Distinct Expression and Clinical Significance of Zinc Finger AN-1-Type Containing 4 in Oral Squamous Cell Carcinomas

Abstract

Zinc finger AN1-type containing 4 (ZFAND4) has emerged as a promising prognostic marker and predictor of metastasis for patients with oral squamous cell carcinoma (OSCC). However, further validation is fundamental before clinical implementation. Hence, this study evaluated the expression pattern of ZFAND4 protein expression by immunohistochemistry using an independent cohort of 125 patients with OSCC, and correlations with the clinicopathologic parameters and disease outcome. Remarkably, ZFAND4 expression, while negligible in normal epithelium, exhibited two distinct expression patterns in tumors that did not overlap. A gross granular staining was characteristic of the undifferentiated cells at the invasive front of tumors, whereas the most differentiated cells located at the center of the tumor nests showed diffuse non-granular staining. ZFAND4 staining was higher in undifferentiated than in differentiated areas of tumors. High ZFAND4 expression in differentiated cells was significantly associated to well-differentiated (p = 0.04) and non-recurrent tumors (p = 0.04), whereas ZFAND4 expression in undifferentiated cells correlated with tumor location (p = 0.005). No correlations between the ZFAND4 expression and patient survival were found. These data question the clinical relevance of ZFAND4 expression as a prognostic biomarker in OSCC, and also reveal distinct ZFAND4 expression patterns depending on the differentiation areas of tumors that should be evaluated separately.

AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion

“…ZF proteins ensure a plethora of cellular functions in health and disease, such as DNA recognition, RNA packaging, transcriptional regulation, and are involved in many aspects of cancer progression 29 . In humans, there are eight ZFAND family members, of which only ZFAND2a and ZFAND4 have recently been implicated in cancer [30][31][32][33] . Members of the ZFAND family are associated with stress response and proteasomal degradation through recruitment of the 26 S proteasome, e.g., ZFAND1 34 , ZFAND2A/B 30,35 , ZFAND5 36 , and ZFAND6 37 .…”

The Role of Zinc Finger Proteins in Various Oral Conditions

“…e ZEB1 and ZEB2 [25, 26, 31-35, 37, 38, 49, 54] were the most studied ZNFs followed by Gli [19][20][21][22]51], ZNF750 [12][13][14][15], Snail [23,25,26,29], Slug [24,25,42], ZNF582 [16][17][18], A20 [9,28], KLF [29,30,43], and ZFAND4 [50,52]. Other ZNFs like ZASC1 [43], REST [45], GKLF [40], ZNF185 [41], MZF1 [46], ZF9 [36], ZFX [47], KRT17 [22], IRF [39], PRDM1 [39], NAC1 [48], ZBTB7A [55], MORF [56], ZNF718, HOXA4, and ZNF57 [57] were evaluated in very few studies.…”

“…(9) ZFAND4. e zinc finger, ZFAND4 also known as AN1 ubiquitin-like homolog (ANUBL1), is one of the most upregulated genes identified in recurrent OSCC [52,78]. Its expression levels are usually higher in advanced cases.…”

“…Its expression levels are usually higher in advanced cases. e ZFAND4 promotes cell proliferation by activating cyclindependent kinase and downregulation of p21 and p53 [52,79].…”

“…Its overexpression was considered an independent poor prognostic factor and marker for predicting metastasis [50]. Likewise, increased ZFAND4 staining in the undifferentiated areas of tumors in about 125 patients correlated with the tumor location [52]. Its increased expression was seen in well-differentiated and nonrecurrent tumors.…”