title: MicroRNA profile of tumorigenic cells during carcinogenesis of lung adenocarcinoma.
abstract: To obtain microRNA (miRNA) profile and clarify their biological function in tumorigenic Sca-1(+) CD34(+) cells during carcinogenesis of lung adenocarcinoma. After intranasal infection with recombinant Adeno-Cre viruses (AdV-Cre), lung adenocarcinoma was identified pathologically in Lox-stop-lox Kras (LSL-Kras) G12D mice. Sca-1(+) CD34(+) cells were sorted by flow cytometry and tested for tumor-initiating ability, self-renewal and tumorigenicity. MiRNA profiles were obtained using microarray and further confirmed by real-time RT-PCR (qRT-PCR). MiRNA functions were predicted bioinformatically, and miR-294 function was verified to explore its role in tumor migration and invasion. Lung adenocarcinoma was induced in LSL-Kras G12D mice within 30 days. In vivo, the tumorigenicity of Sca-1(+) CD34(+) cells was 25 times stronger than Sca-1(-) CD34(-) cells. During tumorigenesis of lung adenocarcinoma, the expression of 145 miRNAs in Sca-1(+) CD34(+) cells increased and 72 miRNAs decreased (P < 0.01). Four successively up-regulated miRNAs (miR-15a*, miR-203, miR-294 and miR-295*) and three successively down-regulated ones (miR-19b, miR-483 and miR-615-5p) were identified. Among them, miR-294 could constitutively bind to 3'-UTR of matrix metalloproteinase 3 (MMP3), and down-regulate MMP3 protein expression. MiR-294 also significantly inhibited migration and invasion of Lewis lung cancer cells. MiRNAs are characteristically expressed in tumor-initiating Sca-1(+) CD34(+) cells of lung adenocarcinoma, and may play important roles during the carcinogenesis of lung adenocarcinoma.
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Zhen-guo
authors.initials: ZG
authors.lastname: Zhao
authors.forename: Jun-yu
authors.initials: JY
authors.lastname: Jin
authors.forename: An-mei
authors.initials: AM
authors.lastname: Zhang
authors.forename: Lu-ping
authors.initials: LP
authors.lastname: Zhang
authors.forename: Xin-xin
authors.initials: XX
authors.lastname: Wang
authors.forename: Jian-guo
authors.initials: JG
authors.lastname: Sun
authors.forename: Zheng-tang
authors.initials: ZT
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002469:Cell Separation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015203:Reproducibility of Results
chemical_list: D018952:Antigens, CD34; D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs
keywords: CARCINOGENESIS; LUNG ADENOCARCINOMA; TUMORIGENIC CELLS; miRNAs