Pancreatic adenocarcinoma is one of the most deadly malignancies, and endometrial cancer represents the most common gynecologic cancer in the USA. Better understanding on the pathologic mechanisms and pathways is required for effective treatment of these malignancies. Recently, human epididymis protein 4 (HE4 or WFDC2), a secretory glycoprotein, was found to be overexpressed in pancreatic and endometrial cancers. In addition, studies have shown that HE4 overexpression in endometrial cancer cell lines led to faster cancer progression in a mouse subcutaneous model. These findings raise a question on the role(s) of secretory, extracellular HE4 in cancer development. In the present study, we found that treatment of pancreatic and endometrial cancer cell lines with purified, extracellular HE4 protein led to a significant increase in cell viability and proliferation. Moreover, extracellular HE4 protein was able to increase DNA synthesis, and modulate the mRNA and protein levels of cell cycle marker PCNA and cell cycle inhibitor p21. These effects appeared to be robust and sustainable and required a relatively low concentration of HE4 protein. The findings indicated the secreted, extracellular HE4 may carry some physiopathological functions. Via paracrine/endocrine actions, circulatory HE4 produced by malignant cells may contribute to pancreatic and endometrial cancer progression and/or metastasis.

Syncytin-1 is a member of human endogenous retroviral W gene family (HERVW1). Known to be expressed in human placental trophoblast, syncytin-1 protein mediates the fusion of cytotrophoblasts for the formation of syncytiotrophoblasts, the terminally differentiated form of trophoblast lineage. In addition, in vitro studies indicate that syncytin-1 possessed nonfusogenic functions such as those for immune suppression, cell cycle regulation and anti-apoptotic activities. Overexpression of syncytin-1 has been observed in various malignant tissues including breast, endometrial and ovarian cancers. It was reported that syncytin-1 gene expression is associated with dynamic changes of DNA hypomethylation in the 5' LTR. In this study, applying the real-time PCR, Western blot analysis and immunohistochemistry methods, we demonstrate a constitutive expression of syncytin-1 in normal pancreas tissues as well as normal tissues adjacent to cancer lesions. Moreover, a reduced expression is found in the pancreatic adenocarcinoma tissues. The expression levels of syncytin-1 are not correlated with the stage, historical grade and gender, but inversely correlated with patients' age. Furthermore, COBRA and bisulfite sequencing results indicated that the lower expression of syncytin-1 is correlated with the hypermethylation of two CpG dinucleotides in the 5' LTR of syncytin-1 gene. The nonfusogenic function of syncytin-1 in normal pancreas as well as its role(s) in the pathogenesis and progression of pancreatic cancers remains to be investigated. Identification of the two CpG dinucleotides around transcription start site as key epigenetic elements has provided valuable information for further studies on the epigenetic regulation of syncytin-1 in pancreatic cancer cells.

Human epididymis protein 4 (HE4) is a recognized biomarker in ovarian and endometrial cancer and over-expressed in pancreatic adenocarcinoma. The diagnostic value of HE4 in pancreatic adenocarcinoma remains unknown. Here we elucidate mRNA, protein and serum level of HE4 in pancreatic adenocarcinoma. HE4 mRNA level in tumor adjacent tissues and pancreatic adenocarcinoma tissues were tested by real time-PCR. Tissue microarray containing normal, adenocarcinoma, and adjacent pancreatic tissue was tested by immunohistochemistry (IHC). Serum level of HE4, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3) and carbohydrate antigen 125 (CA125) were detected by ELISA assay in control and tumor patients. Further we compared the sensitivity and specificity of determining HE4, CA19-9, CA15-3, and CA125 for diagnosis of pancreatic adenocarcinoma and assessed the complementary diagnostic value of HE4, CA19-9, CA15-3 and CA125. Real time PCR showed significantly increased HE4 mRNA level in pancreatic adenocarcinoma compared with control. Result of IHC showed that HE4 significantly higher expressed in the human pancreatic carcinoma tissues than in both normal and adjacent non-tumorous pancreatic tissues, and the staining intensity is inversely correlated with the clinical stage. HE4 was highly expressed in early stage of pancreatic adenocarcinoma. Serum HE4 level is higher in cases with pancreatic adenocarcinoma than in the controls. Serum HE4 levels could research to a sensitivity of 45.83% and specificity of 93.75% when the Cutoff was set at 4.59 ng/mL. The Combined HE4 and CA19-9 increased the sensitivity to 83.33%; and interestingly, the combination of HE4 with CA15-3 led to the most powerful sensitivity of 87.5%. Combined with CA19-9 and CA15-3, HE4 could be a potential biomarker to improve the diagnostic power for pancreatic adenocarcinoma.

BACKGROUND:The results of prostate specific antigen (PSA) and digital rectal examination (DRE) screenings lead to both under and over treatment of prostate cancer (PCa). As such, there is an urgent need for the identification and evaluation of new markers for early diagnosis and disease prognosis. Studies have shown a link between PCa, lipids and lipid metabolism. Therefore, the aim of this study was to examine the concentrations and distribution of serum lipids in patients with PCa as compared with serum from controls.METHOD:Using Electrospray ionization mass spectrometry (ESI-MS/MS) lipid profiling, we analyzed serum phospholipids from age-matched subjects who were either newly diagnosed with PCa or healthy (normal).RESULTS:We found that cholester (CE), dihydrosphingomyelin (DSM), phosphatidylcholine (PC), egg phosphatidylcholine (ePC) and egg phosphatidylethanolamine (ePE) are the 5 major lipid groups that varied between normal and cancer serums. ePC 38:5, PC 40:3, and PC 42:4 represent the lipids species most prevalent in PCa as compared with normal serum. Further analysis revealed that serum ePC 38:5 ≥0.015 nmoles, PC 40.3 ≤0.001 nmoles and PC 42:4 ≤0.0001 nmoles correlated with the absence of PCa at 94% prediction. Conversely, serum ePC 38:5 ≤0.015 nmoles, PC 40:3 ≥0.001 nmoles, and PC 42:4 ≥0.0001 nmoles correlated with the presence of PCa.CONCLUSION:In summary, we have demonstrated that ePC 38:5, PC 40:3, and PC 42:4 may serve as early predictive serum markers for the presence of PCa.

With an estimated 37,000 deaths per year, pancreatic cancer is the fourth leading cause of cancer deaths in the USA. A total of 95% of pancreatic cancers are exocrine neoplasms, known as pancreatic ductal adenocarcinomas (PDACs). The difficulty of early diagnosis and the high prevalence of metastasis associated with PDAC contribute to its dismal prognosis. The past decade has witnessed intensive study and impressive progress in searching for more sensitive, specific and cost-effective biomarkers. This review focuses on the epigenetic biomarkers potentially useful for the management of PDAC. The authors begin with an overview on the available biomarkers, and subsequently discuss the recent development in epigenetic biomarkers, including DNA methylation, miRNA and histone modifications in diversified specimens of cell lines, xenograft, cancer tissues, pancreatic juice and patient blood. These findings raise the possibility for clinical application of epigenetic biomarkers towards screening, early diagnosis, prognosis, chemosensitivity prediction and recurrence surveillance of PDAC patients.

15‐LOX‐1 and its metabolites are involved in colorectal cancer. Recently, we reported that 15‐LOX‐1 overexpression in HCT‐116 human colorectal cancer cells inhibited cell growth by induction of p53 phosphorylation (4). To determine whether the 15‐LOX‐1 protein or its metabolites are responsible for phosphorylation of p53 in HCT‐116 cells, we used HCT‐116 cells that expressed a mutant 15‐LOX‐1. The mutant 15‐LOX‐1 enzyme, with a substitution of Leu at residue His361, was devoid of enzymatic activity. HCT‐116 cells transiently transfected with either native or mutant 15‐LOX‐1 showed an increase in p53 phosphorylation and an increase in the expression of downstream genes. Thus, 15‐LOX‐1 induces p53 phosphorylation independent of enzymatic activity. Treatment of A549 human lung carcinoma cells with IL‐4 increased the expression of 15‐LOX‐1 and also increased the expression of downstream targets of p53. This confirmed that the activation of p53 was also observed in wild‐type cells expressing physiological 15‐LOX‐1. Immunoprecipitation experiments revealed that 15‐LOX‐1 interacts with, and binds to, DNA‐dependent protein kinase (DNA‐PK). The binding of 15‐LOX‐1 to DNA‐PK caused an approximate 3.0‐fold enhancement in kinase activity, resulting in increased p53 phosphorylation at Ser15. Knockdown of DNA‐PK by small interfering RNA (siRNA) significantly reduced p53 phosphorylation. Furthermore, confocal microscopy demonstrated a colocalization of 15‐LOX and DNA‐PK in the cells. We propose that the 15‐LOX‐1 protein binds to DNA‐PK, increasing its kinase activity and results in downstream activation of the tumor suppressor p53, thus revealing a new mechanism by which lipoxygenases (LOX) may influence the phenotype of tumor cells. Published 2008 Wiley‐Liss, Inc.

Lipoxygenases oxidatively metabolize polyunsaturated fatty acids to a rich spectrum of biologically active products. One enzyme of the lipoxygenase family, Arachidonate 15-lipoxygenase-1 (arachidonate:oxygen 15-oxidoreductase, EC 1.13.11.33) [15-LO-1], is implicated in several forms of epithelial cell cancers, and provides a rationale for exploring its role in the progression and metastasis of cancers. Thus, 15-LO-1 could be a marker of the growth and spread of cancers. The importance of 15-LO-1 expression is imparted by its metabolic product of linoleic acid, yielding 13-(S)-hydroxyoctadecadienoic acid (13-(S)-HODE). In order to maximize our understanding of the roles of lipoxygenases and cyclooxygenases in cancer, it is necessary to correlate their metabolic pathways to the respective expression levels, and not exaggerate the presence or absence of an enzyme or its function when it clearly is not there. It is also important to acknowledge that some forms of these enzymes may not even be relevant to human disease. Although it is unlikely that any single gene is sufficient to account for the complex etiology of cancer, 15-LO-1 overexpression is clearly a key component in the cell proliferation process. This article is divided into three sections emphasizing the key role of 15-LO-1 in prostate, colorectal, and breast cancers.