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ADAM8 expression is associated with increased invasiveness and reduced patient survival in pancreatic cancer.

Valkovskaya N, Kayed H, Felix K, Hartmann D, Giese NA, Osinsky SP, Friess H, Kleeff J - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: ADAM8 mRNA was significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissues (5.3-fold increase; P= 0.0008), and high ADAM8 mRNA and protein expression levels correlated with reduced survival time of PDAC patients (P= 0.048 and P= 0.065, respectively).In addition, decreased proteolytic activity was measured in cell culture supernatants following silencing of ADAM8.In conclusion, ADAM8 is overexpressed in PDAC, influences cancer cell invasiveness and correlates with reduced survival, suggesting that ADAM8 might be a potential target in pancreatic cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

ABSTRACT
ADAM8 belongs to a family of transmembrane proteins implicated in cell-cell interactions, proteolysis of membrane proteins, and various aspects of carcinogenesis. In the present study, we aimed to evaluate the expression and function of ADAM8 in pancreatic cancer. ADAM8 mRNA levels were analysed by quantitative RT-PCR and correlated to patient survival. Immunohistochemistry was performed to localize ADAM8 in pancreatic tis-sues. Silencing of ADAM8 expression was carried out by transfection with specific siRNA oligonucleotides. Cell growth and invasion assays were used to assess the functional consequences of ADAM8 silencing. SELDI-TOF-MS was performed to detect the proteolytic activity of ADAM8 in pancreatic cancer cells. ADAM8 mRNA was significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissues (5.3-fold increase; P= 0.0008), and high ADAM8 mRNA and protein expression levels correlated with reduced survival time of PDAC patients (P= 0.048 and P= 0.065, respectively). Silencing of ADAM8 expression did not significantly influence pancreatic cancer cell growth but suppressed invasiveness. In addition, decreased proteolytic activity was measured in cell culture supernatants following silencing of ADAM8. In conclusion, ADAM8 is overexpressed in PDAC, influences cancer cell invasiveness and correlates with reduced survival, suggesting that ADAM8 might be a potential target in pancreatic cancer therapy.

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Related in: MedlinePlus

(A) Domain organization and proposed model for ADAM8 processing. The pro-form of ADAM8 is processed by auto-catalytic prodomain removal into two active forms: the processed form and the remnant protein form. Additional proteolytic cleavage results in two soluble forms: the ectodomain and the MP domain (adapted according to ref.[11]). Pro:prodomain;MP: metalloprotease;DI:disintegrin; CRD: cysteine-rich domain; ELD: EGF-like domain; TM: transmembrane; CTD: cyto-plasmic domain. (B) ADAM8 protein expression in pancreatic tissues. Immunoblot analysis of ADAM8 in normal, chronic pancreatitis and pancreatic cancer tissues. Equal loading of the protein samples was confirmed using an ERK-2 anti-body. Size markers are indicated on the right.
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fig01: (A) Domain organization and proposed model for ADAM8 processing. The pro-form of ADAM8 is processed by auto-catalytic prodomain removal into two active forms: the processed form and the remnant protein form. Additional proteolytic cleavage results in two soluble forms: the ectodomain and the MP domain (adapted according to ref.[11]). Pro:prodomain;MP: metalloprotease;DI:disintegrin; CRD: cysteine-rich domain; ELD: EGF-like domain; TM: transmembrane; CTD: cyto-plasmic domain. (B) ADAM8 protein expression in pancreatic tissues. Immunoblot analysis of ADAM8 in normal, chronic pancreatitis and pancreatic cancer tissues. Equal loading of the protein samples was confirmed using an ERK-2 anti-body. Size markers are indicated on the right.

Mentions: ADAM8 is processed by autocatalysis into two forms: one is derived by removal of a prodomain (processed form) and the other is a remnant protein composed of the extracellular region, with a disintegrin domain at the amino terminus [11] (Fig. 1A). It acts as an active metalloprotease in vitro, hydrolyzing myelin basic protein (MBP), β-amyloid precursor protein [12], CD23 [13], interleukins [14] and tumour necrosis factorα (TNF-α) [9]. ADAM8 activity is not inhibited by tissue inhibitors of matrix metalloproteinases (TIMPs), which is in contrast to other proteolytic proteins [15].


ADAM8 expression is associated with increased invasiveness and reduced patient survival in pancreatic cancer.

Valkovskaya N, Kayed H, Felix K, Hartmann D, Giese NA, Osinsky SP, Friess H, Kleeff J - J. Cell. Mol. Med. (2007 Sep-Oct)

(A) Domain organization and proposed model for ADAM8 processing. The pro-form of ADAM8 is processed by auto-catalytic prodomain removal into two active forms: the processed form and the remnant protein form. Additional proteolytic cleavage results in two soluble forms: the ectodomain and the MP domain (adapted according to ref.[11]). Pro:prodomain;MP: metalloprotease;DI:disintegrin; CRD: cysteine-rich domain; ELD: EGF-like domain; TM: transmembrane; CTD: cyto-plasmic domain. (B) ADAM8 protein expression in pancreatic tissues. Immunoblot analysis of ADAM8 in normal, chronic pancreatitis and pancreatic cancer tissues. Equal loading of the protein samples was confirmed using an ERK-2 anti-body. Size markers are indicated on the right.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401277&req=5

fig01: (A) Domain organization and proposed model for ADAM8 processing. The pro-form of ADAM8 is processed by auto-catalytic prodomain removal into two active forms: the processed form and the remnant protein form. Additional proteolytic cleavage results in two soluble forms: the ectodomain and the MP domain (adapted according to ref.[11]). Pro:prodomain;MP: metalloprotease;DI:disintegrin; CRD: cysteine-rich domain; ELD: EGF-like domain; TM: transmembrane; CTD: cyto-plasmic domain. (B) ADAM8 protein expression in pancreatic tissues. Immunoblot analysis of ADAM8 in normal, chronic pancreatitis and pancreatic cancer tissues. Equal loading of the protein samples was confirmed using an ERK-2 anti-body. Size markers are indicated on the right.
Mentions: ADAM8 is processed by autocatalysis into two forms: one is derived by removal of a prodomain (processed form) and the other is a remnant protein composed of the extracellular region, with a disintegrin domain at the amino terminus [11] (Fig. 1A). It acts as an active metalloprotease in vitro, hydrolyzing myelin basic protein (MBP), β-amyloid precursor protein [12], CD23 [13], interleukins [14] and tumour necrosis factorα (TNF-α) [9]. ADAM8 activity is not inhibited by tissue inhibitors of matrix metalloproteinases (TIMPs), which is in contrast to other proteolytic proteins [15].

Bottom Line: ADAM8 mRNA was significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissues (5.3-fold increase; P= 0.0008), and high ADAM8 mRNA and protein expression levels correlated with reduced survival time of PDAC patients (P= 0.048 and P= 0.065, respectively).In addition, decreased proteolytic activity was measured in cell culture supernatants following silencing of ADAM8.In conclusion, ADAM8 is overexpressed in PDAC, influences cancer cell invasiveness and correlates with reduced survival, suggesting that ADAM8 might be a potential target in pancreatic cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

ABSTRACT
ADAM8 belongs to a family of transmembrane proteins implicated in cell-cell interactions, proteolysis of membrane proteins, and various aspects of carcinogenesis. In the present study, we aimed to evaluate the expression and function of ADAM8 in pancreatic cancer. ADAM8 mRNA levels were analysed by quantitative RT-PCR and correlated to patient survival. Immunohistochemistry was performed to localize ADAM8 in pancreatic tis-sues. Silencing of ADAM8 expression was carried out by transfection with specific siRNA oligonucleotides. Cell growth and invasion assays were used to assess the functional consequences of ADAM8 silencing. SELDI-TOF-MS was performed to detect the proteolytic activity of ADAM8 in pancreatic cancer cells. ADAM8 mRNA was significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissues (5.3-fold increase; P= 0.0008), and high ADAM8 mRNA and protein expression levels correlated with reduced survival time of PDAC patients (P= 0.048 and P= 0.065, respectively). Silencing of ADAM8 expression did not significantly influence pancreatic cancer cell growth but suppressed invasiveness. In addition, decreased proteolytic activity was measured in cell culture supernatants following silencing of ADAM8. In conclusion, ADAM8 is overexpressed in PDAC, influences cancer cell invasiveness and correlates with reduced survival, suggesting that ADAM8 might be a potential target in pancreatic cancer therapy.

Show MeSH
Related in: MedlinePlus