- Title
- MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer
- Creator
- Guo, S. T.; Jiang, C. C.; Thorne, R. F.; Jin, L.; Zhang, X. D.; Wang, G. P.; Li, Y. P.; Wang, C. Y.; Guo, X. Y.; Yang, R. H.; Feng, Y.; Wang, F. H.; Tseng, H-Y.
- Relation
- NSW State Cancer Council
- Relation
- Oncogene Vol. 32, Issue 15, p. 1910-1920
- Publisher Link
- http://dx.doi.org/10.1038/onc.2012.214
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2013
- Description
- Past studies have shown that amplified insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1-R) signalling has an important role in colorectal cancer (CRC) development, progression and resistance to treatment. In this report, we demonstrate that downregulation of microRNA-497 (miR-497) as a result of DNA copy number reduction is involved in upregulation of IGF1-R in CRC cells. MiR-497 and miR-195 of the miR-15/16/195/424/497 family that share the same 3' untranslated region (3′UTR) binding seed sequence and are predicted to target IGF1-R were concurrently downregulated in the majority of CRC tissues relative to paired adjacent normal mucosa. However, only overexpression of miR-497 led to suppression of the IGF1-R 3′UTR activity and downregulation of the endogenous IGF1-R protein in CRC cells. This was associated with inhibition of cell survival, proliferation and invasion, and increased sensitivity to apoptosis induced by various stimuli including the chemotherapeutic drugs cisplatin and 5-fluorouracil, and the death ligand tumour necrosis factor-related apoptosis-inducing ligand. The biological effect of miR-497 on CRC cells was largely mediated by inhibition of phosphatidylinositol 3-kinase/Akt signalling, as overexpression of an active form of Akt reversed its impact on cell survival and proliferation, recapitulating the effect of overexpression of IGF1-R. Downregulation of miR-497 and miR-195 appeared to associate with copy number loss of a segment of chromosome 17p13.1, where these miRs are located at proximity. Similarly to miR-195, the members of the same miR family, miR-424 that was upregulated, and miR-15a, miR-15b and miR-16 that were unaltered in expression in CRC tissues compared with paired adjacent normal mucosa, did not appear to have a role in regulating the expression of IGF1-R. Taken together, these results identify downregulation of miR-497 as an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.
- Subject
- colorectal cancer; miR-497; IGF1-R; Akt; copy number variations
- Identifier
- http://hdl.handle.net/1959.13/1063337
- Identifier
- uon:17258
- Identifier
- ISSN:0950-9232
- Language
- eng
- Full Text
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