miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

Abstract

Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) plays a critical role in tumorigenesis. However, the precise underlying mechanism is still not fully understood. Although accumulating evidence suggests that mTORC1 signaling is regulated by microRNAs (miRNAs), whether miRNAs are involved in the tumorigenesis mediated by mTORC1 dysregulation remains largely unclear. In our study, the comparison between tuberous sclerosis complex 1 (Tsc1) -/-or Tsc2-/-mouse embryonic fibroblasts (MEFs) and the control cells revealed the involvement of microRNA-125b-5p (miR-125b-5p) in the tumorigenesis driven by mTORC1 activation. Our study also showed that loss of TSC1 or TSC2 led to significant downregulation of miR-125b-5p and upregulation of signal transducer and activator of transcription 3 (STAT3) via mTORC1 activation. Overexpression of miR-125b-5p inhibited the proliferation of the cells with hyperactivated mTORC1 both in vitro and in vivo. Furthermore, we demonstrated that STAT3 is a direct target of miR-125b-5p. Depletion of STAT3 mimicked the effect of ectopic expression of miR-125b-5p, and reintroduction of STAT3 rescued the compromised cell proliferation driven by miR-125b-5p overexpression in Tsc1-/-or Tsc2-/-MEFs. We conclude that the miR-125b-5p/STAT3 pathway plays a crucial role in hyperactivated mTORC1-mediated tumorigenesis and miR-125b-5p is a potential therapeutic target.

RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

“…Thus, these findings provide the first evidence that mTORC1 activates STAT3, at least in part, by transactivating EGFR expression. Together with previous findings that mTORC1 upregulates STAT3 protein levels by virtue of the suppression of miR-125b-5p and that mTORC1 can phosphorylate STAT3 at Ser727, 48 , 49 these findings indicate that mTORC1 modulates STAT3 at multiple levels.…”

Differential miRNA Expression Profiling Reveals Correlation of miR125b-5p with Persistent Infection of Japanese Encephalitis Virus

“…Stat3 plays a key role in many cellular processes such as cell growth and apoptosis [ 56 ]. It has been shown that miR-125b-5p displays a tumor-suppressive role via targeting STAT3 [ 57 ]. These reports imply that both phosphorylating and dephosphorylating proteins could be regulated by miR-125b-5p and control the development of persistent infection.…”

STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth

“…Because the TSC1/TSC2 complex is the principal suppressor of mTORC1 signaling and hyperactivated mTORC1 is the main reason for tumor formation in TSC disease [ 24 ], Tsc1 − / − or Tsc2 − / − MEFs and TSC samples are excellent models for the study of mTORC1 signaling. In our previous study, 51 differentially expressed miRNAs (13 upregulated and 38 downregulated) in Tsc2 − / − MEFs as compared with Tsc2 + / + MEFs (fold change > 2) were identified [ 25 ]. To examine effectively functional miRNAs downstream of mTORC1, a Venn analysis was performed using the aforementioned 51 miRNAs and miRNAs that are abnormally expressed in the serum of patients with TSC [ 26 ].…”