Expression of circadian clock genes and proteins in urothelial cancer is related to cancer-associated genes

Abstract

BackgroundThe purpose of this study was to evaluate invasive and metastatic potential of urothelial cancer by investigating differential expression of various clock genes/proteins participating in the 24 h circadian rhythms and to compare these gene expressions with transcription of other cancer-associated genes.MethodsTwenty seven paired samples of tumour and benign tissue collected from patients who underwent cystectomy were analysed and compared to 15 samples of normal bladder tissue taken from patients who underwent cystoscopy for benign prostate hyperplasia (unrelated donors). Immunohistochemical analyses were made for clock and clock-related proteins. In addition, the gene-expression levels of 22 genes (clock genes, casein kinases, oncogenes, tumour suppressor genes and cytokeratins) were analysed by real-time quantitative PCR (qPCR).ResultsConsiderable up- or down-regulation and altered cellular distribution of different clock proteins, a reduction of casein kinase1A1 (CSNK1A1) and increase of casein kinase alpha 1 E (CSNK1E) were found. The pattern was significantly correlated with simultaneous up-regulation of stimulatory tumour markers, and a down-regulation of several suppressor genes. The pattern was mainly seen in aneuploid high-grade cancers. Considerable alterations were also found in the neighbouring bladder mucosa.ConclusionsThe close correlation between altered expression of various clock genes and common tumour markers in urothelial cancer indicates that disturbed function in the cellular clock work may be an important additional mechanism contributing to cancer progression and malignant behaviour.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2580-y) contains supplementary material, which is available to authorized users.

Environment and bladder cancer: molecular analysis by interaction networks

“…Then, to highlight in greater detail the involvement of these HUB nodes in BC development, we searched if they correlated with clock genes already reported to be altered in BC [ 9 ], and if they can be target of miRNAs reported to be implicated in BC [ 38 ].…”

“…In the last years, BC risk has been linked to the smoking, to the occupational exposures [ 4 ], to the use of drugs like cyclophosphamide or chlornaphazine [ 5 ], to the environmental pollutants and the arsenicals [ 6 , 7 ], and to the chronic inflammation with the related up-regulation of some pro-inflammatory proteins like interleukin (IL)-6, tumor necrosis factor (TNF) and C-reactive protein (CRP) [ 8 ]. Moreover, a strong correlation between altered expression of various clock genes (PER1 and PER2) and common tumor markers (TP53, PTEN and PAI-1) evidenced that a disturbed function in the cellular clock system can clearly represent an another mechanism of BC progression [ 9 ].…”

Persistent myopathy despite release of partial obstruction: in vivo reversal of dysfunction and transcriptional responses using rapamycin

“…The expression of key clock genes and their proteins found in rodent bladders 53,55,79,80 is also shown in human bladder tissues. 82 Furthermore, circadian dysregulation may also cause bladder pathologies in humans including bladder cancer, prostate cancer, LUTS, nocturia, and overactive bladder. [82][83][84][85] Specifically, the circadian rhythm of androgen in humans, which is key to the development of benign prostatic hyperplasia also exists and is under the control of clock genes in human studies.…”

“…82 Furthermore, circadian dysregulation may also cause bladder pathologies in humans including bladder cancer, prostate cancer, LUTS, nocturia, and overactive bladder. [82][83][84][85] Specifically, the circadian rhythm of androgen in humans, which is key to the development of benign prostatic hyperplasia also exists and is under the control of clock genes in human studies. 86 The mechanism whereby clock genes control BMP2, IGFBP7, and SOD3 in bladder obstruction, discovered here, may have important implications in the pathogenesis and treatment of prostatic hypertrophy and bladder outflow obstruction.…”

Circadian clock and cancer: From a viewpoint of cellular differentiation

“…For instance, expression levels of Per1 , Per2 and/or Per3 are altered in colorectal, pancreatic, gastric, oral, breast and non‐small cell lung cancers, as well as in glioma, hepatocellular carcinoma, head and neck squamous cell carcinoma, and myeloid leukemia 39–50 . For urological cancers including renal, bladder and prostate cancers, altered expression of clock genes has also been reported 51–53 . A recent comprehensive genomic analysis showed differential expression of most clock and clock‐associated genes in several cancer types 54 .…”