Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types

Tailor, Prashant D; Kodeboyina, Sai Karthik; Bai, Shan; Patel, Nikhil; Sharma, Satendra; Ratnani, Akshay; Copland, John A.; She, Jin Xiong; Sharma, Ashok

doi:10.18632/oncotarget.24947

Cited by 43 publications

(38 citation statements)

References 70 publications

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“…Several reports have shown that KLK10 is significantly downregulated in RCC. 42,43 Here, we found that KLK10 expression tended to be lower in clear cell tumors relative to benign tumors (≤4 cm), although this was not significant on univariate analysis.…”

Section: Discussionmentioning

confidence: 66%

Searching for prognostic biomarkers for small renal masses in the urinary proteome

Meo

Batruch

Brown

et al. 2019

Intl Journal of Cancer

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Renal cell carcinoma (RCC) is frequently diagnosed incidentally as an early‐stage small renal mass (SRM; pT1a, ≤4 cm). Overtreatment of patients with benign or clinically indolent SRMs is increasingly common and has resulted in a recent shift in treatment recommendations. There are currently no available biomarkers that can accurately predict clinical behavior. Therefore, we set out to identify early biomarkers of RCC progression. We employed a quantitative label‐free liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS) proteomics approach and targeted parallel‐reaction monitoring to identify and validate early, noninvasive urinary biomarkers for RCC‐SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤4 cm) cases, 30 progressive and 26 nonprogressive clear cell RCC (ccRCC)‐SRM cases, in addition to 26 healthy controls. We identified six proteins, which displayed significantly elevated expression in clear cell RCC‐SRMs (ccRCC‐SRMs) relative to healthy controls. Proteins C12ORF49 and EHD4 showed significantly elevated expression in ccRCC‐SRMs compared to renal oncocytoma (≤4 cm). Additionally, proteins EPS8L2, CHMP2A, PDCD6IP, CNDP2 and CEACAM1 displayed significantly elevated expression in progressive relative to nonprogressive ccRCC‐SRMs. A two‐protein signature (EPS8L2 and CCT6A) showed significant discriminatory ability (areas under the curve: 0.81, 95% CI: 0.70–0.93) in distinguishing progressive from nonprogressive ccRCC‐SRMs. Patients (Stage I–IV) with EPS8L2 and CCT6A mRNA alterations showed significantly shorter overall survival (p = 1.407 × 10−6) compared to patients with no alterations. Our in‐depth proteomic analysis identified novel biomarkers for early‐stage RCC‐SRMs. Pretreatment characterization of urinary proteins may provide insight into early RCC progression and could potentially help assign patients to appropriate management strategies.

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Section: Discussionmentioning

confidence: 66%

Searching for prognostic biomarkers for small renal masses in the urinary proteome

Meo

Batruch

Brown

et al. 2019

Intl Journal of Cancer

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“…Thus, it is possible that tissue-specific factors influence and condition KLK12 gene expression in both healthy and tumor tissues. However, KLKs are known to be dysregulated in many tumors in comparison with the healthy tissues (Mavridis and Scorilas 2010;Tailor et al 2018). KLK12 is one of the 9 KLK genes (namely, KLK1, KLK2, KLK6, KLK7, KLK9, KLK10, KLK11, KLK12 and KLK14) whose mRNA levels were found to be significantly down-regulated in malignant breast tissues compared to normal breast tissues (Mange et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of kallikrein-related peptidase 12 (KLK12) mRNA expression in triple-negative breast cancer patients

Gong

Liu

Preis

et al. 2020

Mol Med

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Background: The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Differential expression accompanied by either increased or decreased enzymatic activity has been linked to several diseases including cancer. Triple-negative breast cancer (TNBC) represents a very aggressive subgroup of breast cancer with high tumor recurrence rates and poor patient prognosis. Here, we quantified the KLK12 mRNA expression levels in tumor tissue of TNBC patients and analyzed their prognostic value. Methods: In the present study, KLK12 mRNA expression in tumor tissue of TNBC patients (n = 116) was determined by quantitative real-time PCR assay. The association of KLK12 mRNA levels with clinical parameters, and patients' outcome was analyzed using Chi-square tests, Cox regression models and Kaplan-Meier survival analysis. Results: Positive, but low KLK12 mRNA levels were detected in about half of the cases (54 out of 116; 47%), the other samples were negative for KLK12 mRNA expression. No significant association was observed between KLK12 mRNA levels and clinicopathological variables (age, lymph node status, tumor size, and histological grade). In univariate Cox analyses, positive KLK12 mRNA expression was significantly associated with shortened disease-free survival (DFS; hazard ratio [HR] = 2.12, 95% CI = 1.19-3.78, p = 0.010) as well as overall survival (OS; HR = 1.91, 95% CI = 1.04-3.50, p = 0.037). In multivariable Cox analysis, including all clinical parameters plus KLK12 mRNA, the lattertogether with age -remained an independent unfavorable predictive marker for DFS (HR = 2.33, 95% CI = 1.28-4.24, p = 0.006) and showed a trend towards significance in case of OS (HR = 1.80, 95% CI = 0.96-3.38, p = 0.066).Conclusions: Positive KLK12 expression is remarkably associated with shortened DFS and OS, suggesting that KLK12 plays a tumor-supporting role in TNBC.

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“…KLK6 displays aberrant expression in various types of cancer, including breast cancer (Anisowicz et al ., ; Haritos et al ., ; Wang et al ., ), head and neck squamous cell cancer (Schrader et al ., ), renal cancer (Tailor et al ., ), and colon cancer (Kim et al ., ; Petrak et al ., ). Very recently, we showed that KLK6 accelerates nonmelanoma skin cancer formation in vivo by increasing tumor‐associated inflammation (Khoury et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Biochemical pathways mediated by KLK6 protease in breast cancer

et al. 2019

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Kallikrein‐related peptidase 6 (KLK6) is a serine protease normally expressed in mammary tissue and aberrantly regulated in breast cancer. At physiological levels, KLK6 functions as a suppressor of breast cancer, while its aberrant overexpression (> 50‐fold higher than normal) is characteristic of a subset of breast cancers and has been linked to accelerated growth of primary breast tumors in severe combined immunodeficiency mice (Pampalakis et al. Cancer Res 2009, 69, 3779). Here, we investigated the molecular mechanisms underlying the concentration‐dependent functions of KLK6 by comparing MDA‐MB‐231 stable transfectants expressing increasing levels of KLK6 in in vitro and in vivo tumorigenicity assays (soft agar, xenograft growth, tail vein metastasis). Quantitative proteomics was applied to identify proteins that are altered upon re‐expression of KLK6 in MDA‐MB‐231 at normal or constitutive levels. Overexpression of KLK6 is associated with increased metastatic ability of breast cancer cells into lungs, increased expression of certain S100 proteins (S100A4, S100A11) and keratins (KRT), and downregulation of the apoptosis‐related proteases CASP7 and CASP8, and RABs. On the other hand, KLK6 re‐expression at physiological levels leads to inhibition of lung metastases associated with suppression of S100 proteins (S100A4, S100A10, S100A13, S100A16) and induced CASP7 and CASP8 expression. As this is the first report that KLK6 expression is associated with S100 proteins, caspases, RABs, and KRTs, we validated this finding in clinical datasets. By integrating proteomics and microarray data from breast cancer patients, we generated two composite scores, KLK6 + S100B‐S100A7 and KLK6 + S100B‐S100A14‐S100A16, to predict long‐term survival of breast cancer patients. We present previously unknown pathways implicating KLK6 in breast cancer. The findings promise to aid our understanding of the functional roles of KLK6 in breast cancer and may yield new biomarkers for the cancer types in which KLK6 is known to be aberrantly upregulated.

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Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types

Cited by 43 publications

References 70 publications

Searching for prognostic biomarkers for small renal masses in the urinary proteome

Searching for prognostic biomarkers for small renal masses in the urinary proteome

Prognostic value of kallikrein-related peptidase 12 (KLK12) mRNA expression in triple-negative breast cancer patients

Biochemical pathways mediated by KLK6 protease in breast cancer

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