Kallikrein family proteases KLK6 and KLK7 are potential early detection and diagnostic biomarkers for serous and papillary serous ovarian cancer subtypes

Tamir, Ayala; Jag, Ushma; Sarojini, Sreeja; Schindewolf, Craig; Tanaka, Takemi; Gharbaran, Rajendra; Patel, Hiren; Sood, Anil K.; Hu, Wei; Patwa, Ruzeen; Blake, P. R.; Chirina, Polina; Jeong, Jin Oh; Lim, Heejin; Goy, André; Pecora, Andrew L.; Suh, Kwang S.

doi:10.1186/preaccept-1736656869122663

Cited by 8 publications

(12 citation statements)

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“…Elevated KLK6 levels have been associated with late stage ovarian cancer but not benign tumors [ 34 ]. A recent study using western blots of serum depleted of high abundance proteins suggests that serum KLK6 levels are elevated in early stages of serous ovarian cancer [ 62 ]. Analyses of our Proseek ® data support these findings of a high correlation between KLK6 serum levels and late stage ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

A multiplex platform for the identification of ovarian cancer biomarkers

et al. 2017

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BackgroundCurrently, there are no FDA approved screening tools for detecting early stage ovarian cancer in the general population. Development of a biomarker-based assay for early detection would significantly improve the survival of ovarian cancer patients. MethodsWe used a multiplex approach to identify protein biomarkers for detecting early stage ovarian cancer. This new technology (Proseek® Multiplex Oncology Plates) can simultaneously measure the expression of 92 proteins in serum based on a proximity extension assay. We analyzed serum samples from 81 women representing healthy, benign pathology, early, and advanced stage serous ovarian cancer patients. ResultsPrinciple component analysis and unsupervised hierarchical clustering separated patients into cancer versus non-cancer subgroups. Data from the Proseek® plate for CA125 levels exhibited a strong correlation with current clinical assays for CA125 (correlation coefficient of 0.89, 95% CI 0.83, 0.93). CA125 and HE4 were present at very low levels in healthy controls and benign cases, while higher levels were found in early stage cases, with highest levels found in the advanced stage cases. Overall, significant trends were observed for 38 of the 92 proteins (p < 0.001), many of which are novel candidate serum biomarkers for ovarian cancer. The area under the ROC curve (AUC) for CA125 was 0.98 and the AUC for HE4 was 0.85 when comparing early stage ovarian cancer versus healthy controls. In total, 23 proteins had an estimated AUC of 0.7 or greater. Using a naïve Bayes classifier that combined 12 proteins, we improved the sensitivity corresponding to 95% specificity from 93 to 95% when compared to CA125 alone. Although small, a 2% increase would have a significant effect on the number of women correctly identified when screening a large population.ConclusionsThese data demonstrate that the Proseek® technology can replicate the results established by conventional clinical assays for known biomarkers, identify new candidate biomarkers, and improve the sensitivity and specificity of CA125 alone. Additional studies using a larger cohort of patients will allow for validation of these biomarkers and lead to the development of a screening tool for detecting early stage ovarian cancer in the general population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-017-9169-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A multiplex platform for the identification of ovarian cancer biomarkers

et al. 2017

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“…A library of OVC cell lines and corresponding normal ovarian cells were obtained and cultured in specified conditioned media as described previously [ 12 ]. Briefly, OVC cells lines used were TOV112D, OV-90, CAOV3, SKOV3, PA-1, SW626, and ES-2 (ATCC, Manassas, VA); SKOV-1, IGROV-1, HEY, A2780, and 2008 (S. Howell, UCSD); UCI-101 and UCI-107 (P. Carpenter, UCI); DOV-13 (R. Bast, MD Anderson Cancer Center, TX); 2774 (J. Wolf, MD Anderson Cancer Center, TX); BG-1 (Dr. K. Korach, NIH, NC); normal ovarian epithelial cell lines FHIOSE118 (J. Cheng, Moffitt Cancer Center, FL) and IOSE523 (N. Auersperg, University of British Columbia, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…In situ hybridization was performed as we previously described [ 12 ]. The probe sequence for PRSS8 was; 5’- DIGN-GCAGTAAAACTCCTGACTCTCA.…”

Section: Methodsmentioning

confidence: 99%

“…Overexpression of these proteins is highly specific for OVC but not other cancer types; these proteins are significantly overexpressed in OVC cells, and are secreted into bodily fluids. We have recently published the potential of KLK6 and KLK7 as early detection biomarkers [ 12 ]. The current study provides data and analysis that define the potential use of PRSS8 as a biomarker for early detection of OVC.…”

Section: Introductionmentioning

confidence: 99%

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The serine protease prostasin (PRSS8) is a potential biomarker for early detection of ovarian cancer

et al. 2016

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BackgroundOvarian cancer (OVC) is the deadliest of all gynecologic cancers, primarily as a consequence of asymptomatic progression. The complex nature of OVC creates challenges for early detection, and there is a lack of specific and sensitive biomarkers suitable for screening and detecting early stage OVC.MethodsPotential OVC biomarkers were identified by bioinformatic analysis. Candidates were further screened for differential expression in a library of OVC cell lines. OVC-specific overexpression of a candidate gene, PRSS8, which encodes prostasin, was confirmed against 18 major human cancer types from 390 cancer samples by qRT-PCR. PRSS8 expression profiles stratified by OVC tumor stage-, grade- and subtype were generated using cDNA samples from 159 OVC samples. Cell-specific expression and localization of prostasin was determined by immunohistological tissue array analysis of more than 500 normal, benign, and cancerous ovarian tissues. The presence of prostasin in normal, benign, and OVC serum samples was also determined.ResultsGene expression analysis indicated that PRSS8 was expressed in OVC at levels more than 100 fold greater than found in normal or benign ovarian lesions. This overexpression signature was found in early stages of OVC and was maintained in higher stages and grades of OVC. The PRSS8 overexpression signature was specific for OVC and urinary bladder cancer among 18 human cancer types. The majority of ovarian cell lines overexpressed PRSS8. In situ hybridization and histopathology studies of OVC tissues indicated that overexpression of prostasin was largely localized to tumor epithelium and was absent in neighboring stroma. Significantly higher levels of prostasin were found in early stage OVC serum samples compared to benign ovarian and normal donor samples.ConclusionsThe abundant amounts of secreted prostasin found in sera of early stage OVC can potentially be used as a minimally invasive screening biomarker for early stage OVC. Overexpression of PRSS8 mRNA and high levels of prostasin in multiple subtypes of early stage ovarian tumors may provide clinical biomarkers for early detection of OVC, which can potentially be used with CA125 and HE4.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0228-9) contains supplementary material, which is available to authorized users.

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“…Although there is less confidence associated with the scores for these particular cancer types, potential biomarkers could still be identified. For example, the top-scoring candidate for ovarian cancer (OV) was WFDC2 (also known as HE4), which is an established OV protein biomarker in both urine and serum ( Hellström et al, 2003 , 2010 ), and the next top 6 candidates included FOLR1, KLK6, KLK7, and MSLN, all of which have been experimentally confirmed as biofluid diagnostic markers of OV ( Badgwell et al, 2007 ; Diamandis et al, 2003 ; Leung et al, 2013 ; Tamir et al, 2014 ).…”

Section: Methodsmentioning

confidence: 99%

A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome

et al. 2019

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SUMMARY The collection of proteins secreted from a cell—the secretome—is of particular interest in cancer pathophysiology due to its diagnostic potential and role in tumorigenesis. However, cancer secretome studies are often limited to one tissue or cancer type or focus on biomarker prediction without exploring the associated functions. We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes. Using transcriptomic data spanning 32 cancer types and 30 healthy tissues, we quantified the relative diagnostic potential of secretome proteins for each cancer. Furthermore, we offer a potential mechanism by which cancer cells relieve secretory pathway stress by decreasing the expression of tissue-specific genes, thereby facilitating the secretion of proteins promoting invasion and proliferation. These results provide a more systematic understanding of the cancer secretome, facilitating its use in diagnostics and its targeting for therapeutic development.

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Kallikrein family proteases KLK6 and KLK7 are potential early detection and diagnostic biomarkers for serous and papillary serous ovarian cancer subtypes

Cited by 8 publications

References 0 publications

A multiplex platform for the identification of ovarian cancer biomarkers

A multiplex platform for the identification of ovarian cancer biomarkers

The serine protease prostasin (PRSS8) is a potential biomarker for early detection of ovarian cancer

A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome

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