Download Gene Section KLK11 (Kallikrein-related peptidase 11) Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Review
KLK11 (Kallikrein-related peptidase 11)
Liu-Ying Luo, Eleftherios P Diamandis
R&D Systems, Inc. 614 McKinley Place, N. E. Minneapolis, MN 55413, USA (LYL), Department of
Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave. Toronto, ON M5G 1X5,
Canada (EPD)
Published in Atlas Database: March 2008
Online updated version: http://AtlasGeneticsOncology.org/Genes/KLK11ID41077ch19q13.html
DOI: 10.4267/2042/44378
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
the cells. Upon activation, the propetide is removed to
generate the mature active protein.
Other names: Hippostasin; hK11; PRSS20; TLSP
HGNC (Hugo): KLK11
Location: 19q13.41
Local order: Telomere to centromere.
Expression
The KLK11 gene is about 5.8 Kb in length, consisting
of 6 exons and 5 introns.
KLK11 is mainly expressed in epithelial tissues, such
as stomach, trachea, and skin, with high levels in the
brain and the prostate. KLK11 has also been identified
in many biological fluids. Seminal plas-ma, containing
an average of 15 µg/mL of KLK11, is the biological
fluid reported to have the most abundant KLK11 so far.
Other specimens, includ-ing serum, lactating milk,
cerebrospinal fluid, and amniotic fluid, all have
detectable amounts of KLK11.
Transcription
Localisation
Three alternatively spliced variants have been
described in the literature: including isoform 1, isoform
2, and isoform 3. Isoform 1 is preferentially expressed
in the brain and it encodes a protein of 250 amino
acids. Isoform 2 and isoform 3 are mainly expressed in
the prostate. Compared to isoform 1, isoform 2 has
additional 32 amino acids at the N-terminus and
isoform 3 contains extra 25 amino acids inserted in the
catalytic triad. Tissue-specific expression of these
isoforms is regulated by multiple promoters that locate
in the first exon of each isoform.
Secreted.
DNA/RNA
Description
Function
The physiology functions of KLK11 and the
mechanisms of its involvement in cancer have yet to be
determined. Using positional scanning combinatorial
tetrapeptide substrate library, it has revealed that
KLK11 preferentially cleaves peptide bonds after
methionine, arginine, and lysine. However, its
physiology substrates remain unidenti-fied. One
hypothesis is that KLK11 may be part of a proteolytic
cascade consisting of multiple kalli-kreins (KLKs).
Since KLK11 is unable to auto-activate, in the cascade,
it is likely that KLK11 is activated by upstream KLKs,
then
subsequently
activate/inactaivate
other
downstream KLKs or other proteins. Accumulating
experimental evi-dence is in accord with this
hypothesis. It has been shown in in vitro experiments
that, both KLK12 and KLK14 are able to activate
KLK11. Another hypothesis is that KLK11 may be
involved in the homeostasis of insulin growth factor.
This hypo-thesis comes from the observation that
KLK11 is able to degrade insulin growth factor binding
Pseudogene
Not identified so far
Protein
Description
Full-length KLK11 is composed of a signal peptide (aa
1-50), a propeptide (aa 51-53), and a mature chain (aa
54-282). KLK11 is synthesized as a full-length protein
intracellularly. In the secretary pathway, the signal
peptide is cleaved and the zymogen is released outside
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
15
KLK11 (Kallikrein-related peptidase 11)
Luo LY, Diamandis EP
from noncancer individuals whose total PSA levels are
in the range of 2.5 to 10 ng/mL.
Prognosis
Tissue expression levels of KLK11 may be used as a
prognostic indicator for prostate cancer. Lower KLK11
mRNA levels have been found to be associated with
higher tumor grade, tumor stage, and Gleason score,
suggesting that KLK11 might be able to indicate the
aggressiveness of prostate tumors.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid/Mutated gene
Not identified so far.
protein 3 (IGFBP3) to facilitate the release of insulin
growth factor. KLK11 enzymatic activity is mainly
regulated by internal cleavage. In seminal plasma,
about half the KLK11 is in the cleaved inactive form.
Some abundant serine protease inhibitors present in the
circulation or in seminal plasma, such as α1-antitrypsin,
protein C inhibitor, α2-antiplasmin, and C1 inhibitor,
fail to show rapid inhibition of KLK11.
Homology
Human KLK11 protein sequence shares 98% and 82%
identity
with
that
of
chimpanzee
and
dog/bovine/mouse/rat, respectively.
Mutations
Ovarian cancer
Note
No germinal or somatic mutations are identified to be
associated with cancer so far.
Disease
KLK11 has shown promise as a diagnostic biomarker
for ovarian cancer. Earlier studies have revealed that
serum KLK11 concentrations are elevated in the
majority of ovarian cancer patients. Subsequent
investigations further demonstrate that KLK11 is able
to distinguish ovarian cancer cases from healthy
controls. More importantly, it is less sensitive to benign
ovarian diseases than is CA125, the most widely used
diagnostic marker for ovarian cancer. Moreover, it has
high temporal stability, which implies that it could be
used in a longitudinal screening program for early
detection.
Prognosis
Many investigations have clearly demonstrated that
KLK11 has elevated protein levels in primary ovarian
tumors than in normal tissue, benign or nonovarian
metastatic tumors. In general, higher levels of KLK11
in ovarian tumor extracts are predictive of favorable
outcome. They are more likely to be associated with
early stage, responsive to chemotherapy, and longer
progression free survival.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid/Mutated gene
Not identified so far.
Implicated in
Prostate cancer
Disease
A number of investigations have been reported
concerning the role of KLK11 as a potential diagnostic
biomarker for prostate cancer (CaP). Prostate specific
antigen (PSA) is currently the most widely used
diagnostic marker for CaP. However, measuring PSA
alone is lack of specificity, since some benign prostatic
diseases, such as benign prostatic hyperplasia (BPH)
and prostatitis, can also have increased serum PSA
levels, whereas some CaP patients may have only mild
elevation of PSA (4-10 ng/mL). To improve the
specificity, a number of additional analyses, such as
measuring the molecular forms of PSA, have been
proposed. Patients with low free to total PSA ratios are
considered to have higher risk of developing CaP. In
spite of these efforts, false positive and false negative
still occur and doctors frequently need to rely on
prostate biopsy to make the final diagnosis. Some
investigations have shown that measuring serum
KLK11 concentrations may help discriminate CaP from
BPH and reduce the number of unnecessary biopsies.
Similar to PSA, serum KLK11 concentrations are
elevated in the majority of CaP patients. However,
compared to the BPH patients, the CaP patients tend to
have lower serum KLK11 concentrations and lower
KLK11 to total PSA ratios. In those patients that have
less than 20% free PSA, measuring KLK11 to total
PSA ratio identified 54% to have BPH. As such, it
seems that KLK11 to total PSA ratio might be a
complementary marker for free PSA percentage and
combination of these two markers results in better
specificity for CaP. KLK11 might not be superior to
PSA in population screening. In a retrospective study,
serum KLK11 or KLK11 to PSA ratio showed no
advantage over PSA alone to differentiate CaP patients
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
Lung cancer
Prognosis
The prognostic role of KLK11 has also been explored
in lung cancer both at the mRNA and protein levels.
With quantitative PCR, it has shown that KLK11
mRNA levels are lower in tumor tissues in comparison
with adjacent normal counter-parts. No significant
correlation is identified with clinical stages, tumor
status, and lymph node status. However, those patients
with low KLK11 mRNA expression seem to have a
significantly worse prognosis than those with high
levels. At the protein level, serum KLK11
concentrations in non-small cell lung cancer patients
are higher than in healthy controls and they are
positively correlated with tumor stages.
16
KLK11 (Kallikrein-related peptidase 11)
Luo LY, Diamandis EP
candidate prostate and ovarian cancer biomarker, from
seminal plasma. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):74250
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid/Mutated gene
Not identified so far.
Mitsui S, Nakamura T, Okui A, Kominami K, Uemura H,
Yamaguchi N. Multiple promoters regulate tissue-specific
alternative splicing of the human kallikrein gene,
KLK11/hippostasin. FEBS J. 2006 Aug;273(16):3678-86
Breakpoints
Planque C, Aïnciburu M, Heuzé-Vourc'h N, Régina S, de
Monte M, Courty Y. Expression of the human kallikrein genes
10 (KLK10) and 11 (KLK11) in cancerous and non-cancerous
lung tissues. Biol Chem. 2006 Jun;387(6):783-8
Note
Not described so far.
References
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Kobayashi Y, Yano M, Fujii Y. Decreased kallikrein 11
messenger RNA expression in lung cancer. Clin Lung Cancer.
2006 Jul;8(1):45-8
Mitsui S, Yamada T, Okui A, Kominami K, Uemura H,
Yamaguchi N. A novel isoform of a kallikrein-like protease,
TLSP/hippostasin, (PRSS20), is expressed in the human brain
and prostate. Biochem Biophys Res Commun. 2000 May
27;272(1):205-11
Scorilas A, Gregorakis AK. mRNA expression analysis of
human kallikrein 11 (KLK11) may be useful in the
discrimination of benign prostatic hyperplasia from prostate
cancer after needle prostate biopsy. Biol Chem. 2006
Jun;387(6):789-93
Nakamura T, Mitsui S, Okui A, Kominami K, Nomoto T,
Ukimura O, Kawauchi A, Miki T, Yamaguchi N. Alternative
splicing isoforms of hippostasin (PRSS20/KLK11) in prostate
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Stephan C, Meyer HA, Cammann H, Nakamura T, Diamandis
EP, Jung K. Improved prostate cancer detection with a human
kallikrein 11 and percentage free PSA-based artificial neural
network. Biol Chem. 2006 Jun;387(6):801-5
Diamandis EP, Okui A, Mitsui S, Luo LY, Soosaipillai A, Grass
L, Nakamura T, Howarth DJ, Yamaguchi N. Human kallikrein
11: a new biomarker of prostate and ovarian carcinoma.
Cancer Res. 2002 Jan 1;62(1):295-300
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A, Diamandis EP, Harbeck N. Primary tumor levels of human
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IA, Luo LY, Soosaipillai A, Puopolo M, Grass L, Scorilas A,
Diamandis EP, Katsaros D. Favorable prognostic value of
tissue human kallikrein 11 (hK11) in patients with ovarian
carcinoma. Int J Cancer. 2003 Sep 10;106(4):605-10
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Validation and characterization of human kallikrein 11 as a
serum marker for diagnosis of ovarian carcinoma. Clin Cancer
Res. 2007 Aug 1;13(15 Pt 1):4422-8
Nakamura T, Mitsui S, Okui A, Miki T, Yamaguchi N. Molecular
cloning and expression of a variant form of hippostasin/KLK11
in prostate. Prostate. 2003 Mar 1;54(4):299-305
Memari N, Jiang W, Diamandis EP, Luo LY. Enzymatic
properties of human kallikrein-related peptidase 12 (KLK12).
Biol Chem. 2007 Apr;388(4):427-35
Nakamura T, Scorilas A, Stephan C, Jung K, Soosaipillai AR,
Diamandis EP. The usefulness of serum human kallikrein 11
for discriminating between prostate cancer and benign
prostatic hyperplasia. Cancer Res. 2003 Oct 1;63(19):6543-6
Ochiai A, Shukla A, Davis JW, Fritsche HA, Bhadkamkar V,
Babaian RJ. Is there a role for serum human tissue kallikrein in
detection of prostate cancer? Urology. 2007 Sep;70(3):519-22
Nakamura T, Stephan C, Scorilas A, Yousef GM, Jung K,
Diamandis EP. Quantitative analysis of hippostasin/KLK11
gene expression in cancerous and noncancerous prostatic
tissues. Urology. 2003 May;61(5):1042-6
Sano A, Sangai T, Maeda H, Nakamura M, Hasebe T, Ochiai
A. Kallikrein 11 expressed in human breast cancer cells
releases insulin-like growth factor through degradation of
IGFBP-3. Int J Oncol. 2007 Jun;30(6):1493-8
Yousef GM, Polymeris ME, Yacoub GM, Scorilas A,
Soosaipillai A, Popalis C, Fracchioli S, Katsaros D, Diamandis
EP. Parallel overexpression of seven kallikrein genes in
ovarian cancer. Cancer Res. 2003 May 1;63(9):2223-7
Zheng Y, Katsaros D, Shan SJ, de la Longrais IR, Porpiglia M,
Scorilas A, Kim NW, Wolfert RL, Simon I, Li L, Feng Z,
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associated with poor prognosis in patients with epithelial
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Emami N, Diamandis EP. Human kallikrein-related peptidase
14 (KLK14) is a new activator component of the KLK
proteolytic cascade. Possible function in seminal plasma and
skin. J Biol Chem. 2008 Feb 8;283(6):3031-41
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Expression analysis and prognostic significance of human
kallikrein 11 in prostate cancer. Clin Chim Acta. 2005 Jul
24;357(2):190-5
Planque C, Li L, Zheng Y, Soosaipillai A, Reckamp K, Chia D,
Diamandis EP, Goodglick L. A multiparametric serum kallikrein
panel for diagnosis of non-small cell lung carcinoma. Clin
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seven human tissue kallikreins reveals individual subsite
preferences. J Biol Chem. 2006 Sep 1;281(35):25678-88
This article should be referenced as such:
Luo LY, Diamandis EP. KLK11 (Kallikrein-related peptidase
11). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1):1517.
Luo LY, Jiang W. Inhibition profiles of human tissue kallikreins
by serine protease inhibitors. Biol Chem. 2006 Jun;387(6):8136
Luo LY, Shan SJ, Elliott MB, Soosaipillai A, Diamandis EP.
Purification and characterization of human kallikrein 11, a
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
17