Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p.
KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3'UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients. Rescue experiments with mutated KRas 3'UTR showed very significantly that the anti-tumour effect of miR-193a-3p is via specific direct targeting of KRas and not due to other targets. Ex vivo and in vivo studies utilizing nanoliposome packaged miR-193a-3p demonstrated significant inhibition of tumour growth, circulating tumour cell viability and decreased metastasis. These studies show the broader applicability of using miR-193a-3p as a therapeutic agent to target KRas-mutant cancer.
Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
E G
EG
Seviour
Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
V
V
Sehgal
Methodist Hospital Research Institute, Houston, TX, USA.
D
D
Mishra
Department of Gynecologic Oncology, UTMDACC, Houston, TX, USA.
R
R
Rupaimoole
Department of Experimental Therapeutics, UTMDACC, Houston, TX, USA.
C
0000-0002-7880-7723
C
Rodriguez-Aguayo
Department of Experimental Therapeutics, UTMDACC, Houston, TX, USA.|Center for RNA Interference and Non-coding RNA, UTMDACC, Houston, TX, USA.
G
G
Lopez-Berestein
Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.|Center for RNA Interference and Non-coding RNA, UTMDACC, Houston, TX, USA.
J-S
JS
Lee
Department of Gynecologic Oncology, UTMDACC, Houston, TX, USA.|Center for RNA Interference and Non-coding RNA, UTMDACC, Houston, TX, USA.
A K
AK
Sood
Methodist Hospital Research Institute, Houston, TX, USA.
M P
MP
Kim
Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
G B
GB
Mills
Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.|Center for RNA Interference and Non-coding RNA, UTMDACC, Houston, TX, USA.
P T
PT
Ram
D020413:3' Untranslated Regions; D002453:Cell Cycle; D045744:Cell Line, Tumor; D030541:Databases, Genetic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics
D020413:3' Untranslated Regions; C117307:KRAS protein, human; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016283:Proto-Oncogene Proteins p21(ras)
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