miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer.
Accumulating evidence indicates that altered miRNA expression is crucially involved in lung cancer development, though scant information is available regarding how MYC, an archetypical oncogene, is regulated by miRNAs, especially via a mechanism involving MYC cofactors. In this study, we attempted to identify miRNAs involved in regulation of MYC transcriptional activity in lung cancer. To this end, we utilized an integrative approach with combinatorial usage of miRNA and mRNA expression profile datasets of patient tumor tissues, as well as those of MYC-inducible cell lines in vitro. In addition to miRNAs previously reported to be directly regulated by MYC, including let-7 and miR-17-92, our strategy also helped to identify miR-342-3p as capable of indirectly regulating MYC activity via direct repression of E2F1, a MYC-cooperating molecule. Furthermore, miR-342-3p module activity, which we defined as a gene set reflecting the experimentally substantiated influence of miR-342-3p on mRNA expression, was found to be inversely correlated with MYC activity reflected by MYC module activity in three independent datasets of lung adenocarcinoma patients obtained from the Director's Challenge Consortium of the United States (P = 1.94 × 10(-73)), the National Cancer Center of Japan (P = 9.05 × 10(-34)) and the present study (P = 1.17 × 10(-19)). Our integrative approach appears to be useful to elucidate inter-regulatory relationships between miRNAs and protein coding genes of interest, even those present in patient tumor tissues, which remains a challenge to better understand the pathogenesis of this devastating disease.
Mei Chee
MC
Tai
Taisuke
T
Kajino
Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
Masahiro
M
Nakatochi
Chinatsu
C
Arima
Yukako
Y
Shimada
Motoshi
M
Suzuki
Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN, Tsukuba, Japan and.
Hiroyuki
H
Miyoshi
Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.
Yasushi
Y
Yatabe
Kiyoshi
K
Yanagisawa
Takashi
T
Takahashi
D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D034622:RNA Interference; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D020413:3' Untranslated Regions; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C546176:MIRN342 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc