Downregulation of PLZF in human hepatocellular carcinoma and its clinical significance

Abstract

Abstract. Promyelocytic leukemia zinc finger (PLZF) acts as a tumor-suppressor gene in a series of cancers including prostate, melanoma, colon cancer and leukemia. However, its role in hepatocellular carcinoma (HCC) has not yet been illustrated. The present study aimed to investigate the expression and epigenetic regulation of PLZF as well as its clinical significance in HCC. We found that the expression of PLZF was significantly downregulated in HCC samples at both the RNA level (P<0.001) and protein level compared with these levels in adjacent normal tissues. The relative expression level of PLZF was also positively correlated with the ALP level (P= 0.026) noted in the HCC patients. However, hypermethylation was only detected in one out of 5 paired HCC samples, indicating that methylation of the selected promoter region (from -1702 to -1388) may not be the major regulatory mechanism for the downregulation of PLZF in HCC. A receiver operating characteristic (ROC) curve was created to evaluate the diagnostic value for differentiating between HCC and benign diseases. The area under the ROC curve (AUC) for indicating the value of PLZF as an HCC biomarker was 0.794 (95% CI, 0.697-0.892; P<0.001). Taken together, our results suggest that PLZF may play an important role in HCC development and may be a potential biomarker for the diagnosis of HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and is the third leading cause of cancer-related death due to its aggressive metastasis and poor clinical diagnosis (1). In China, the mortality rate of HCC is the second highest of all cancers, and the five-year survival rate is less than 5% with nearly 60,000 HCC patients succumbing to the disease every year (2). Increasing evidence suggests that multiple genetic and epigenetic alterations contribute to the tumorigenesis of different cancers. Recently, increased attention has been given to the role of epigenetically regulated genes in HCC.Promyelocytic leukemia zinc finger (PLZF), also known as zinc finger (ZF) and BTB domain containing 16 (ZBTB16), belongs to the POK (POZ and Krüppel ZF) family, which plays an important role in stem cell maintenance and oncogenesis. With DNA binding capability conferred by 9 Krüppel-type zinc-finger motifs at the carboxyl terminus, PLZF can function as a transcriptional factor to regulate various genes (3). In mammals, PLZF is co-expressed with Oct4 in undifferentiated spermatogonia and is essential for stem cell self-renewal (4-6). In acute promyelocytic leukemia, PLZF may function as a chromosomal translocation partner (7). As a transcriptional repressor, PLZF is able to regulate cyclin A2, c-Myc, HoxD11 and other growth-related targets (8).Downregulation of PLZF has been reported in various solid tumors and malignant cell lines. For example, PLZF expression was found to be downregulated in the majority of pancreatic cancer samples among which 35.2% of the samples presented with hypermethylation in the PLZF promoter (9). PLZF was also fou...

DAPK1 as an independent prognostic marker in liver cancer

“…PCOLCE (Procollagen C-Endopeptidase Enhancer) has been shown to be the strongest in its correlation with the liver fibrosis phenotype (Ippolito et al, 2016). ZBTB16, also named as PLZF, has previously been shown to be down-regulated in hepatocellular carcinoma, which supports our current study that ZBTB16 was down-regulated in liver cancer specimens compared to non-tumor liver specimens (Hui et al, 2015). PIN1 has been shown to contribute to hepatic carcinogenesis (Pang et al, 2006), while targeting PIN1 has been suggested to be a promising therapeutic approach for hepatocellular carcinoma .…”

Tumor suppressor PLZF regulated by lncRNA ANRIL suppresses proliferation and epithelial mesenchymal transformation of gastric cancer cells

“…3). These effects were similar to observations in lung cancer, melanoma, prostate cancer and hepatocellular carcinoma (7,8,34,35).…”

“…Except for hematological malignancies, PLZF has also been implicated in various solid tumors. The loss of PLZF expression in tumors compared with normal tissue has been observed in melanoma, hepatocellular carcinoma, pancreatic and lung cancer, thyroid carcinoma, prostate and gallbladder cancer (5)(6)(7)(8)(9)(10)(11), and increased PLZF expression in tumors has been observed in clear cell renal cell carcinoma, colon cancer, glioblastoma and testicular seminoma (3,12). However, the expression and value of PLZF in gastric cancer (GC) have not been studied, and it is reasonable to think that PLZF may play an important role in GC.…”

MiR‐4319 suppresses colorectal cancer progression by targeting ABTB1

“…23 Furthermore, the expression of PLZF was dramatically downregulated in hepatocellular carcinoma samples at both the RNA and protein levels in comparison to those of adjacent normal tissues. 25 Besides, PLZF expression was found to be substantially lower in high-risk melanomas than that in low-risk melanomas. 26 Although PLZF has emerged as an promising functional component during CRC progression, the underlying mechanism of tumorigenesis mediated by PLZF is not fully understood.…”