Mir-148a improves response to chemotherapy in sensitive and resistant oesophageal adenocarcinoma and squamous cell carcinoma cells.
BACKGROUND
Response to chemotherapy varies widely in patients with advanced oesophageal cancer. We investigated the impact of manipulating certain microRNAs on response to cisplatin and 5-fluorouracil (5-FU) in oesophageal cancer cells.


METHODS
Cisplatin-/5-fluorouracil-resistant oesophageal squamous cell carcinoma (SCC) and adenocarcinoma (EAC) cell lines were established, and the impact of ectopic upregulation of miR-106a and miR-148a on response to both drugs was assessed.


RESULTS
The impact of miR-106a-upregulation was inconsistent. Upregulation was followed by reduced sensitivity to cisplatin in chemotherapy-sensitive EAC cells (cell survival, +8.7 ± 0.8%; p = 0.003) and an improved response to 5-FU in cisplatin-resistant EAC cells (cell survival, -6.4 ± 2.5%; p = 0.011). MiR-148a upregulation significantly increased sensitivity to chemotherapy in seven out of ten cell lines, represented by a decrease in cell viability of 22.6 ± 7.9% to 50.5 ± 10.6% after cisplatin (p ≤ 0.014) and 6.0 ± 0.8% to 15.0 ± 4.1% after 5-FU treatment (p ≤ 0.012). The only cell lines in which miR-148a upregulation had no effect were cisplatin-resistant EAC exposed to cisplatin and 5-FU-sensitive and 5-FU-resistant SCC cells exposed to 5-FU.


CONCLUSIONS
MiR-148a sensitized chemotherapy-sensitive oesophageal cancer cell lines to cisplatin and, to a lesser extent, to 5-flurouracil and attenuated resistance in chemotherapy-resistant variants. Further experimental and clinical studies to investigate the exact mechanisms involved are warranted.
Department of Surgery, Flinders University, Room 3D213, Flinders Medical Centre, 5042 Bedford Park, South Australia, Australia. richard.hummel@flinders.edu.au
Richard
R
Hummel
David I
DI
Watson
Cameron
C
Smith
Jakob
J
Kist
Michael Z
MZ
Michael
Joerg
J
Haier
Damian J
DJ
Hussey
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; C542541:MIRN106 microRNA, human; C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D002945:Cisplatin; D005472:Fluorouracil
Hepatology. 2010 Mar;51(3):881-90
20146264
Gastroenterology. 2009 May;136(5):1689-700
19422085
Gut. 2004 Jul;53(7):925-30
15194636
Am J Pathol. 2009 May;174(5):1940-8
19342367
Clin Cancer Res. 2006 Dec 15;12(24):7322-8
17121874
Clin Cancer Res. 2009 Sep 15;15(18):5744-52
19737949
J Biol Chem. 2010 Jun 18;285(25):19076-84
20406806
Ann Surg. 2005 Nov;242(5):684-92
16244542
Cell. 2003 Jun 13;113(6):673-6
12809598
Clin Cancer Res. 2009 Mar 15;15(6):1915-22
19276261
J Thorac Cardiovasc Surg. 2008 Feb;135(2):255-60; discussion 260
18242245
Am J Surg. 2003 Jun;185(6):538-43
12781882
Ann Surg Oncol. 2011 Jan;18(1):253-60
20628822
Lancet Oncol. 2007 Mar;8(3):226-34
17329193
J Biol Chem. 2010 Mar 12;285(11):7986-94
20075075
Int J Cancer. 2008 Jul 15;123(2):372-379
18449891
Med Mol Morphol. 2009 Jun;42(2):102-9
19536617
Dev Biol. 2007 Feb 1;302(1):1-12
16989803
Blood. 2009 Oct 29;114(18):3872-9
19717645
Clin Cancer Res. 2009 Oct 1;15(19):6192-200
19789312
BMC Cancer. 2008 Sep 21;8:266
18803879
Mol Cancer. 2007 Sep 25;6:60
17894887
Cancer Treat Rev. 2007 Jun;33(4):369-80
17451886
Oncogene. 2008 Nov 6;27(52):6667-78
18663355
J Biol Chem. 2008 Apr 11;283(15):9674-80
18268015
Br J Surg. 2010 Jun;97(6):853-61
20301167
Cancer Res. 2007 Nov 1;67(21):10361-7
17974979
J Biol Chem. 2007 Mar 16;282(11):8256-64
17220301
Int J Cancer. 2010 Dec 15;127(12):2804-14
21351259
Anticancer Drugs. 2007 Aug;18(7):749-54
17581296
Eur J Cancer. 2010 Jan;46(2):298-311
19948396
World J Gastroenterol. 2004 Jul 1;10(13):1979-83
15222051
Stem Cells Dev. 2010 Jan;19(1):17-26
19435428
Cancer Res. 2008 Dec 15;68(24):10307-14
19074899
Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):19-27
19149685
Cancer Res. 2008 Jan 1;68(1):26-33
18172293
Gynecol Oncol. 2009 May;113(2):249-55
19237188
J Gastrointest Surg. 2009 May;13(5):846-53
19190970
Mol Cancer. 2010 Mar 02;9:46
20196838
Trends Mol Med. 2006 Dec;12(12):580-7
17071139
Ann Surg. 2007 May;245(5):707-16
17457163
RNA. 2008 May;14(5):872-7
18367714
APMIS. 2007 Oct;115(10):1090-106
18042145
Mol Cancer Ther. 2008 Jul;7(7):2152-9
18645025
Exp Cell Res. 2009 Sep 10;315(15):2529-38
19501585
Transl Oncol. 2009 Aug 18;2(3):157-63
19701500