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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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC7463355 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Zhang Ju J Jiang Ming M Qian Lili L Lin Xiao X Song Weiguo W Gao Yunfeng Y Zhou Ying Y

Molecular oncology 20200701 9

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 regul ...[more]

PMID: 32491253

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Project description:Long non‑coding RNA forkhead box D3 antisense RNA 1 (FOXD3‑AS1) functions as an oncogenic regulator in several types of cancer, including breast cancer, glioma and cervical cancer. However, the effects and mechanisms underlying FOXD3‑AS1 in cervical cancer (CC) are not completely understood. The present study aimed to investigate the biological functions and potential molecular mechanisms underlying FOXD3‑AS1 in CC progression. Reverse transcription‑quantitative PCR was performed to detect FOXD3‑AS1, microRNA (miR)‑128‑3p and LIM domain kinase 1 (LIMK1) expression levels in CC tissues and cells. Immunohistochemical staining and western blotting were conducted to assess LIMK1 protein expression levels in CC tissues and cells, respectively. Cell Counting Kit‑8 and BrdU assays were used to determine the role of FOXD3‑AS1 in regulating cell proliferation. CC cell migration and invasion were assessed by performing Transwell assays. Dual‑luciferase reporter assays were conducted to verify the binding between miR‑128‑3p and FOXD3‑AS1. FOXD3‑AS1 expression was significantly increased in CC tissues and cell lines compared with adjacent healthy tissues and normal cervical epithelial cells, respectively. High FOXD3‑AS1 expression was significantly associated with poor differentiation of tumor tissues, increased tumor size and positive lymph node metastasis. FOXD3‑AS1 overexpression significantly increased CC cell proliferation, migration and invasion compared with the negative control (NC) group, whereas FOXD3‑AS1 knockdown resulted in the opposite effects compared with the small interfering RNA‑NC group. Moreover, the results demonstrated that FOXD3‑AS1 targeted and negatively regulated miR‑128‑3p, which indirectly upregulated LIMK1 expression. Therefore, the present study demonstrated that FOXD3‑AS1 upregulated LIMK1 expression via competitively sponging miR‑128‑3p in CC cells, promoting CC progression.

Dataset Information

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

Publications

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

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