Research Papers:

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

Brandi L. Carofino, Kayla M. Dinshaw, Pui Yan Ho, Christophe Cataisson, Aleksandra M. Michalowski, Andrew Ryscavage, Addie Alkhas, Nathan W. Wong, Vishal Koparde and Stuart H. Yuspa _

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Oncotarget. 2019; 10:7251-7275. https://doi.org/10.18632/oncotarget.27387

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Brandi L. Carofino1, Kayla M. Dinshaw1,2, Pui Yan Ho1,3, Christophe Cataisson1, Aleksandra M. Michalowski1, Andrew Ryscavage1, Addie Alkhas4, Nathan W. Wong5,6, Vishal Koparde5,6 and Stuart H. Yuspa1

1 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

2 Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, CA, USA

3 Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

4 Oncology-Gynecology, Park Ridge, IL, USA

5 CCR Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

6 Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

Correspondence to:

Stuart H. Yuspa,email: [email protected]

Keywords: in situ hybridization; single-cell RNA-sequencing; stroma; miRNA; immune infiltration

Received: October 11, 2019     Accepted: December 02, 2019     Published: December 31, 2019


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.

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