Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E‐cadherin

Johnson, Sarah K.; Ramani, Vishnu C.; Hennings, Leah; Haun, Randy S.

doi:10.1002/cncr.22606

Cited by 112 publications

(113 citation statements)

References 36 publications

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“…The matrix metalloproteases (MMP), cathespins and kallikreins are proteases reported to cleave E-cadherin within its ectodomain. 18,21,23,[58][59][60][61][62] In addition, hepatocyte growth factor/scatter factor (HGF/SF) expression has been associated with E-cadherin ectodomain shedding and increased invasiveness of cancer cells. 63 The protease(s) responsible for E-cadherin cleavage in CC-RCC has not been identified.…”

Section: Discussionmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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Section: Discussionmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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“…The peptides in each fraction were purified with a ZipTipC 18 pipette tip (Millipore) and eluted in 4 l buffer B (90% ACN, 0.1% formic acid, 10% H 2 O, 0.02% TFA). The peptides were initially bound to a 2-cm C 18 precolumn with a 200-m diameter and eluted onto a resolving 5-cm analytical C 18 column (75-m diameter) with a 15-mm tip (New Objective). The liquid chromatography setup was connected to a Thermo LTQ Orbitrap XL mass spectrometer with a nanoelectrospray ionization source (Proxeon).…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, KLK3 was reported to activate latent TGF-␤ (16), and KLKs 1, 2, 3, 4, 11, and 14 were proposed to modify the bioavailability of insulin-like growth factors (IGFs) by fragmentation of IGF-binding proteins (IGFBP) (13,14). Moreover, KLKs have been involved in regulation of cell-cell interactions through hydrolysis of desmosomal cadherins (17) and shedding of E-cadherin (18). Finally, it is currently known that KLKs regulate cell signaling via the protease-activated receptors (19).…”

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confidence: 99%

Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

Guillon-Munos

Οικονομοπούλου

Michel

et al. 2011

Journal of Biological Chemistry

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Kallikrein-related peptidases (KLKs) are an emerging group of secreted serine proteases involved in several physiological and pathological processes. We used a degradomic approach to identify potential substrates of KLK12. MDA-MB-231 cells were treated either with KLK12 or vehicle control, and the proteome of the overlying medium was analyzed by mass spectrometry. CCN1 (cyr61, ctgf, nov) was among the proteins released by the KLK12-treated cells, suggesting that KLK12 might be responsible for the shedding of this protein from the cell surface. Fragmentation of CCN1 by KLK12 was further confirmed in vitro, and the main cleavage site was localized in the hinge region between the first and second half of the recombinant protein. KLK12 can target all six members of the CCN family at different proteolytic sites. Limited proteolysis of CCNs (cyr61, ctgf, nov) was also observed in the presence of other members of the KLK family, such as KLK1, KLK5, and KLK14, whereas KLK6, KLK11, and KLK13 were unable to fragment CCNs. Because KLK12 seems to have a role in angiogenesis, we investigated the relations between KLK12, CCNs, and several factors known to be involved in angiogenesis. Solid phase binding assays showed that fragmentation of CCN1 or CCN5 by KLK12 prevents VEGF 165 binding, whereas it also triggers the release of intact VEGF and BMP2 from the CCN complexes. The KLK12-mediated release of TGF-␤1 and FGF-2, either as intact or truncated forms, was found to be concentration-dependent. These findings suggest that KLK12 may indirectly regulate the bioavailability and activity of several growth factors through processing of their CCN binding partners.

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“…Immunohistochemical staining was carried out as previously described (10). Briefly, formalin-fixed, paraffinembedded sections were deparaffinized and rehydrated in xylene followed by graded ethanol.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

“…We previously generated an expression profile of serine proteases expressed in both normal and adenocarcinoma pancreatic tissues and found that kallikrein-related peptidase 7 (KLK7) is overexpressed in PDACs (10). KLK7, a chymotryptic-like serine protease, was initially purified and characterized from human skin extracts and is thought to play a role in desquamation of human skin (11,12).…”

Section: Introductionmentioning

confidence: 99%

Expression of Kallikrein-Related Peptidase 7 Predicts Poor Prognosis in Patients with Unresectable Pancreatic Ductal Adenocarcinoma

Iakovlev

Siegel

Tsao

et al. 2012

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Kallikrein-related peptidase 7 (KLK7) is overexpressed in pancreatic ductal adenocarcinomas (PDAC). The aims of this study were to examine the expression of KLK7 during progression of pancreatic intraepithelial neoplasia (PanIN) to invasive PDAC and to assess its prognostic significance for PDAC.Methods: Immunohistochemistry was used to assess KLK7 expression using a tissue microarray (TMA) and full sections of pancreatic tissue containing normal tissue, PanIN, and invasive adenocarcinoma, and the association between KLK7 expression and prognosis was examined by a population-based pancreatic cancer TMA.Results: Normal pancreatic epithelium was negative for KLK7 in either TMAs or full sections. Analysis by TMAs showed that 91% of cases showed KLK7 positivity in the adenocarcinoma component, which was significantly higher than PanIN 2/3. In full tissue sections of PDAC, KLK7 expression was detected in less than 1% of cells among PanIN 1A lesions, and increased with grade among PanIN 1B and PanIN2/3 lesions before reaching 69% in the invasive PDAC. In patients with unresected PDAC, KLK7 positivity was significantly associated with shorter overall survival.Conclusions: Aberrant KLK7 expression starts in intermediate-to-late stages of PanIN progression, and KLK7-positive staining is associated with almost a three-fold increase in mortality rate of patients with unresected PDAC.Impact: The association of KLK7 expression and poor outcome of patients with unresectable PDAC suggests that inhibiting either KLK7 expression and/or activity could be a therapeutic strategy. Because the vast majority of patients present with unresectable disease, such an intervention could have a significant impact upon the overall survival of this patient population. Cancer Epidemiol Biomarkers Prev; 21(7); 1135-42. Ó2012 AACR.

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Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E‐cadherin

Cited by 112 publications

References 36 publications

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

Expression of Kallikrein-Related Peptidase 7 Predicts Poor Prognosis in Patients with Unresectable Pancreatic Ductal Adenocarcinoma

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