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Head and neck squamous cancer progression is marked by CLIC4 attenuation in tumor epithelium and reciprocal stromal upregulation of miR-142-3p, a novel post-transcriptional regulator of CLIC4
- Source :
- Oncotarget
- Publication Year :
- 2019
- Publisher :
- Impact Journals LLC, 2019.
-
Abstract
- Chloride intracellular channel 4 (CLIC4) is a tumor suppressor implicated in processes including growth arrest, differentiation, and apoptosis. CLIC4 protein expression is diminished in the tumor parenchyma during progression in squamous cell carcinoma (SCC) and other neoplasms, but the underlying mechanisms have not been identified. Data from The Cancer Genome Atlas suggest this is not driven by genomic alterations. However, screening and functional assays identified miR-142-3p as a regulator of CLIC4. CLIC4 and miR-142-3p expression are inversely correlated in head and neck (HN) SCC and cervical SCC, particularly in advanced stage cancers. In situ localization revealed that stromal immune cells, not tumor cells, are the predominant source of miR-142-3p in HNSCC. Furthermore, HNSCC single-cell expression data demonstrated that CLIC4 is lower in tumor epithelial cells than in stromal fibroblasts and endothelial cells. Tumor-specific downregulation of CLIC4 was confirmed in an SCC xenograft model concurrent with immune cell infiltration and miR-142-3p upregulation. These findings provide the first evidence of CLIC4 regulation by miRNA. Furthermore, the distinct localization of CLIC4 and miR-142-3p within the HNSCC tumor milieu highlight the limitations of bulk tumor analysis and provide critical considerations for both future mechanistic studies and use of miR-142-3p as a HNSCC biomarker.
- Subjects :
- 0301 basic medicine
Stromal cell
In situ hybridization
03 medical and health sciences
0302 clinical medicine
Immune system
Downregulation and upregulation
Stroma
CLIC4
microRNA
medicine
stroma
single-cell RNA-sequencing
miRNA
biology
immune infiltration
Epithelium
3. Good health
stomatognathic diseases
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
biology.protein
Cancer research
in situ hybridization
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 10
- Issue :
- 68
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....f858a2999b412f0cb596fde914de63a6