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Published in: Journal of Cancer Research and Clinical Oncology 8/2012

01-08-2012 | Original Paper

Tumor suppressor miR-22 suppresses lung cancer cell progression through post-transcriptional regulation of ErbB3

Authors: Bo Ling, Gui-Xue Wang, Guang Long, Ju-Hui Qiu, Zhong-Lei Hu

Published in: Journal of Cancer Research and Clinical Oncology | Issue 8/2012

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Abstract

Background

Development of efficient therapies of lung cancer and deep understanding of their anti-tumor mechanism are very important. The aim of the present study is to investigate the therapeutic effect of microRNA-22 (miR-22) on lung cancer using in vitro and in vivo methods.

Methods

Expression level of miR-22 in lung cancer specimens and relative normal tissues was detected by microRNA-specific quantitative real-time PCR (Q-PCR). Invasion assay, cell counting kit-8 assay, and Annexin V/7-AAD analysis were performed to test the invasion and proliferation of lung cancer cell after transfection. The effect of miR-22 on lung cancer in vivo was validated by murine xenograft model.

Results

Q-PCR detection of miR-22 in clinical samples showed that the relative expression level of miR-22 in lung cancer tissues and lung cancer cell lines was lower than that in normal tissues. Transfection of miR-22 expression plasmids could significantly inhibit the increased cell numbers and invasion of A549 and H1299 lung cancer cell lines. Furthermore, miR-22 was demonstrated to inhibit the expression of ErbB3 through post-transcriptional regulation via binding to ErbB3 3’-UTR. Co-transfection of ErbB3 expression plasmid could promote the proliferation and invasion of A549 and H1299. In vivo experiments using nude mice demonstrated that over-expression of miR-22 could significantly decrease the volume and weight of tumors.

Conclusions

miR-22 exhibited excellent anti-lung cancer activity in vitro and in vivo, and post-transcriptional regulation of ErbB3 might be a potential mechanism.
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Literature
go back to reference Bar N, Dikstein R (2010) miR-22 foms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics. PLoS One 5:e10859PubMedCrossRef Bar N, Dikstein R (2010) miR-22 foms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics. PLoS One 5:e10859PubMedCrossRef
go back to reference Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C, Cichowski K, Johnson BE, Cantley LC (2005) ErbB3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 102:3788–3793PubMedCrossRef Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C, Cichowski K, Johnson BE, Cantley LC (2005) ErbB3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 102:3788–3793PubMedCrossRef
go back to reference Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114PubMedCrossRef Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114PubMedCrossRef
go back to reference Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 100:8933–8938PubMedCrossRef Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 100:8933–8938PubMedCrossRef
go back to reference Jemal A, Bray F, Center MM, Felay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRef Jemal A, Bray F, Center MM, Felay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRef
go back to reference Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139PubMedCrossRef Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139PubMedCrossRef
go back to reference Laskin JJ, Sandler AB (2005) State of the art in therapy for non-small cell lung cancer. Cancer Invest 23:427–442PubMedCrossRef Laskin JJ, Sandler AB (2005) State of the art in therapy for non-small cell lung cancer. Cancer Invest 23:427–442PubMedCrossRef
go back to reference Pandey DP, Picard D (2009) miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. Mol Cell Biol 29:3783–3790PubMedCrossRef Pandey DP, Picard D (2009) miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. Mol Cell Biol 29:3783–3790PubMedCrossRef
go back to reference Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, Wong KK (2010) An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res 2010(70):2485–2494CrossRef Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, Wong KK (2010) An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res 2010(70):2485–2494CrossRef
go back to reference Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, Moustafa Z, Thomas RK, Greulich H, Schinzel A, Zaghlul S, Batt D, Ettenberg S, Meyerson M, Schoeberl B, Kung AL, Hahn WC, Drapkin R, Livingston DM, Liu JF (2010) An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17:298–310PubMedCrossRef Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, Moustafa Z, Thomas RK, Greulich H, Schinzel A, Zaghlul S, Batt D, Ettenberg S, Meyerson M, Schoeberl B, Kung AL, Hahn WC, Drapkin R, Livingston DM, Liu JF (2010) An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17:298–310PubMedCrossRef
go back to reference Wang H, Wu J, Meng X, Ying X, Zuo Y, Liu R, Pan Z, Kang T, Huang W (2011) MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Carcinogenesis 32:1033–1042PubMedCrossRef Wang H, Wu J, Meng X, Ying X, Zuo Y, Liu R, Pan Z, Kang T, Huang W (2011) MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Carcinogenesis 32:1033–1042PubMedCrossRef
go back to reference Xiong J, Yu D, Wei N, Fu H, Cai T, Huang Y, Wu C, Zheng X, Du Q, Lin D, Liang Z (2010a) An estrogen receptor alpha suppressor, microRNA-22, is downregulated in estrogen receptor alpha-positive human breast cancer cell lines and clinical samples. FEBS J 277:1684–1694PubMedCrossRef Xiong J, Yu D, Wei N, Fu H, Cai T, Huang Y, Wu C, Zheng X, Du Q, Lin D, Liang Z (2010a) An estrogen receptor alpha suppressor, microRNA-22, is downregulated in estrogen receptor alpha-positive human breast cancer cell lines and clinical samples. FEBS J 277:1684–1694PubMedCrossRef
go back to reference Xiong J, Du Q, Liang Z (2010b) Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein. Oncogene 29:4980–4988PubMedCrossRef Xiong J, Du Q, Liang Z (2010b) Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein. Oncogene 29:4980–4988PubMedCrossRef
go back to reference Xu D, Takeshita F, Hino Y, Fukunaga S, Kudo Y, Tamaki A, Matsunaga J, Takahashi R, Takata T, Shimamoto A, Ochiya T, Tahara H (2011) miR-22 represses cancer progression by inducing cellular senescence. J Cell Biol 193:409–424PubMedCrossRef Xu D, Takeshita F, Hino Y, Fukunaga S, Kudo Y, Tamaki A, Matsunaga J, Takahashi R, Takata T, Shimamoto A, Ochiya T, Tahara H (2011) miR-22 represses cancer progression by inducing cellular senescence. J Cell Biol 193:409–424PubMedCrossRef
go back to reference Yamakuchi M, Yagi S, Ito T, Lowenstein CJ (2011) MicroRNA-22 regulates hypoxia signaling in colon cancer cells. PLoS One 6:e20291PubMedCrossRef Yamakuchi M, Yagi S, Ito T, Lowenstein CJ (2011) MicroRNA-22 regulates hypoxia signaling in colon cancer cells. PLoS One 6:e20291PubMedCrossRef
go back to reference Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S, Wu M, Pan Z, Zhou W (2010) microRNA-22, downregulated in heptocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 103:1215–1220PubMedCrossRef Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S, Wu M, Pan Z, Zhou W (2010) microRNA-22, downregulated in heptocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 103:1215–1220PubMedCrossRef
Metadata
Title
Tumor suppressor miR-22 suppresses lung cancer cell progression through post-transcriptional regulation of ErbB3
Authors
Bo Ling
Gui-Xue Wang
Guang Long
Ju-Hui Qiu
Zhong-Lei Hu
Publication date
01-08-2012
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 8/2012
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-012-1194-2

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