The STAT3‐miR‐223‐TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma

• Published in: Molecular oncology 2020-09, Vol.14 (9), p.2313-2331
• Main Authors: Zhang, Ju, Jiang, Ming, Qian, Lili, Lin, Xiao, Song, Weiguo, Gao, Yunfeng, Zhou, Ying
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Binding sites; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cervical cancer; Cervical carcinoma; Cervix; Cytokines; Disease Progression; E6 protein; E7 protein; Enzymes; Exosomes - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic; Growth factors; HMGCS1; Human papillomavirus; Humans; Hydroxymethylglutaryl-CoA Synthase - genetics; Hydroxymethylglutaryl-CoA Synthase - metabolism; Interleukin-6 - metabolism; Macrophages; Macrophages - metabolism; Mice, Nude; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; miR‐223; Models, Biological; Monocytes; Monocytes - metabolism; Neoplasm Staging; Papillomaviridae; Plasmids; Proteins; Proteoglycans - genetics; Proteoglycans - metabolism; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; Squamous cell carcinoma; Stat3 protein; STAT3 Transcription Factor - metabolism; TGFBR3; Therapeutic applications; Transcription, Genetic; Up-Regulation - genetics; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology; Xenografts
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.12737

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. Human papillomaviruses (HPVs) produce early protein 6 of HPVs protein in infected female cervical tissue cells to enhance signal transducer and activator of transcription 3 (STAT3) activation, which promotes microRNA‐223‐3p (miR‐223) transcription, leading to normal tissue to cervical squamous cancer transformation. Mechanistically, miR‐223 represses TGFBR3 or HMGCS1 at post‐transcriptional level. In tumor loci, exosomal miR‐223 derived from cervical cancer cells induces interleukin‐6 secretion of monocyte/macrophage, which, in turn, stimulates STAT3 signals.