Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression.
The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.
Genome Institute of Singapore, Singapore 138672, Singapore.
Wen Cai
WC
Zhang
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.|Department of Haematology-Oncology, National University Cancer Institute, Singapore 119074, Singapore.
Tan Min
TM
Chin
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
Henry
H
Yang
Department of Pathology, National University Hospital, Singapore 119074, Singapore.
Min En
ME
Nga
Institute of Medical Biology, Singapore 138648, Singapore.
Declan Patrick
DP
Lunny
Genome Institute of Singapore, Singapore 138672, Singapore.
Edwin Kok Hao
EK
Lim
Genome Institute of Singapore, Singapore 138672, Singapore.
Li Li
LL
Sun
Department of Pathology, National University Hospital, Singapore 119074, Singapore.
Yin Huei
YH
Pang
Genome Institute of Singapore, Singapore 138672, Singapore.
Yi Ning
YN
Leow
Genome Institute of Singapore, Singapore 138672, Singapore.
Shanneen Rossellini Y
SR
Malusay
Genome Institute of Singapore, Singapore 138672, Singapore.
Priscilla Xin Hui
PX
Lim
Genome Institute of Singapore, Singapore 138672, Singapore.
Jeravan Zili
JZ
Lee
Genome Institute of Singapore, Singapore 138672, Singapore.
Benedict Jian Wei
BJ
Tan
Genome Institute of Singapore, Singapore 138672, Singapore.
Ng
N
Shyh-Chang
Department of Respiratory Medicine, Tan Tock Seng Hospital, Singapore 308433, Singapore.|Department of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
Elaine Hsuen
EH
Lim
Department of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
Wan Teck
WT
Lim
Genome Institute of Singapore, Singapore 138672, Singapore.|Department of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
Daniel Shao Weng
DS
Tan
Department of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
Eng Huat
EH
Tan
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore.
Bee Choo
BC
Tai
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.|Department of Haematology-Oncology, National University Cancer Institute, Singapore 119074, Singapore.
Ross Andrew
RA
Soo
Genome Institute of Singapore, Singapore 138672, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Wai Leong
WL
Tam
Genome Institute of Singapore, Singapore 138672, Singapore.
Bing
B
Lim
D000072283:A549 Cells; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008207:Lymphatic Metastasis; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D016019:Survival Analysis; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
C577700:MIRN1246 microRNA, human; C574604:MIRN1290 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D011799:Quinazolines; C477371:locked nucleic acid; D006886:Hydroxychloroquine; D000077156:Gefitinib