Cervical cancer is induced by
persistent infections with high-risk human papillomaviruses (HPVs), which produce the early
protein 6 of HPVs (E6)/E7
protein that is involved in cell transformation by interacting with several
oncoproteins or
tumor suppressors. However, the role of
noncoding RNA in mediating the pathogenesis of
cervical cancer remains unclear. Here, we report that the novel
signal transducer and activator of transcription 3 (STAT3)-microRNA-223-3p (miR-223)-
TGFBR3/HMGCS1 axis regulated by the E6
protein controls cervical
carcinogenesis. miR-223 was highly expressed in cervical
tumor tissues, whereas
TGFBR3 or HMGCS1 was significantly downregulated. miR-223 targeted the 3'-UTRs of
TGFBR3 and HMGCS1 and suppressed their expression, leading to increased anchorage-independent growth and cervical
squamous cell carcinoma (CSCC)
tumor growth in vitro and in vivo. The increased expression of miR-223 was mediated by the
transcription factor STAT3, whose activity was enhanced by E6 in the context of
interleukin (IL)-6 stimulation. In addition, exosomal miR-223 derived from CSCC cells induced
IL-6 secretion by monocyte/macrophage in a coculture system in vitro, and
IL-6 secretion, in turn, led to enhanced STAT3 activity in CSSC cells, forming a positive feedback loop. Furthermore, modified miR-223 inhibitor effectively suppressed
tumor growth in cell line-derived xenograft model, suggesting that miR-223 is a potential promising therapeutic target in CSCC. In conclusion, our results demonstrate that the STAT3-miR-223-HMGCS1/
TGFBR3 axis functions as a key signaling pathway in
cervical cancer progression and provides a new therapeutic target.