HtrA1 in human urothelial bladder cancer: A secreted protein and a potential novel biomarker

• Published in: International journal of cancer Vol. 133; no. 11; pp. 2650 - 2661
• Main Authors: Lorenzi, Teresa, Lorenzi, Maria, Altobelli, Emma, Marzioni, Daniela, Mensà, Emanuela, Quaranta, Alexia, Paolinelli, Francesca, Morroni, Manrico, Mazzucchelli, Roberta, De Luca, Antonio, Procopio, Antonio Domenico, Baldi, Alfonso, Muzzonigro, Giovanni, Montironi, Rodolfo, Castellucci, Mario
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 01.12.2013; Wiley Subscription Services, Inc
• Subjects: Aged; Biological and medical sciences; Biomarkers; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - urine; Bladder cancer; Cancer; Cystitis - diagnosis; Cystitis - urine; Female; High-Temperature Requirement A Serine Peptidase 1; human urothelial bladder cancer; Humans; Immunohistochemistry; Male; Medical research; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Nephrology. Urinary tract diseases; Proteins; Serine Endopeptidases - biosynthesis; Serine Endopeptidases - urine; serine protease HtrA1; T24 cell lines; TCC‐SUP; Tumors; Tumors of the urinary system; urinary biomarkers; Urinary Bladder Neoplasms - diagnosis; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urinary Bladder Neoplasms - urine; Urinary tract. Prostate gland; UROtsa; Human; Urothelial cancer; Urinary system disease; Serine endopeptidases; Enzyme; T24 cell lines; UROtsa; human urothelial bladder cancer; Biological marker; Urinary tract disease; Malignant tumor; Protein A; Bladder cancer; Peptidases; Cancerology; TCC-SUP; Secretory protein; serine protease HtrAl; urinary biomarkers; Hydrolases; Bladder disease; Cancer; serine protease HtrA1
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.28280

Our aim was to analyze the expression of the serine protease HtrA1 in human bladder tissue and urine in order to point out its possible association with the presence of urothelial bladder cancer. Bladder tissue and urine specimens from cancer patients with different tumor grades and stages (n = 68) and from individuals with cystitis (n = 16) were collected along with biopsy specimens and urine from healthy individuals (n = 68). For the first time, we demonstrated by immunohistochemistry that HtrA1 protein is produced by bladder urothelium in both physiological and inflammatory conditions, whereas it is not detectable in urothelial cancer cells regardless of tumor grade and stage. A different HtrA1 expression between normal‐looking and neoplastic bladder tissue, despite similar HtrA1 mRNA levels, was also found by western blotting, which disclosed the presence of two forms of HtrA1, a native form of ∼50 kDa and an autocatalytic form of ∼38 kDa. Our investigations documented the presence of the two forms of HtrA1 also in urine. The ∼38 kDa form was significantly down‐regulated in neoplastic tissue, whereas significantly higher amounts of both HtrA1 forms were found in urine from cancer patients compared with both healthy subjects and patients with cystitis. Our findings suggest that HtrA1 is a downexpressed molecule since an early stage of bladder urothelial carcinoma development and that urinary HtrA1 protein may be considered, if successfully validated, as an early and highly sensitive and specific biomarker for this neoplasia (the sensitivity and specificity of HtrA1 are 92.65% and 95.59%, respectively). What's new? Four‐fifths of urothelial bladder cancer patients suffer a relapse of disease within one to two years of initial treatment, a problem that could be alleviated by advances in biomarker‐based early stage screening. This investigation introduces one possible biomarker, the secreted serine protease HtrA1. While previous studies have suggested that HtrA1 may function as a tumor suppressor in certain solid tumors, this report indicates that a reduction in its expression may be an early, highly sensitive and specific biomarker particularly for urothelial bladder cancer. The recoverability of HtrA1 in urine would allow for a noninvasive means of routine screening.