| First Author | Liu HJ | Year | 2019 |
| Journal | Oncogene | Volume | 38 |
| Issue | 49 | Pages | 7367-7383 |
| PubMed ID | 31420607 | Mgi Jnum | J:304587 |
| Mgi Id | MGI:6695686 | Doi | 10.1038/s41388-019-0957-5 |
| Citation | Liu HJ, et al. (2019) Rapamycin-upregulated miR-29b promotes mTORC1-hyperactive cell growth in TSC2-deficient cells by downregulating tumor suppressor retinoic acid receptor beta (RARbeta). Oncogene 38(49):7367-7383 |
| abstractText | miR-29b has been identified as a rapamycin-induced microRNA (miRNA) in Tsc2-deficient, mTORC1-hyperactive cells. The biological significance of this induction of miR-29b is unknown. We have found that miR-29b acts as an oncogenic miRNA in Tsc2-deficient cells: inhibition of miR-29b suppressed cell proliferation, anchorage-independent cell growth, cell migration, invasion, and the growth of Tsc2-deficient tumors in vivo. Importantly, the combination of miR-29b inhibition with rapamycin treatment further inhibited these tumor-associated cellular processes. To gain insight into the molecular mechanisms by which miR-29b promotes tumorigenesis, we used RNA sequencing to identify the tumor suppressor retinoid receptor beta (RARbeta) as a target gene of miR-29b. We found that miR-29b directly targeted the 3'UTR of RARbeta. Forced expression of RARbeta reversed the effects of miR-29b overexpression in proliferation, migration, and invasion, indicating that it is a critical target. miR-29b expression correlated with low RARbeta expression in renal clear cell carcinomas and bladder urothelial carcinomas, tumors associated with TSC gene mutations. We further identified growth family member 4 (ING4) as a novel interacting partner of RARbeta. Overexpression of ING4 inhibited the migration and invasion of Tsc2-deficient cells while silencing of ING4 reversed the RARbeta-mediated suppression of cell migration and invasion. Taken together, our findings reveal a novel miR-29b/RARbeta/ING4 pathway that regulates tumorigenic properties of Tsc2-deficient cells, and that may serve as a potential therapeutic target for TSC, lymphangioleiomyomatosis (LAM), and other mTORC1-hyperactive tumors. |
