Disease relevance of KLK6

• PATIENTS AND METHODS: Using real-time reverse transcription-PCR, we analyzed the KLK6 expression status with respect to various clinicopathologic variables in 66 patients with gastric cancer [1].
• Elevated KLK6 expression was significantly correlated with serosal invasion (P < 0.05), liver metastasis (P < 0.05), and advanced Duke's stage (P < 0.01) [2].
• Twelve kallikreins, including KLK6, are concurrently upregulated in ovarian cancer [3].
• X-profiler comparison of two pools of normal and cancerous pancreatic libraries further verified the significant increase of KLK6 expression levels in pancreatic cancer [4].
• Similar results were obtained by EST screening; no KLK6 clones were detected in any of the 28 normal libraries examined, while 10 KLK6 EST clones were found in colon adenocarcinoma [4].

Psychiatry related information on KLK6

• Decreased cerebrospinal fluid levels of neurosin (KLK6), an aging-related protease, as a possible new risk factor for Alzheimer's disease [5].

High impact information on KLK6

• However, hK6 in presurgical serum of ovarian cancer patients was highly elevated (mean, 6.8 micro g/L; P <.001) [6].
• The extended substrate specificity profiles are in good agreement with known substrate cleavage sites but also in accord with experimentally solved (hK4, hK6, and hK7) or modeled structures [7].
• Human kallikrein 6 (hK6) is abundantly expressed in the central nervous system and is implicated in demyelinating disease [8].
• These results further supported the hypothesis that hK6 expressed in the central nervous system is involved in normal myelin turnover/demyelination processes, but it is unlikely to self-activate [8].
• This study provided biochemical data about the substrate specificity and activation of hK6 by glycosaminoglycans and by kosmotropic salts, which followed the Hofmeister series [8].

Chemical compound and disease context of KLK6

• We conclude that KLK6 is transcriptionally upregulated in ovarian cancer, but probably not through alternative mRNA transcript expression, genomic mutation, or steroid hormone induction.British Journal of Cancer (2007) 96, 362-372. doi:10.1038/sj.bjc.6603556 www.bjcancer.com [3].
• KLK6 can be reactivated in non-expressing breast cancer cells by treatment with 5-aza-2'-deoxycytidine (5-aza-dC), a compound causing DNA demethylation [9].
• In some breast cancer cell lines, KLK6 expression could be restored by the vitamin D3 analog EB1089 [9].
• Hybrid sandwich assays (capture antibody for hK6 and detection antibody for inhibitors), utilizing a panel of known serine protease inhibitors, indicated that alpha(1)-antichymotrypsin forms a complex with hK6 in milk and ascites fluid [10].
• To investigate the role of protease M/neurosin during experimental demyelination and remyelination, mice were fed cuprizone (bis-cyclohexanon oxaldihydrazone) [11].

Biological context of KLK6

• RESULTS: The KLK6 gene expression in cancerous tissue (0.37 +/- 0.53) was significantly (P < 0.000001) higher than that in noncancerous tissue (0.026 +/- 0.060) [1].
• Our findings also suggest that KLK6 may possibly be a novel target for gastric cancer therapy by gene-silencing procedures [1].
• In addition, we established a KLK6 stably suppressed gastric cancer cell line (MKN28) using small interfering RNA-mediated gene silencing, and investigated its effects on the cell proliferation rate, cell cycle, and invasiveness [1].
• We then scrutinised a few mechanisms that could explain KLK6 upregulation [3].
• Genomic mutation screening of all exons and the 5'-flanking region of the KLK6 gene identified two linked single-nucleotide polymorphisms in the 5'-untranslated region, but neither correlated with KLK6 expression [3].

Anatomical context of KLK6

• In this study, we measured KLK6 expression in a large series of ovarian tissue cytosols and examined possible mechanisms of KLK6 up-regulation in ovarian cancer [3].
• We show that in normal mammary epithelial cells and mammary tumor cell lines that overexpress the KLK6 gene, splice variants account for approximately 10-20% of all mRNA species [12].
• Tissue expression studies indicate that zyme is expressed mainly in brain tissue, including spinal cord and cerebellum, in mammary gland, and in kidney and uterus [13].
• RESULTS: Three other hKs, namely hK6, hK8 and hK13, were immunohistochemically identified as new skin serine proteases in the whole SC, SG, sebaceous glands, eccrine sweat glands, hair follicles and nerves [14].
• Neurosin is present in the cerebrospinal fluid (CSF) as a proenzyme and does not show any enzymatic activity [5].

Associations of KLK6 with chemical compounds

• BACKGROUND: The human kallikrein 6 gene (KLK6) encodes for a secreted serine protease, hK6, which is highly expressed in brain [15].
• Zyme is regulated by steroid hormones in the breast carcinoma cell line BT-474 [13].
• The screening of fluorescence resonance energy transfer (FRET) peptide families derived from Abz-KLRSSKQ-EDDnp resulted in the finding that Abz-AFRFSQ-EDDnp (where Abz is ortho-aminobenzoic acid and EDDnp is N-[2,4-dinitrophenyl]ethylenediamine)) is the best synthetic substrate described so far for hK6 (kcat/Km 38,667 s(-1) mm(-1)) [8].
• This report also suggested the possible modulation of ionotropic glutamate receptors and activation of PAR 2 by hK6 [8].
• However, combined 5-aza-dC/TSA treatment resulted in synergistic activation of KLK6 [9].

Regulatory relationships of KLK6

• When Zyme cDNA is co-expressed with the APP cDNA in 293 (human embryonic kidney) cells, amyloidogenic fragments are detected using C-terminal antibody to APP [16].

Other interactions of KLK6

• At least two kallikreins, KLK6 and KLK10, are significantly up-regulated in pancreatic cancer [4].
• Three kallikrein genes, KLK6, 8 and 10 are overexpressed in colon cancer compared to normal colon, while one kallikrein, KLK1, is down-regulated [4].
• Experimental evidence has shown that at least two kallikreins, KLK6 and KLK8, have potential functions in the CNS [17].
• Therefore, we showed that KLK6 gene silencing with KLK6 small interfering RNA effectively suppressed the cell proliferation rate (P = 0.002), cell population in the S phase (P < 0.01), and invasiveness (P < 0.01) in comparison to mock-transfected cells [1].
• Zyme appears to play a role in Alzheimer disease as well as in breast cancer [13].

Analytical, diagnostic and therapeutic context of KLK6

• Using a newly developed enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies, we quantified KLK6 expression in ovarian tissue cytosols, and confirmed the upregulation of KLK6 in ovarian cancer and its unfavourable prognostic value [3].
• RESULTS: The newly developed hK6 immunofluorometric assay has a detection limit of 0.5 microg/L and upper concentration range of 200 microg/L [18].
• Results:Screening for disseminated cancer cells in blood from 24 ovarian cancer patients, with RT-PCR for KLK6 mRNA, resulted in 75% positivity; however, this was not different from the positivity of normal controls [19].
• RESULTS: hK6 gene expression levels were significantly higher in USPC when compared with endometrioid carcinoma (mean copy number by real-time PCR, 1,927 versus 239, USPC versus endometrioid carcinoma; P < 0.01) [20].
• METHODS: hK6 protein was immunoaffinity-purified and positively identified by Western blotting, N-terminal sequencing, and mass spectrometry. hK6 in cerebrospinal fluid (CSF), milk, ascites, and serum was size-fractionated by chromatography and then measured by a highly sensitive and specific immunoassay [10].

References