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

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.

ZBTB7A functioned as an oncogene in colorectal cancer

“…ZBTB7A has been proved to be a critical factor for diagnosis, prognostication and prediction of treatment effect in multiple types of cancer [12][13][14][15][16]. Although a few studies have identi ed ZBTB7A as a functional gene in CRC, the functional studies were not comprehensive [19][20][21][22].…”

“…is reported as an oncoprotein for directly inhibiting the expression of tumor suppressor gene ARF in non-Hodgkin lymphoma tissues [9]. Recently, overexpression of ZBTB7A has been found in multiple tumors, including lung cancer [12,13], breast cancer [14], oral carcinoma [15], and ovarian cancer [16]. In addition, some opposite functions of ZBTB7A have been reported in other kinds of cancers, such as melanoma and prostate cancer [17,18].…”

ZBTB7A functioned as an oncogene in colorectal cancer

“…Initially, ZBTB7A is reported as an oncoprotein for directly inhibiting the expression of tumor suppressor gene ARF in non-Hodgkin lymphoma tissues [ 9 ]. Recently, overexpression of ZBTB7A has been found in multiple tumors, including lung cancer [ 12 , 13 ], breast cancer [ 14 ], oral carcinoma [ 15 ], and ovarian cancer [ 16 ]. In addition, some opposite functions of ZBTB7A have been reported in other kinds of cancers, such as melanoma and prostate cancer [ 17 , 18 ].…”

Activation of the miR-371/372/373 miRNA Cluster Enhances Oncogenicity and Drug Resistance in Oral Carcinoma Cells

“…The oncogenic roles of miR-372 / 373 , which involves targeting of LATS2, have been well studies in various malignancies [ 12 , 13 ]. In OSCC, miR-371/372/373 has been found to be up-regulated in tumors relative to control mucosa [ 2 , 14 , 15 , 16 , 17 ]. In addition, miR-372 and miR-373 are known to be associated in OSCC with nodal metastasis, lymphovascular permeation, and a worse prognosis [ 15 ].…”