Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO

Abstract

ObjectiveTo explore the clinical significance and mechanisms of altered miRNAs in squamous cell carcinoma of head and neck (SCCHN) and provide references for SCCHN diagnosis and prognosis.MethodDifferential expressed miRNAs (DEMs) in SCCHN were screened through gene expression omnibus (GEO) DataSets and verified by the cancer genome atlas (TCGA) database. Next, the overall survival analysis, receiver operating characteristics, and clinical correlation analysis were adopted to filter the miRNAs with diagnostic and prognostic values. Finally, functional enrichment analyses were conducted for inquiring into the mechanisms of miRNAs.ResultsTotal 103 DEMs (p < 0.05, fold change ≥ 2) in SCCHN were screened out from GSE124566. Partly, the expression levels of the selected (12/17) miRNAs were verified by TCGA. Followed, of the 12 miRNAs, two miRNA expression levels were associated with the overall survival, and five miRNAs showed diagnostic values (AUC ≥ 0.85). Besides, miR-223-3p and miR-204-5p expression levels were correlated to certain clinical features. Epithelial–mesenchymal transition (EMT) related biological process and energy metabolism controlling related AMPK signaling pathway might mediate the roles of miR-223-3p and miR-204-5p, respectively.ConclusionWith diagnostic and prognostic values, miR-223-3p and miR-204-5p may be involved in the progression of SCCHN through EMT-related biological process and energy balance related AMPK signaling pathway, respectively.

Macrophage Reprogramming with Anti‐miR223‐Loaded Artificial Protocells Enhances In Vivo Cancer Therapeutic Potential

“…miR223 is an anti‐inflammatory miR that is dysregulated in numerous inflammatory conditions and in several human cancers. [ 13 , 14 , 15 , 16 , 17 , 26 ] Pre‐clinical mouse models have shown that miR223 is highly expressed in myeloid cells during progression of breast cancer and melanoma metastasis. [ 27 ] In the context of wound inflammation, deletion of this miR in mice leads to enhanced clearance of bacteria from infected wounds, [ 18 ] and similarly miR223‐deficient zebrafish exhibit an augmented wound inflammatory response.…”

“…As miR223 has an established role in regulating the pro-inflammatory phenotype of leukocytes, and is very well conserved across species, [20] it may be a therapeutic target, not just for melanoma but for other solid tumors where it also appears to be linked to poor patient prognosis. [14,17] Clearly, such a treatment would be less appropriate for tumor types where Moreover, other known anti-inflammatory miRs could also be similarly targeted by PC-delivered phagocytic uptake, for example, miR21, [52] miR132, [53] or miR146. [54] Alternatively, our novel PC vector approach could be adapted for delivery of small molecules for immune cell reprogramming such as synthetic agonists of endosomal TLR7 (Imiquimod and 852A), TLR7/8 (Resiquimod and 3M-052), and TLR9 (IMO-2055), which have previously been shown to effectively re-polarize macrophages in ways that enhance their anti-tumoral activities in mouse models, and one of which, Imiquimod, is currently approved for local treatment of superficial basal cell carcinoma.…”

“…Our proof of principle studies indicate that therapeutic reprogramming of leukocytes in vivo can significantly inhibit cancer progression in a zebrafish model of melanoma. We first show that the miR223, which often associates with poor cancer prognosis in patients, [ 13 , 14 , 15 , 16 , 17 ] is a good target with a series of genetic knockout and knockdown experiments that result in reduced levels of cancer in juvenile and adult fish. We then test a novel therapeutic strategy involving targeted knockdown of miR223 in neutrophils and macrophages by PC delivery of anti‐miR223 to these phagocytic lineages, and show successful leukocyte reprogramming leading to growth suppression of established adult melanomas.…”

“…As miR223 has an established role in regulating the pro‐inflammatory phenotype of leukocytes, and is very well conserved across species, [ 20 ] it may be a therapeutic target, not just for melanoma but for other solid tumors where it also appears to be linked to poor patient prognosis. [ 14 , 17 ] Clearly, such a treatment would be less appropriate for tumor types where there is no demonstrated association with miR223 expression levels.…”

“…For example, several clinical studies have associated high levels of immune cell‐expressed microRNA‐223 (miR223) with poor prognostic outcome in a range of cancers, including both cutaneous and uveal melanoma, gastric carcinoma, and squamous cell carcinoma of head and neck. [ 13 , 14 , 15 , 16 , 17 ] In addition, genetic knockout of miR223 in mouse and zebrafish reprograms leukocytes, increasing their pro‐inflammatory behavior particularly in a wound inflammatory setting. [ 18 , 19 ] Moreover, extensive sequence/evolutionary comparisons and expression studies indicate that miR223 is highly conserved between zebrafish and human, and thus, shares functions in both species, [ 20 ] suggesting that zebrafish studies could potentially be directly translated into the clinic.…”