMedCentralCrossRefPubMed
22.
Uhlmann S, Mannsperger H, Zhang JD, Horvat EÁ, Schmidt C, Küblbeck M, Henjes F, Ward A, Tschulena U, Zweig K: Global microRNA level regulation of EGFR‒driven cell‒cycle protein network in breast cancer. Mol Syst Biol. 2012, 8: 570-PubMedCentralCrossRefPubMed
23.
Nakano H, Yamada Y, Miyazawa T, Yoshida T: Gain-of-function microRNA screens identify miR-193a regulating proliferation and apoptosis in epithelial ovarian cancer cells. Int J Oncol. 2013, 42: 1875-1882.PubMedCentralPubMed
24.
Salvi A, Conde I, Abeni E, Arici B, Grossi I, Specchia C, Portolani N, Barlati S, De Petro G: Effects of miR-193a and sorafenib on hepatocellular carcinoma cells. Mol Cancer. 2013, 12: 162-PubMedCentralCrossRefPubMed
25.
Wang J, Yang B, Han L, Li X, Tao H, Zhang S, Hu Y: Demethylation of miR-9-3 and miR-193a genes suppresses proliferation and promotes apoptosis in non-small cell lung cancer cell lines. Cell Physiol Biochem. 2013, 32: 1707-1719. 10.1159/000356605CrossRefPubMed
26.
Kwon JE, Kim BY, Kwak SY, Bae IH, Han YH: Ionizing radiation-inducible microRNA miR-193a-3p induces apoptosis by directly targeting Mcl-1. Apoptosis. 2013, 18: 896-909. 10.1007/s10495-013-0841-7CrossRefPubMed
27.
Yu T, Li J, Yan M, Liu L, Lin H, Zhao F, Sun L, Zhang Y, Cui Y, Zhang F, Li J, He X, Yao M: MicroRNA-193a-3p and -5p suppress the metastasis of human non-small-cell lung cancer by downregulating the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway. Oncogene. 2014, ᅟ: ᅟ-doi:10.1038/onc.2013.574,
28.
Santarpia L, Calin GA, Adam L, Ye L, Fusco A, Giunti S, Thaller C, Paladini L, Zhang X, Jimenez C: A miRNA signature associated with human metastatic medullary thyroid carcinoma. Endocr Relat Cancer. 2013, 20: 809-823. 10.1530/ERC-13-0357CrossRefPubMed
29.
Ma K, He Y, Zhang H, Fei Q, Niu D, Wang D, Ding X, Xu H, Chen X, Zhu J: DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. J Biol Chem. 2012, 287: 5639-5649. 10.1074/jbc.M111.291229PubMedCentralCrossRefPubMed
30.
31.
Zhao Y, Lin J, Xu B, Hu S, Zhang X, Wu L: MicroRNA-mediated repression of nonsense mRNAs. 2014,
32.
Bloom DA, Jaiswal AK: Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD (P) H: quinone oxidoreductase-1 gene expression. J Biol Chem. 2003, 278: 44675-44682. 10.1074/jbc.M307633200CrossRefPubMed
33.
Sarkar S, Dutta D, Samanta SK, Bhattacharya K, Pal BC, Li J, Datta K, Mandal C, Mandal C: Oxidative inhibition of Hsp90 disrupts the super‒chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo. Int J Cancer. 2013, 132: 695-706. 10.1002/ijc.27687PubMedCentralCrossRefPubMed
34.
Bosch-Presegué L, Raurell-Vila H, Marazuela-Duque A, Kane-Goldsmith N, Valle A, Oliver J, Serrano L, Vaquero A: Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol Cell. 2011, 42: 210-223. 10.1016/j.molcel.2011.02.034CrossRefPubMed
35.
Scola N, Goeroegh T: LOXL4 as a selective molecular marker in primary and metastatic head/neck carcinoma. Anticancer Res. 2010, 30: 4567-4571.PubMed
36.
Weise JB, Rudolph P, Heiser A, Kruse M-L, Hedderich J, Cordes C, Hoffmann M, Brant O, Ambrosch P, Csiszar K: LOXL4 is a selectively expressed candidate diagnostic antigen in head and neck cancer. Eur J Cancer. 2008, 44: 1323-1331. 10.1016/j.ejca.2008.03.026CrossRefPubMed
37.
Sebban S, Golan-Gerstl R, Karni R, Vaksman O, Davidson B, Reich R: Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer. Clin Exp Metastasis. 2013, 30: 103-117. 10.1007/s10585-012-9514-0CrossRefPubMed
38.
Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ: A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 2002, 62: 4478-4483.PubMed
39.
Görögh T, Weise J, Holtmeier C, Rudolph P, Hedderich J, Gottschlich S, Hoffmann M, Ambrosch P, Csiszar K: Selective upregulation and amplification of the lysyl oxidase like‒4 (LOXL4) gene in head and neck squamous cell carcinoma. J Pathol. 2007, 212: 74-82. 10.1002/path.2137CrossRefPubMed
40.
Weise JB, Csiszar K, Gottschlich S, Hoffmann M, Schmidt A, Weingartz U, Adamzik I, Heiser A, Kabelitz D, Ambrosch P: Vaccination strategy to target lysyl oxidase-like 4 in dendritic cell based immunotherapy for head and neck cancer. Int J Oncol. 2008, 32: 317-322.PubMed
41.
Kim Y, Roh S, Park J-Y, Kim Y, Cho DH, Kim JC: Differential expression of the LOX family genes in human colorectal adenocarcinomas. Oncol Rep. 2009, 22: 799-804.PubMed
42.
Wu G, Guo Z, Chang X, Kim MS, Nagpal JK, Liu J, Maki JM, Kivirikko KI, Ethier SP, Trink B: LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer. Cancer Res. 2007, 67: 4123-4129. 10.1158/0008-5472.CAN-07-0012CrossRefPubMed
43.
44.
Soler‒López M, Badiola N, Zanzoni A, Aloy P: Towards Alzheimer’s root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction. Bioessays. 2012, 34: 532-541. 10.1002/bies.201100193CrossRef
45.
Türei D, Papp D, Fazekas D, Földvári-Nagy L, Módos D, Lenti K, Csermely P, Korcsmáros T: NRF2-ome: an integrated web resource to discover protein interaction and regulatory networks of NRF2. Oxid Med Cell Longev. 2013, 2013: 737591-PubMedCentralCrossRefPubMed
46.
Papp D, Lenti K, Módos D, Fazekas D, Dúl Z, Türei D, Földvári-Nagy L, Nussinov R, Csermely P, Korcsmáros T: The NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops. FEBS Lett. 2012, 586: 1795-1802. 10.1016/j.febslet.2012.05.016CrossRefPubMed
47.
Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, Shyr C, Wakabayashi N, Kensler TW, Wasserman WW: Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res. 2010, 38: 5718-5734. 10.1093/nar/gkq212PubMedCentralCrossRefPubMed
48.
Sandelin A, Alkema W, Engström P, Wasserman WW, Lenhard B: JASPAR: an open‒access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res. 2004, 32: D91-D94. 10.1093/nar/gkh012PubMedCentralCrossRefPubMed
49.
Gañán-Gómez I, Wei Y, Yang H, Boyano-Adánez MC, García-Manero G: Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med. 2013, 65: 750-764.CrossRefPubMed
50.
Xu B, He Y, Wu X, Luo C, Liu A, Zhang J: Exploration of the correlations between interferon-gamma in patient serum and HEPACAM in bladder transitional cell carcinoma, and the interferon-gamma mechanism Inhibiting BIU-87 proliferation. J Urol. 2012, 188: 1346-1353. 10.1016/j.juro.2012.06.005CrossRefPubMed
51.
Andrisano V, Bartolini M, Gotti R, Cavrini V, Felix G: Determination of inhibitors’ potency (IC50) by a direct high-performance liquid chromatographic method on an immobilised acetylcholinesterase column. J Chromatogr B Biomed Sci Appl. 2001, 753: 375-383. 10.1016/S0378-4347(00)00571-5CrossRefPubMed
52.
Ohashi K, Marion PL, Nakai H, Meuse L, Cullen JM, Bordier BB, Schwall R, Greenberg HB, Glenn JS, Kay MA: Sustained survival of human hepatocytes in mice: a model for in vivo infection with human hepatitis B and hepatitis delta viruses. Nat Med. 2000, 6: 327-331. 10.1038/73187CrossRefPubMed
Metadata
Title
miR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the Oxidative Stress pathway
Authors
Hui Deng
Lei Lv
Yang Li
Cheng Zhang
Fang Meng
Youguang Pu
Jun Xiao
Liting Qian
Weidong Zhao
Qi Liu
Daming Zhang
Yingwei Wang
Hongyu Zhang
Yinghua He
Jingde Zhu
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-234

Other articles of this Issue 1/2014

Molecular Cancer 1/2014 Go to the issue

Research

High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor

Research

Bortezomib treatment causes long-term testicular dysfunction in young male mice

Research

Critical role of histone demethylase RBP2 in human gastric cancer angiogenesis

Research

PP2A inhibition overcomes acquired resistance to HER2 targeted therapy

Research

Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis

Research

A mechanically-induced colon cancer cell population shows increased metastatic potential
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