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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 31, 2011 |
| Title |
TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Adenocarcinoma is the most common histologic subtype of lung cancer, which is the leading cause of cancer death. We and others previously identified TTF-1, a lineage-specific transcription factor required for branching morphogenesis and physiological lung functions, as a lineage-survival oncogene in lung adenocarcinoma. However, how TTF-1 mediates survival signals remains elusive. Here we show that TTF-1 induces receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn mediates TTF-1 survival signaling in lung adenocarcinoma. Inhibition of ROR1 impaired prosurvival signaling through the PI3K-AKT pathway and induced nuclear accumulation of FOXO1. These were found to be imposed, at least in part, through PTEN inactivation via c-Src, while ROR1 was shown to physically interact with and phosphorylate c-Src. ROR1 inhibition also elicited marked p38 activation, provoking ill-balance between prosurvival and proapoptotic signaling, and consequential “oncogenic shock.” In addition, we found that ROR1 is crucially involved in EGFR- and MET-mediated prosurvival signaling. ROR1 knockdown effectively induced apoptosis in lung adenocarcinoma cell lines with acquired EGFR TKI resistance conferred by a secondary T790M EGFR mutation, or HGF-elicited MET signaling and resultant switching of the addicted receptor tyrosine kinases (RTKs). Taken together, our findings indicate that ROR1 RTK is a very promising molecular target for development of a novel therapeutic means to treat this hard-to-cure cancer.
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| Overall design |
Dye-swap experiment, vector control vs. stable TTF-1 transfectant of HPL1D, immortalized human peripheral lung epithelial cell line.
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| Contributor(s) |
Yamaguchi T, Sugiyama R, Yanagisawa K, Hosono Y, Shimada Y, Arima C, Kato S, Tomida S, Suzuki M, Osada H, Takahashi T |
| Citation(s) |
22439932 |
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| Submission date |
Dec 03, 2010 |
| Last update date |
Dec 06, 2012 |
| Contact name |
Takashi Takahashi |
| Organization name |
Aichi Cancer Center
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| Street address |
1-1 Kanokoden, Chikusa-ku
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| City |
Nagoya |
| State/province |
Aichi |
| ZIP/Postal code |
464-8681 |
| Country |
Japan |
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| Platforms (1) |
| GPL1708 |
Agilent-012391 Whole Human Genome Oligo Microarray G4112A (Feature Number version) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA135741 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE25830_RAW.tar |
26.9 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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