The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma.

Li-Yin Yeh,Hsiao-Li Wu,Shou-Yen Kao,Chung-Ji Liu,Cheng-Chieh Yang,Yi-Fen Chen,Kuo-Wei Chang,Shu-Chun Lin

doi:10.3389/fonc.2020.00047

Abstract

miR-372 has been shown a potent oncogenic miRNA in the pathogenesis of oral squamous cell carcinoma (OSCC). The zinc finger and BTB domain containing 7A protein (ZBTB7A) is a transcriptional regulator that is involved in a great diversity of physiological and oncogenic regulation. However, the modulation of ZBTB7A in OSCC remains unclear. Tissue analysis identifies a reverse correlation in expression between miR-372 and ZBTB7A in OSCC tumors. When OSCC cells have stable knockdown of ZBTB7A, their oncogenic potential and drug resistance is increased. By way of contrast, such an increase is attenuated by expression of ZBTB7A. Screening and validation confirms that ZBTB7A is able to modulate expression of the death receptors TRAIL-R1, TRAIL-R2, Fas and p53 phosphorylated at serine-15. In addition, ZBTB7A transactivates TRAIL-R2, which sensitizes cells to cisplatin-induced apoptosis. The ZBTB7A-TRAIL-R2 cascade is involved in both the extrinsic and intrinsic cisplatin-induced pathways of apoptosis. Database analysis indicates that the expression level of and the copy status of ZBTB7A and TRAIL-R2 are important survival predictors for head and neck cancers. Collectively, this study indicates the importance of the miR-372-ZBTB7A-TRAIL-R2 axis in mediating OSCC pathogenesis and in controlling OSCC drug resistance. Therefore, silencing miR-372 and/or upregulating ZBTB7A would seem to be promising strategies for enhancing the sensitivity of OSCC to cisplatin therapy.

Highlights

Head and neck squamous cell carcinoma (HNSCC), including oral SCC (OSCC), is one of the prevalent neoplasms worldwide [1, 2]
In data-sets obtained from The Cancer Genome Atlas (TCGA), ZBTB7A expression and ZBTB7A copy number was found to be decreased in HNSCC (Figure 1C)
Further investigation disclosed that there was downregulation of ZBTB7A expression in HNSCC tumors compared to their control normal mucosa, and that the degree of downregulation of ZBTB7A in HNSCC tumors increased in tumors that were at a more advanced stage (Figure 1E)

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC), including oral SCC (OSCC), is one of the prevalent neoplasms worldwide [1, 2]. The miRNAs miR-371, miR-372, and miR-373 form a miRNA cluster on chromosome 19q13, a locus where many oncogenic events related to HNSCC are known to reside [10] This cluster of miRNAs was originally found to be crucial to the maintenance of stemness in embryonic cells miR-372-ZBTB7A-TRAIL-R2 Regulatory Axis in OSCC [11]. MiR-372/miR-373 were found to be oncogenes that target LATS2, CD44 and various other differentiation regulators active in tumors [12, 13] They are upregulated in malignancies and their upregulation of expression of miR-372/miR-373 has been found in HNSCC and miR-372 expression in tumors is a prognostic marker of OSCC [6, 8, 14]. We have identified previously that miR-372 targets p62, which, in turn, enhances OSCC cell progression [4]

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Conclusion