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

Abstract

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.

Histone deacetylase 10 exerts antitumor effects on cervical cancer via a novel microRNA‐223/TXNIP/Wnt/β‐catenin pathway

“…Intriguingly, miR-223 was highly expressed in CC tissues, 15 and the increased expression of miR-223 in CC tissues was possibly modulated by the transcription factor STAT3. 16 Our prediction using the UCSC bioinformatics website and ChIP assay revealed that HDAC10 bound to the miR-223 promoter and positively regulated its acetylation level, indicating a novel acetylation-dependent regulation of miR-223 upregulation in CC. miR-223 was upregulated in gastric cancer, which predicted poor disease-specific survival.…”

Extracellular Vesicles in Cervical Cancer and HPV Infection

“…This IL-6 promoted STAT3 activation in SiHa cells and consequently a positive regulation of miR-223. This positive feedback through STAT3 hyperactivation could be critical for cell cycle progression and neoplastic transformation [ 59 ]. Another miRNA, the exosomal miR-1468-5p, can suppress HMBOX1-SOCS1 expression and activate JAK2/STAT3 signaling in lymphocytes promoting immune escape of cancer cells and tumor progression [ 60 ].…”

“…Small arrows indicate increase or decrease of the molecules or processes indicated. References for a: [ 24 , 42 ]; b: [ 25 ]; c: [ 26 ]; d: [ 33 ]; e: [ 55 , 56 , 57 , 64 ]; f: [ 58 ]; g: [ 59 , 60 ]. Some images are from .…”

Transcriptome Analysis of Cervical Cancer Exosomes and Detection of HPVE6*I Transcripts in Exosomal RNA

“…Tumor-derived exosomes have emerged as mediators of cancer initiation, tumor promotion, metastastic spread, enhanced angiogenesis and drug resistance in a variety of cancers by conditioning the stromal cells and the tumor microenvironment (4,5). Cervical cancer exosomes are known to regulate metastasis (6, 7), angiogenesis (8,9), drug resistance (10,11) and tumor progression (12). All three major classes of macromolecules namely DNA, RNA and proteins have been reported in tumor exosomes (13).…”

“…Multiple RNA types are packaged into the exosomal RNA pool, which include selected portion of the source cell's RNA spectrum (15). Small non-coding RNAs are the dominant molecules of the exosomal RNA cargo (7)(8)(9)(10)12). Similarly, a differential exosomal export of lncRNAs HOTAIR, MALAT1, and MEG3 levels in cervico-lavage samples correlated with cervical cancer progression(16).…”