KLK7 expression in human tumors: a tissue microarray study on 13,447 tumors

Abstract

Background: Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells.

Methods: To comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry.

Results: KLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p = 0.0005), blood vessel infiltration (p = 0.0037), and lymph vessel infiltration (p < 0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p = 0.0382), advanced pathological tumor stage in papillary thyroid cancer (p = 0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p < 0.0001).

Conclusions: These data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated.

Keywords: Immunohistochemistry; KLK7; Neoplastic human tissues; Tissue microarray.

Fig. 1

KLK7 immunostaining in normal tissues. The panels show a strong membranous and cytoplasmic KLK7 staining of the granular layer of the epidermis of the skin (A) (inset shows higher magnification of the granular layer), a weak to moderate KLK7 positivity of the upper two thirds of the squamous epithelium of the esophagus (B), a strong KLK7 staining around the keratinizing zone of corpuscles of Hassall‘s of the thymus (C), and a weak to moderate KLK7 positivity in a subset of cells of squamous epithelium of tonsil crypts (D). KLK7 staining is largely absent in non-keratinizing squamous epithelium of the uterine cervix (E) and completely lacking in the mucosa of the colon (F)

Fig. 2

KLK7 immunostaining in cancer. The panels show a focal KLK7 immunostaining (staining intensity (int) 2 + in 10% of tumor cells) in areas of keratinization of an HPV-negative squamous cell carcinoma of the vulva (A), the oral cavity (int 1 + in 10%) (B), and of the urinary bladder (int 1 + in 20%) (C). A focal KLK7 staining is also seen in a urothelial carcinoma of the bladder with focal squamous differentiation (int 2 + in 10%) (D) while KLK7 staining is absent in a poorly differentiated squamous cell carcinoma of the esophagus lacking keratinization (int 0) (E). KLK7 positivity of variable intensity is also seen in samples from a serous high-grade carcinoma of the ovary (int 2 + in 40%) (F) as well as from an intestinal adenocarcinoma of the stomach (int 2 + in 30%) (G) and the pancreas (int 2 + in 30%) (H)

Fig. 3

Ranking order of KLK7 immunostaining in cancers. Both the percentage of positive cases (blue dots) and the percentage of strongly positive cases (orange dots) are shown

Fig. 4

KLK7 in the TCGA data set and in the literature. KLK7 mRNA expression in different cancer types. Data plot generated from the cBioPortal [42, 43] database querying 10,976 samples from the “TCGA PanCancer Atlas Studies” sample set including 32 studies with KLK7 mRNA sequencing data

Fig. 5

Comparison with previous KLK7 literature. Comparison of the percentage of samples with KLK7 expression (at least weak staining) with the corresponding data from published studies. An “X” indicates the fraction of KLK7 positive cancers in the present study, dots indicate the reported frequencies from the literature for comparison: red dots mark studies with ≤ 10 analyzed tumors, yellow dots mark studies with 11–25 analyzed tumors, and green dots mark studies with > 25 analyzed tumors. All studies are listed in the reference list