Rapamycin-upregulated miR-29b promotes mTORC1-hyperactive cell growth in TSC2-deficient cells by downregulating tumor suppressor retinoic acid receptor β (RARβ).

Abstract

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 (RARβ) as a target gene of miR-29b. We found that miR-29b directly targeted the 3'UTR of RARβ. Forced expression of RARβ 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 RARβ 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 RARβ. Overexpression of ING4 inhibited the migration and invasion of Tsc2-deficient cells while silencing of ING4 reversed the RARβ-mediated suppression of cell migration and invasion. Taken together, our findings reveal a novel miR-29b/RARβ/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.

• Authors: Heng-Jia Liu, Hilaire C Lam, Christian V Baglini, Julie Nijmeh, Alischer A Cottrill, Stephen Y Chan, Elizabeth P Henske
• Journal: Oncogene (Oncogene) Vol. 38 Issue 49 Pg. 7367-7383 (12 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 31420607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• MIRN29 microRNA, mouse
• MicroRNAs
• Receptors, Retinoic Acid
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• retinoic acid receptor beta
• Mechanistic Target of Rapamycin Complex 1
• Sirolimus

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis
• Carcinoma, Renal Cell (genetics, metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Embryo, Mammalian (cytology, drug effects, metabolism)
• Female
• Fibroblasts (cytology, drug effects, metabolism)
• Gene Expression Regulation
• Humans
• Kidney Neoplasms (genetics, metabolism, pathology)
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Mice, Nude
• MicroRNAs (genetics)
• Receptors, Retinoic Acid (genetics, metabolism)
• Sirolimus (pharmacology)
• Tuberous Sclerosis Complex 2 Protein (physiology)
• Tumor Cells, Cultured
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)
• Xenograft Model Antitumor Assays