Biomedical Engineering Reference
In-Depth Information
results in loss of E-cadherin and induction of vimentin, which is a hallmark of
EMT.
20
Additionally, KLK6 in vivo
21
and KLK7 in vitro
22
have been impli-
cated in E-cadherin shedding. In breast-cancer cells, induction of KLK6
expression at physiological concentrations reduces growth of primary breast
tumors with concomitant downregulation of vimentin expression.
23
Further-
more, the aberrant overexpression of KLK6 observed in a small subset of
breast tumors has been linked to hyperproliferation of breast
23
and non-small-
cell lung cancer.
24
Cumulatively, KLKs seem to play dual roles in cancer
depending on the concentration and amount of active enzyme and the tissue,
type, and stage of cancer,
8
as also illustrated from many studies on the func-
tions of KLK3/PSA that can act either as a cancer fighter or as a cancer
promoter.
25
9.1.2.2 Skin Diseases
9.1.2.2.1 Netherton Syndrome. Netherton syndrome (NS) is a severe type of
ichthyosis characterized by generalized exfoliative erythroderma, a hair-shaft
defect known as trichorrhexis invaginata, and severe atopic manifestations. NS
is caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5)
gene that encodes for the serpin LEKTI (lympho-epithelial Kazal-type inhi-
bitor) with a rare incidence of one case every 100 000 newborns.
26
Spink5
-/-
mice recapitulate the clinical feature of NS, while they exhibit high activities of
KLK5 and KLK7 proteases in epidermis.
27
The fundamental role of KLK5 in
the induction of inflammation associated with NS has been demonstrated in
Spink5
-/-
mice, and in part, it is mediated through activation of PAR-2.
28,29
LEKTI is a 15-domain (D1 to D15) type inhibitor of serine proteases.
30
Each
domain is separated by 14 spacing fragments. LEKTI requires proteolytic
processing that releases the inhibitory domains.
31
Only D2 and D15 match the
Kazal motif (C-X
n
-C-X
7
-C-X
10
-C-X
2/3
-C-X
m
-C) perfectly; the rest exhibit a
Kazal-type four-cysteine residue pattern.
30
Interestingly, overactivation of
KLKs in the absence of their endogenous LEKTI inhibitors leads to over-
activation of cathelicidin and associated production of high levels of anti-
microbial and proinflammatory peptides (LL-37 and derivatives).
32
LL-37,
which is a peptide of 37 amino acid residues derived from cathelicidin con-
taining two Leu residues at the N-terminus, is a potent chemoattractant for
neutrophils, monocytes and T-cells, and so it can potentiate inflammation.
33,34
In addition, LL-37 complexes with self-DNA are internalized by plasmacytoid
dendritic cells, which become activated to further promote inflammation.
35
9.1.2.2.2 Other Skin Diseases. X-linked ichtyosis is a disease characterized
by hyperkeratosis and increased thickness of the stratum corneum. The dis-
ease is caused by mutations in the gene encoding steroid sulfatase resulting in
increased levels of cholesterol sulfate.
36
In vitro, cholesterol sulfate acts as a
competitive inhibitor of trypsin and chymotrypsin (K
i
5.5 mM and 2.1 mM,
respectively),
37
but it is currently unknown whether it can also inhibit KLK
