leukotriene-d4 and Liver-Neoplasms

Dehydropeptidase 1 (DPEP1) is a zinc-dependent metalloproteinase that is expressed aberrantly in several cancers. The role of DPEP1 in cancer remain controversial. In this study, we demonstrate that DPEP1 functions as a positive regulator for colon cancer cell metastasis. The expression of DPEP1 mRNA and proteins were upregulated in colon cancer tissues compared to normal mucosa. Gain-of-function and loss-of-function approaches were used to examine the malignant phenotype of DPEP1-expressing or DPEP1-depleted cells. DPEP1 expression caused a significant increase in colon cancer cell adhesion and invasion in vitro, and metastasis in vivo. In contrast, DPEP1 depletion induced opposite effects. Furthermore, cilastatin, a DPEP1 inhibitor, suppressed the invasion and metastasis of DPEP1-expressing cells. DPEP1 inhibited the leukotriene D4 signaling pathway and increased the expression of E-cadherin. We also show that DPEP1 mediates TGF-β-induced EMT. TGF-β transcriptionally repressed DPEP1 expression. TGF-β treatment decreased E-cadherin expression and promoted cell invasion in DPEP1-expressing colon cancer cell lines, whereas it did not affect these parameters in DPEP1-depleted cell lines. These results suggest that DPEP1 promotes cancer metastasis by regulating E-cadherin plasticity and that it might be a potential therapeutic target for preventing the progression of colon cancer.

Topics: Animals; Antigens, CD; Cadherins; Cell Adhesion; Cell Line, Tumor; Cilastatin; Colonic Neoplasms; Dipeptidases; Epithelial-Mesenchymal Transition; Female; GPI-Linked Proteins; HCT116 Cells; HT29 Cells; Humans; Leukotriene D4; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; RNA Interference; RNA, Messenger; RNA, Small Interfering; Transforming Growth Factor beta; Transplantation, Heterologous

Hepatocellular carcinoma (HCC) is a type of inflammation-related cancer that usually follows chronic inflammations. Leukotriene D4 (LTD4) is a potent biologically active arachidonic acid-derived lipid mediator that is intimately involved in inflammations and cancers. Although previous researches found overexpression of LTD4 in several other cancers, the circulating LTD4 level in HCC remains unknown. The aim of this study was to examine concentrations of LTD4 and analyze its roles in HCC. The results showed that remarkably high circulating LTD4 in HCC versus healthy subjects (p < 0.001). The levels of LTD4 were neither associated with parameters expressing tumor burden, such as AFP, nor with inflammation factors AST and γ-GT. In addition, the significant increase of circulating LTD4 levels was obtained in patients with HCC accompanied by chronic hepatitis B (CHB), compared with those patients suffering HCC alone(P < 0.05). Furthermore, although the slightly lower levels of LTD4 were detected in HCC patients with non-metastasis and therapy compared with metastasis and non-therapy, no significant differences were detected. Taken together, the levels of circulating LTD4 are elevated in HCC and it may participate in the pathogenesis of HCC as an inflammatory factor from CHB disease to HCC.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Hepatocellular; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leukotriene D4; Liver; Liver Neoplasms; Male; Middle Aged; Prognosis; Survival Rate; Young Adult