miR-135a promotes gastric cancer progression and resistance to oxaliplatin.
Resistance to oxaliplatin (OXA)-based chemotherapy regimens continues to be a major cause of gastric cancer (GC) recurrence and metastasis. We analyzed GC samples and matched non-tumorous control stomach tissues from 280 patients and found that miR-135a was overexpressed in GC samples relative to control tissues. Tumors with high miR-135a expression were more likely to have aggressive characteristics (high levels of carcino-embryonic antigen, vascular invasion, lymphatic metastasis, and poor differentiation) than those with low levels. Patients with greater tumoral expression of miR-135a had shorter overall survival times and times to disease recurrence. Furthermore, miR-135a, which promotes the proliferation and invasion of OXA-resistant GC cells, inhibited E2F transcription factor 1 (E2F1)-induced apoptosis by downregulating E2F1 and Death-associated protein kinase 2 (DAPK2) expression. Our results indicate that higher levels of miR-135a in GC are associated with shorter survival times and reduced times to disease recurrence. The mechanism whereby miR-135a promotes GC pathogenesis appears to be the suppression of E2F1 expression and Sp1/DAPK2 pathway signaling.
Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Lin-Hai
LH
Yan
Department of Pathology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Zhi-Ning
ZN
Chen
Department of Pharmacy, The People Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Li-Li
Department of Medical Image Center, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Jia
J
Chen
Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Wen-E
WE
Wei
Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Xian-Wei
XW
Mo
Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Yu-Zhou
YZ
Qin
Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Yuan
Y
Lin
Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Jian-Si
JS
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D064550:Death-Associated Protein Kinases / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C544965:MIRN135 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D016271:Proto-Oncogene Proteins c-myc; D000077150:Oxaliplatin; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases
gastric cancer; transcription factor E2F1
Biochem Soc Trans. 2015 Oct;43(5):995-1002
26517914
Clin Transl Oncol. 2014 Apr;16(4):374-9
23881463
Carcinogenesis. 2015 Dec;36(12):1464-73
26483346
Mol Cancer. 2015 Jun 19;14:122
26084402
Oncotarget. 2016 Mar 8;7(10):11056-66
26840456
Physiol Rev. 2011 Jul;91(3):827-87
21742789
BMC Cancer. 2012 Mar 23;12:111
22439757
Oncotarget. 2015 May 10;6(13):10840-52
25912306
J Biol Chem. 2010 Jul 9;285(28):21496-507
20460378
Reprod Biol Endocrinol. 2011 Sep 14;9:126
21914226
Oncotarget. 2016 Jan 5;7(1):538-49
26623719
Cancer Sci. 2013 Mar;104(3):304-12
23176581
Elife. 2015 Sep 22;4:e08022
26393419
Sci Rep. 2016 Feb 12;6:21519
26867682
J Exp Bot. 2015 Jun;66(11):3259-74
25873670
Oncogene. 2011 Oct 27;30(43):4386-98
21552288
Cancer Biol Ther. 2012 Mar;13(5):281-8
22310976
Int J Mol Sci. 2016 Mar 22;17 (3):424
27011182
J Transl Med. 2015 Mar 13;13:86
25888950
BMC Surg. 2014 Nov 26;14:98
25428767
Cell Signal. 2014 Jul;26(7):1420-6
24607788
J Cell Biochem. 2014 Jan;115(1):34-41
24038122
Oncogene. 2012 Aug 23;31(34):3866-74
22139076
Clin Epigenetics. 2015 Mar 17;7:29
25806091
Am J Cancer Res. 2014 Dec 15;5(1):321-32
25628941
Bone. 2015 Feb;71:210-6
25460182
Oncogene. 2008 Sep 25;27(43):5706-16
18521079
Mol Cancer Ther. 2014 Dec;13(12):3137-51
25205654
Carcinogenesis. 2014 Sep;35(9):1931-40
24503442
J Mol Cell Cardiol. 2015 Feb;79:54-68
25450615
World J Gastroenterol. 2013 Jul 14;19(26):4155-65
23864778
Apoptosis. 2015 Jul;20(7):1016-7
25931313
Cancer Prev Res (Phila). 2015 Aug;8(8):662-74
26076697
Med Oncol. 2015 Apr;32(4):133
25796504
Pituitary. 2011 Jun;14(2):112-24
21063788