Zinc finger protein X-linked is overexpressed in colorectal cancer and is associated with poor prognosis

Abstract

Abstract. Zinc finger protein X-linked (ZFX) is a zinc finger transcription factor and plays a significant role in the self-renewal ability of embryonic stem cells and various cancers. However, its expression and function in colorectal cancer (CRC) remain unclear. In the present study, we evaluated the expression of ZFX in CRC using quantitative polymerase chain reaction (qPCR), western blot analysis and immunohistochemistry (IHC), and further explored its potential functions in CRC cell lines using cell counting kit-8 and Transwell invasion assays. qPCR and western blot analysis revealed that ZFX was significantly upregulated in CRC tissues; IHC further confirmed this finding, revealing that higher expression of ZFX was significantly associated with larger tumor size (P=0.01), higher pathological stage (P=0.02), depth of invasion (P= 0.047), lymph node invasion (P= 0.02) and higher American Joint Committee on Cancer (AJCC) stage (P= 0.04). CRC patients with higher ZFX expression also exhibited significantly shorter survival times (P= 0.019). Moreover, knockdown of ZFX significantly suppressed proliferation and invasion in CRC cell lines HCT116 and LoVo. These results suggest that ZFX plays a notable role in CRC tumorigenicity and may serve as a novel marker and therapeutic target for CRC. IntroductionColorectal cancer (CRC) is the third most common type of cancer worldwide, with over 1.4 million new cancer cases and 50,000 mortalities reported in 2013 (1). However, the biological and molecular mechanisms underlying CRC development remain largely unknown.Zinc finger protein X-linked (ZFX), a zinc finger protein of the Zfy family, is a transcriptional factor encoded on the mammalian X chromosome which is highly conserved in vertebrates. The full-length ZFX protein contains a DNA-binding domain, an acidic transcriptional activation domain and a nuclear localization sequence (2). Previous studies have demonstrated elevated levels of ZFX in pluripotent embryonic and hematopoietic stem cells, which is required for self-renewal ability (3,4). Overexpression of ZFX has also been demonstrated to confer self-renewal capability in hepatocellular carcinoma (5). In addition, previous studies have revealed that ZFX plays a notable role in regulating the transcription of genes necessary for cell proliferation, cell cycle and cell death (6,7). Therefore, it is speculated that ZFX may also be active in cancers and may represent anti-cancer targets. Notably, ZFX is associated with a number of human cancers, including glioblastoma (8,9), breast cancer (10), osteosarcoma (11,12), lung cancer (13,14), gallbladder cancer (15), prostate cancer (16), laryngeal squamous cell carcinoma (17) and gastric cancer (18). Amini et al also identified that ZFX was significantly upregulated in colon cancer tissues and cell lines (19). However, the biological function of ZFX in CRC remains unclear.In this study, we firstly detected the expression pattern of ZFX in CRC and revealed that the upregulation of ZFX is strongly associated with advanced t...

ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters

“…Similarly, expression of ZFX is high in advanced invasive breast cancers and knockdown of ZFX reduces the proliferation rate of breast cancer cells (Yang et al 2014). High expression of ZFX promotes tumor growth of colon cancer cells and colorectal cancer patients with high ZFX expression have poorer overall and disease-free survival (Jiang and Liu 2015). Moreover, knockdown of ZFX suppresses proliferation and invasion of colon cancer cell lines (Jiang and Liu 2015).…”

“…In contrast, ZFX, a zinc finger protein (ZNF) that contains a DNA binding domain, has been implicated in the initiation or progression of many different types of human cancers, including prostate cancer, breast cancer, colorectal cancer, renal cell carcinoma, glioma, gastric cancer, gallbladder adenocarcinoma, non-small cell lung carcinoma, and laryngeal squamous cell carcinoma (Zhou et al 2011;Fang et al 2012;Jiang et al 2012b,c;Nikpour et al 2012;Li et al 2013;Fang et al 2014a,b;Yang et al 2014;Weng et al 2015). In these previous studies, it was shown that high expression of ZFX is linked to tumorigenesis, and knocking down ZFX can suppress cellular proliferation and increase the proportion of apoptotic cells (Fang et al 2014a;Jiang and Liu 2015;Yang et al 2015;Yan et al 2016). In addition, high ZFX expression correlates with poor survival of cancer patients (Jiang and Liu 2015;Li et al 2015;Yang et al 2015;Yan et al 2016).…”

“…In these previous studies, it was shown that high expression of ZFX is linked to tumorigenesis, and knocking down ZFX can suppress cellular proliferation and increase the proportion of apoptotic cells (Fang et al 2014a;Jiang and Liu 2015;Yang et al 2015;Yan et al 2016). In addition, high ZFX expression correlates with poor survival of cancer patients (Jiang and Liu 2015;Li et al 2015;Yang et al 2015;Yan et al 2016). For example, ZFX expression is significantly related to histological grade (P-value <0.001) in gallbladder adenocarcinoma, and patients that survived <1 yr were found to have significantly higher ZFX expression than patients that survived >1 yr (Weng et al 2015).…”

ZNF280B promotes the growth of gastric cancer in�vitro and in�vivo

“…There exist a number of publications describing the correlation between the expression of ZNF280B and the growth of various types of cancer (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). For example, Gunn et al (22) reported that ZNF280B acts as a tumor suppressor in chronic lymphocytic leukemia.…”

“…By interacting with DNA and proteins, ZNF proteins can provide links between these molecule types (4). An increasing number of studies has reported that ZNF proteins serve critical roles in human cancers (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). For example, ZNF703 acts as an oncogene in invasive gastric carcinoma, and its expression levels are correlated with gastric carcinoma progression (16).…”