The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH 2 -and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH 2 -terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.

No abstract

An 8‐week feeding trial was conducted to determine the quantitative lysine requirement of juvenile grouper Epinephelus coioides (initial mean weight: 15.84 ± 0.23 g, mean ± SD) in eighteen 500‐L indoors flow‐through circular fibreglass tanks provided with sand‐filtered aerated seawater by feeding diets containing six levels of l‐lysine ranging from 19.2 to 39.5 g kg−1 dry diet in 4 g kg−1 increments. The diets, in which 250 g crude protein kg−1 diet came from fish meal and soybean protein concentrate, and 230 g kg−1 from crystalline amino acids, were formulated to simulate the amino acid profile of 480 g kg−1 whole chicken egg protein except for lysine. Each diet was assigned to three tanks in a completely randomized design. Grouper were fed to apparent satiation twice daily during the week and once daily on weekends. Weight gain and specific growth rate increased with increasing levels of dietary lysine up to 27.2 g kg−1 (P < 0.05) and remained nearly the same thereafter (P > 0.05). Feed efficiency was the poorest for fish fed the lowest lysine diet (P < 0.05) and showed no significant differences among other treatments (P > 0.05). Survival could not be related to dietary treatments. Body composition remained relatively constant except for lipid contents in muscle and liver. Total essential amino acid contents in liver increased with dietary lysine level although there was a slight decline for fish fed the highest lysine level of diet. Plasma protein content increased with increasing dietary lysine level (P < 0.05), but cholesterol, triacylglycerol and glucose contents were more variable and could not be related to dietary treatments. Dietary lysine level significantly influenced morphometrical parameters (condition factor, hepatosomatic index and intraperitoneal fat ratio) of juvenile grouper (P > 0.05). Broken‐line analysis of weight gain indicated the dietary lysine requirement of juvenile grouper to be 28.3 g kg−1 diet or 55.6 g kg−1 dietary protein.

Mutation or loss of expression of merlin is responsible for neurofibromatosis type 2 (NF2), which is characterized by the development of schwannomas and other tumors of the nervous system. Like the ERM (ezrin-radixin-moesin) proteins, merlin interacts with CD44, a cell-surface receptor for hyaluronan (HA) that promotes tumorigenesis. However, the relationship between merlin and CD44 and the mechanism by which merlin exerts its tumorsuppressor function have not been elucidated. In the present study, we show that increased expression of wildtype merlin in Tr6BC1 schwannoma cells inhibits HA binding to CD44. Furthermore, we demonstrate that the residues required for this inhibitory effect and the interaction between CD44 and merlin lie within the first 50 amino acids of merlin. Overexpression of merlin inhibited subcutaneous growth of Tr6BC1 cells in immunocompromised Rag1 mice. In contrast, knocking down expression of endogenous merlin promoted tumor cell growth, as did overexpression of a merlin deletion mutant (merlinDel-1) that lacks the first 50 amino acids but not of other NH 2 -terminal deletion mutants. Together, our results demonstrate that inhibition of the CD44-HA interaction contributes to the tumor-suppressor function of merlin, and they suggest that merlin inhibits tumor growth, at least in part, by negatively regulating CD44 function.

Long non-coding RNAs (lncRNAs) have a critical role in cancer initiation and progression, and thus may mediate oncogenic or tumor suppressing effects, as well as be a new class of cancer therapeutic targets. We performed high-throughput sequencing of RNA (RNA-seq) to investigate the expression level of lncRNAs and protein-coding genes in 30 esophageal samples, comprised of 15 esophageal squamous cell carcinoma (ESCC) samples and their 15 paired non-tumor tissues. We further developed an integrative bioinformatics method, denoted URW-LPE, to identify key functional lncRNAs that regulate expression of downstream protein-coding genes in ESCC. A number of known onco-lncRNA and many putative novel ones were effectively identified by URW-LPE. Importantly, we identified lncRNA625 as a novel regulator of ESCC cell proliferation, invasion and migration. ESCC patients with high lncRNA625 expression had significantly shorter survival time than those with low expression. LncRNA625 also showed specific prognostic value for patients with metastatic ESCC. Finally, we identified E1A-binding protein p300 (EP300) as a downstream executor of lncRNA625-induced transcriptional responses. These findings establish a catalog of novel cancer-associated functional lncRNAs, which will promote our understanding of lncRNA-mediated regulation in this malignancy.