Prognostic and therapeutic impact of the chromosome 20q13.2 ZNF217 locus amplification in ovarian clear cell carcinoma

BACKGROUND:

The goal of this study was to examine the clinical significance of ZNF217 amplification and assess whether ZNF217 could be a potential therapeutic target in ovarian clear cell carcinoma (OCCC).

METHODS:

ZNF217 expression and amplification in OCCC was assessed by immunohistochemistry, fluorescence in situ hybridization, and clinical data collected via a retrospective chart review. ZNF217 gene knockdown using silencing RNA (siRNA) was used to assess ZNF217 functions in OCCC cell lines.

RESULTS:

Gene amplification was identified in 12 of 60 (20.0%) OCCCs. ZNF217 copy number correlated significantly with ZNF217 protein expression (r = 0.341; P<.01). ZNF217 amplification correlated significantly with shorter progression‐free (P = .0042) and overall (P = .0199) survival. There were nonsignificant trends between high ZNF217 protein expression and poor progression‐free (P = .2594) and overall (P = .2199) survival. Multivariate analysis revealed ZNF217 gene amplification to be an independent prognostic factor for progression‐free and overall survival after standard platinum agent‐based chemotherapy (P = .0339 and P = .031, respectively). Profound growth inhibition and apoptosis were observed in ZNF217 siRNA‐treated cancer cells with gene amplification compared with cancer cells with ZNF217 moderate expression without ZNF217 gene amplification or with low ZNF217 expression.

CONCLUSION:

These findings indicate that ZNF217 overexpression is critical to growth and survival of OCCCs with ZNF217 gene amplification. Furthermore, they suggest that ZNF217 siRNA‐induced phenotypes depend on amplification status of OCCCs. Therefore, ZNF217‐targeted therapy may benefit OCCC patients with ZNF217 amplification. Cancer 2011. © 2011 American Cancer Society.     

Silencing of ZNF217 gene influences the biological behavior of a human ovarian cancer cell line

Zinc-finger protein 217 (ZNF217), a candidate oncogene on 20q13.2, can lead cultured human ovarian and mammary epithelial cells to immortalization, which indicates selective expression of ZNF217 affecting 20q13 amplification during critical early stages of cancer progression. In this study, we tested the hypothesis that ZNF217 is a key factor in regulating ovarian cancer proliferation and progression. We examined the effect of the inhibition of ZNF217 expression on proliferation and invasion by establishing the ZNF217 knockdown ovarian cancer cell line using RNA interference (RNAi). Our results showed that silencing of ZNF217 resulted in the effective inhibition of ovarian cancer cell growth and invasive ability. The results suggested that ZNF217 might play a crucial role in the proliferation and invasion of ovarian cancer.     

The dark side of ZNF217, a key regulator of tumorigenesis with powerful biomarker value

The recently described oncogene ZNF217 belongs to a chromosomal region that is frequently amplified in human cancers. Recent findings have revealed that alternative mechanisms such as epigenetic regulation also govern the expression of the encoded ZNF217 protein. Newly discovered molecular functions of ZNF217 indicate that it orchestrates complex intracellular circuits as a new key regulator of tumorigenesis. In this review, we focus on recent research on ZNF217-driven molecular functions in human cancers, revisiting major hallmarks of cancer and highlighting the downstream molecular targets and signaling pathways of ZNF217. We also discuss the exciting translational medicine investigating ZNF217 expression levels as a new powerful biomarker, and ZNF217 as a candidate target for future anti-cancer therapies.     

ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion

The Krüppel-like zinc finger protein ZNF217 is a candidate oncogene in breast cancer. In this study, we showed that high levels of expression of ZNF217 mRNA are associated with poor prognosis and the development of metastases in breast cancer. Overexpression of ZNF217 in breast cancer cells stimulated migration and invasion in vitro and promoted the development of spontaneous lung or node metastases in mice in vivo. ZNF217 also promoted epithelial-mesenchymal transition (EMT) in human mammary epithelial cells, and the TGF-β-activated Smad signaling pathway was identified as a major driver of ZNF217-induced EMT. In addition, a TGF-β autocrine loop sustained activation of the TGF-β pathway in ZNF217-overexpressing mammary epithelial cells, most likely because of ZNF217-mediated direct upregulation of TGFB2 or TGFB3. Inhibition of the TGF-β pathway led to the reversal of ZNF217-mediated EMT. Together, our findings indicate that ZNF217 mRNA expression may represent a novel prognostic biomarker in breast cancer. Therapeutic targeting of ZNF217 of the TGF-β signaling pathway may benefit the subset of patients whose tumors express high levels of ZNF217.     

ZNF217 is Overexpressed and Enhances Cell Migration and Invasion in Colorectal Carcinoma

Background: To investigate the expression and clinical significance of zinc finger protein 217 (ZNF217)in human colorectal carcinoma (CRC). Materials and Methods: The expression of ZNF217 in 60 CRCtissues and matched tumor adjacent tissues, collected between January 2013 and June 2014, was assessedimmunohistochemically. The relationship between the expression of ZNF217 and clinicopathlogical features wasanalyzed by Pearson chi-square test. In addition, siRNA was used to down-regulate the expression of ZNF217 inCRC cells. The effects of ZNF217 for cell migration and invasion were measured by wound healing assay andtranswell assay, respectively. Results: The expression level of ZNF217 was significantly higher in CRC tissuesthan in tumor adjacent tissues (p<0.05), positively correlating with tumor size, lymphatic metastasis and advancedTNM stage (p<0.05). Down-regulation of ZNF217 in CRC cells could significantly suppress cell migration andinvasion. Conclusions: ZNF217 is overexpressed in colorectal carcinoma tissues and is associated with tumormalignant clinicopathological features. ZNF217 may promote CRC progression by inducing cell migration andinvasion.     

Coexistence of copy number increases of ZNF217 and CYP24A1 in colorectal cancers in a Chinese population

Evidence suggests that the amplification of chromosome 20q13 is common in colorectal cancers (CRCs). Certain candidate oncogenes located in this region are reported to be associated with tumorigenesis of the gastrointestinal tract. The functional impact of such regions should be extensively investigated in a large number of clinical samples. In this study, 145 CRC samples with matched adjacent normal tissues were collected from a Chinese population for copy number variation (CNV) analysis. Our results showed that both the copy numbers of 25-hydroxy vitamin D3 24-hydroxylase (CYP24A1) and zinc-finger protein 217 (ZNF217) were amplified in a relatively high percentage of CRC samples (51.1 and 60%, respectively). The mRNA expression levels of both CYP24A1 and ZNF217 were found to have increased in the collected CRC samples as compared to the matched adjacent normal tissues. ZNF217, but not CYP24A1, showed a positive correlation between copy number increases and mRNA overexpression. These findings suggest the potential role of CNVs of certain oncogenes in CRCs.     

Detection of Her2/neu, c-MYC and ZNF217 gene amplification during breast cancer progression using fluorescence in situ hybridization

The deletion of tumor suppressor genes and amplification of activating oncogenes appear to be critical events in tumorigenesis. We carried out fluorescence in situ hybridization (FISH) analysis of the breast cancer cell line MCF7 and clinically obtained cancer tissue sections on the basis of which we suggest a breast cancer development model. We selected 28 genes for FISH probes from breast cancer patients. Of the 28 genes studied, 14 were shown to be consistently amplified in the breast cancer cell line MCF7. We selected three genes from clinical tumor samples on the basis of results from MCF7 analysis. The amplification of Her2/neu or ZNF217 is closely associated with the stages of breast cancer. The frequency of amplification of Her2/neu increased notably in patients at stages later than IIB based on TNM staging, whereas the amplification of ZNF217 correlated with T2N1M0 at stage IIB and later stages. c-MYC amplification was not related to the stage. Her2/neu, ZNF217 and c-MYC were found to have a significantly increased copy number in breast cancer cells. In breast cancer progression, c-MYC amplification is an early event, while ZNF217 and Her2/neu amplification may play a role in the later stage of tumor development.