Reduced protocadherin17 expression in leukemia stem cells: the clinical and biological effect in acute myeloid leukemia.

BACKGROUND: Leukemia stem cell (LSC)-enriched genes have been shown to be highly prognostic in acute myeloid leukemia (AML). However, the prognostic value of tumor suppressor genes (TSGs) that are repressed early in LSC remains largely unknown. METHODS: We compared the public available expression/methylation profiling data of LSCs with that of hematopoietic stem cells (HSCs), in order to identify potential tumor suppressor genes in LSC. The prognostic relevance of PCDH17 was analyzed on a cohort of 173 AML patients from The Cancer Genome Atlas (TCGA), and further validated in three independent cohorts (n = 339). RESULTS: We identified protocadherin17 (PCDH17) and demonstrated that it was significantly down-regulated and hypermethylated in LSCs compared with HSCs. Our analyses of primary AML patient samples also confirmed these deregulations. Clinically, low PCDH17 expression was associated with female sex (P = 0.01), higher WBC (P < 0.0001), higher percentages of blasts in bone marrow (BM) and peripheral blood (PB) (P = 0.04 and < 0.001, respectively), presence of FLT3-internal tandem duplications (P = 0.002), mutated NPM1 (P = 0.02), and wild-type TP53 (P = 0.005). Moreover, low PCDH17 expression predicted worse overall survival (OS) in four independent cohorts as well as in the molecularly defined subgroups of AML patients. In multivariable analyses, low PCDH17 expression retained independent prognostic value for OS. Biologically, PCDH17 expression-associated gene signatures were characterized by deregulations of EMT- and Wnt pathway-related genes. CONCLUSIONS: PCDH17 gene was silenced by DNA methylation in AML. Low PCDH17 expression is associated with distinct clinical and biological features and improves risk stratification in patients with AML.

Loss of protocadherin-17 (PCDH-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma.

Metastasis has been one of the major reasons for cancer-related mortality, with multiple genes and pathways being involved in this complex process. Given the molecular variations underlying metastasis of hepatocellular carcinoma (HCC) remains largely unknown; in our previous work, we found copying number of protocadherin-17 (PCDH-17) was significantly deleted in HCC tissues that occurred to metastasize compared with that in the primary HCC without metastasis. Therefore, we hypothesized that PCDH-17 may suppress the metastasis of HCC. There has been, however, no relevant literature available regarding PCDH-17 in HCC. In the present study, we have immunohistochemically detected and clinicopathologically analyzed the expression of PCDH-17 in vivo in clinical tissues; besides, we have explored the role of PCDH-17 ex vivo using a panel of HCC cell lines. It was discovered that PCDH-17 expression was clinically correlated with overall prognosis as well as metastasis in vivo and that PCDH-17 inhibited metastasis via EGFR/MEK/ERK signaling pathway ex vivo. Together, our results obtained both in vivo and ex vivo suggested that activation of EGFR/MEK/ERK signaling pathway through PCDH-17 promotes metastasis in HCC.

MiR-23a-3p promoted G1/S cell cycle transition by targeting protocadherin17 in hepatocellular carcinoma.

MiR-23a-3p has been shown to promote liver cancer cell growth and metastasis and regulate that of chemosensitivity. Protocadherin17 (PCDH17) is a tumor suppressor gene and plays an essential part in cell cycle of hepatocellular carcinoma (HCC). This study aimed at evaluating the effects of miR-23a-3p and PCDH17 on HCC cell cycle and underlining the mechanism. The level of miR-23a-3p was up-regulated, while PCDH17 level was down-regulated in HCC tissues compared to adjacent tissues. For the in vitro studies, high expression of miR-23a-3p down-regulated PCDH17 level; increased cell viability; promoted G1/S cell cycle transition; up-regulated cyclin D1, cyclin E, CDK2, CDK4, p-p27, and p-RB levels; and down-regulated the expression of p27. Dual luciferase reporter assay suggested PCDH17 was a target gene of miR-23a-3p. MiR-23a-3p inhibitor and PCDH17 siRNA led to an increase in cell viability and the number of cells in the S phase and up-regulated cyclin D1 and cyclin E levels, compared with miR-23a-3p inhibitor and NC siRNA group. For the in vivo experiments, high expression of miR-23a-3p promoted tumor growth and reduced PCDH17 level in the cytoplasm. These results indicated that high expression of miR-23a-3p might promote G1/S cell cycle transition by targeting PCDH17 in HCC cells. The miR-23a-3p could be considered as a molecular target for HCC detection.

p53/PCDH17/Beclin-1 Proteins as Prognostic Predictors for Urinary Bladder Cancer.

Purpose: To determine whether p53, PCDH17, Beclin-1 expression is associated with clinicopathological characteristics of bladder cancer. Materials and Methods: 75 patients with non-muscle-invasive and muscle-invasive bladder cancer were included. Immunohistochemical staining for p53, PCDH17 and Beclin-1 were carried out on the same paraffin-embedded blocks serial sections of these patients who underwent surgery between 2010 and 2015. In addition, p53 gene mutations in these tumors were screened by DNA sequencing. Results: Forty-nine (66.7%) of 75 tumors had p53 gene mutations detected by DNA sequencing method. Of these tumors, 43 (86.0%) exhibited p53 high expression. Furthermore, p53 mutation and low expression of PCDH17 were significantly associated with muscle-invasive bladder cancer. Beclin-1 was also strongly associated with T stage. The p53 mutation, the expression of p53 and PCDH17 were significantly associated with survival from bladder cancer. In addition, patients with p53 high-expression or p53 mutation, PCDH17 low-expression and Beclin-1 low-expression significantly had a poor prognosis. Conclusions: Use of a DNA sequencing method to detect p53 gene mutations was consistent with an immunohistochemical method to detect p53 alterations. In conjunction with levels of p53/PCDH17/Beclin-1, p53 and PCDH17 were independently associated with prognosis; Beclin-1 only had a tendency towards overall survival. p53/PCDH17/Beclin-1 phenotype seems to play a more important role than p53 expression in bladder cancer outcome. It is also identified that p53/PCDH17, p53/Beclin-1 or PCDH17/Beclin-1 all have a cooperative and synergistic effect, which may provide us the potential biomarker for bladder cancer patients.

Protocadherin-17 promoter methylation in serum-derived DNA is associated with poor prognosis of bladder cancer.

OBJECTIVE: To investigate the prognostic value of protocadherin 17 (PCDH17) promoter methylation in serum-derived DNA of patients with bladder cancer. METHODS: DNA was isolated from serum of patients with bladder cancer and from age- and sex-matched controls. Methylation-specific polymerase chain reaction was used to examine the methylation status of the PCDH17 promoter. The correlations between methylation status and clinicopathological characteristics and overall survival were examined. RESULTS: PCDH17 promoter methylation was detected in 79/151 (52.3%) of patients with bladder cancer, and none of the 43 control subjects. Methylation was significantly associated with larger tumour diameter (>3 cm), high grade (G3) and advanced stage (T2-T4). Patients with PCDH17 promoter methylation had significantly shorter overall survival than those with unmethylated PCDH17 promoter. Methylation was an independent predictor of overall survival. CONCLUSIONS: PCDH17 promoter methylation was significantly associated with malignant behaviour and poor prognosis of bladder cancer. The detection of PCDH17 promoter methylation in serum-derived DNA may be a convenient and noninvasive predictive biomarker in routine clinical practice.

Protocadherin 17 promoter methylation in tumour tissue from patients with bladder transitional cell carcinoma.

OBJECTIVE: To investigate the clinical significance of protocadherin 17 (PCDH17) promoter methylation in bladder cancer. METHODS: Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of PCDH17 in tumour tissue specimens obtained from patients with bladder cancer, and in normal bladder epithelial tissue specimens obtained from age- and sex-matched controls. The correlations between methylation status and demographic and clinicopathological parameters, and disease outcome, were assessed. RESULTS: Methylation of the PCDH17 promoter was detected in 77/115 (67.0%) patients with bladder cancer and 0/43 (0%) of the controls. Methylation was significantly associated with high cancer grade (G3), advanced cancer stage (T2-T4), large tumour diameter (> 3 cm) and tumour recurrence. Methylation was also associated with significantly shorter survival time compared with unmethylated PCDH17 in patients with bladder cancer, and was an independent predictor of overall survival. CONCLUSIONS: PCDH17 promoter methylation is closely associated with bladder cancer malignancy and may be used as an independent predictor of clinical outcomes in patients with bladder cancer.

Gene methylation in gastric cancer.

Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.