MicroRNA-125b (miR-125b) is downregulated in human cutaneous squamous cell carcinoma (CSCC).,However, its function in CSCC has yet to be extensively explored.,Here, we analyze the relationship between signal transducer and activator of transcription 3 (STAT3) and miR-125b in CSCC.,Western blotting and quantitative RT-PCR were used to determine the expression of the miR-125b-STAT3 axis in human CSCC tissues and cell lines.,The direct regulatory effect of miR-125b on STAT3 expression was assessed using a luciferase reporter gene assay and RNA immunoprecipitation assay.,The MTT assay and flow cytometry were used to determine the role of the miR-125b-STAT3 axis in CSCC cell proliferation and apoptosis.,MiR-125b expression levels were significantly lower in CSCC cell lines and tissues than in normal cell lines and tissues.,STAT3 was identified as the direct target of miR-125b.,Upregulation of miR-125b and downregulation of STAT3 suppressed cell proliferation and promoted cell apoptosis.,Cyclin D1 and Bcl2 were identified as the downstream targets of the miR-125-STAT3 axis.,Our findings indicate that miR-125b acts as a tumor suppressor in CSCC by targeting the STAT3 pathway.,This observation increases our understanding of the molecular mechanisms of CSCC.,Therapies aimed at activating miR-125b or inhibiting STAT3 signaling should be explored as potential treatments for CSCC.
Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation.,Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC.,Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin.,MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFβ signalling ablation (through Tgfbr1 deletion) in LGR5+ve stem cells enables rapid cSCC development in the mouse.,Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5+ve cells also results in cSCC development.,These findings indicate that LGR5+ve stem cells may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.,Cutaneous squamous cell carcinomas is a growing problem but the driver genes causing this remain poorly defined.,Here, the authors demonstrate that inactivating driver mutations in TGFBR1 and TGFBR2 occur in vemurafenib-induced and sporadic cutaneous squamous cell carcinomas.