Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient’s likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.
Young-Ho Ahn, Don L. Gibbons, Deepavali Chakravarti, Chad J. Creighton, Zain H. Rizvi, Henry P. Adams, Alexander Pertsemlidis, Philip A. Gregory, Josephine A. Wright, Gregory J. Goodall, Elsa R. Flores, Jonathan M. Kurie
Title and authors | Publication | Year |
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ZEB1 Sensitizes Lung Adenocarcinoma to Metastasis Suppression by PI3K Antagonism
Yanan Yang, Young-Ho Ahn, Yulong Chen, Xiaochao Tan, Lixia Guo, Don Gibbons, Christin Ungewiss, David Peng, Xin Liu, Steven Lin, Nishan Thilaganathan, Ignacio Wistuba, Jaime Rodriguez, Georgia McLendon, Chad Creighton, Jonathan Kurie |
Journal of Clinical Investigation | 2014 |
FRA-1 as a driver of tumour heterogeneity: a nexus between oncogenes and embryonic signalling pathways in cancer
AS Dhillon, E Tulchinsky |
Oncogene | 2014 |
MicroRNA in lung cancer
P Joshi |
World Journal of Methodology | 2014 |
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JM Bouyssou, S Manier, D Huynh, S Issa, AM Roccaro, IM Ghobrial |
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | 2014 |
MicroRNA regulation of tumorigenesis, cancer progression and interpatient heterogeneity: towards clinical use
SP Nana-Sinkam, CM Croce |
Genome biology | 2014 |
Smoking, p53 Mutation, and Lung Cancer
DL Gibbons, LA Byers, JM Kurie |
Molecular cancer research : MCR | 2014 |
Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression
L Chen, DL Gibbons, S Goswami, MA Cortez, YH Ahn, LA Byers, X Zhang, X Yi, D Dwyer, W Lin, L Diao, J Wang, JD Roybal, M Patel, C Ungewiss, D Peng, S Antonia, M Mediavilla-Varela, G Robertson, S Jones, M Suraokar, JW Welsh, B Erez, II Wistuba, L Chen, D Peng, S Wang, SE Ullrich, JV Heymach, JM Kurie, FX Qin |
Nature Communications | 2014 |
The p53/microRNA connection in gastrointestinal cancer
H Hermeking, M Rokavec, H Li, L Jiang |
Clinical and experimental gastroenterology | 2014 |
MicroRNA and gene networks in human diffuse large B-cell lymphoma
Kunhao Wang, Zhiwen Xu, Ning Wang, Ting Xu, Minghui Zhu |
Oncology Letters | 2014 |
Mir-34: A New Weapon Against Cancer?
G Misso, MT di Martino, GD Rosa, AA Farooqi, A Lombardi, V Campani, MR Zarone, A Gullà, P Tagliaferri, P Tassone, M Caraglia |
Molecular Therapy — Nucleic Acids | 2014 |
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Agostini M, Knight RA |
Oncotarget | 2014 |