Browsing by Subject "Uvomorulin"

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Open Access
Differential expression patterns of metastasis suppressor proteins in basal cell carcinoma
(Wiley-Blackwell Publishing Ltd., 2015) Bozdogan, O.; Yulug, I. G.; Vargel, I.; Cavusoglu, T.; Karabulut, A. A.; Karahan, G.; Sayar, N.
Background: Basal cell carcinomas (BCCs) are common malignant skin tumors. Despite having a significant invasion capacity, they metastasize only rarely. Our aim in this study was to detect the expression patterns of the NM23-H1, NDRG1, E-cadherin, RHOGDI2, CD82/KAI1, MKK4, and AKAP12 metastasis suppressor proteins in BCCs. Methods: A total of 96 BCC and 10 normal skin samples were included for the immunohistochemical study. Eleven frozen BCC samples were also studied by quantitative real time polymerase chain reaction (qRT-PCR) to detect the gene expression profile. Results: NM23-H1 was strongly and diffusely expressed in all types of BCC. Significant cytoplasmic expression of NDRG1 and E-cadherin was also detected. However, AKAP12 and CD82/KAI1 expression was significantly decreased. The expressions of the other proteins were somewhere between the two extremes. Similarly, qRT-PCR analysis showed down-regulation of AKAP12 and up-regulation of NM23-H1 and NDRG1 in BCC. Morphologically aggressive BCCs showed significantly higher cytoplasmic NDRG1 expression scores and lower CD82/KAI1 scores than non-aggressive BCCs. Conclusion: The relatively preserved levels of NM23-H1, NDRG1, and E-cadherin proteins may have a positive effect on the non-metastasizing features of these tumors.
Open Access
Interplay between 15-lipoxygenase-1 and metastasisassociated antigen 1 in the metastatic potential of colorectal cancer
(Wiley-Blackwell Publishing Ltd., 2016) Tunçer, S.; Çağatay, T. S.; Keşküş, A. G.; Çolakoğlu, M.; Konu, Ö.; Banerjee S.
Objectives: Metastasis-associated antigen 1 (MTA1) is implicated in metastasis while 15-lipoxygenase-1 (15-LOX-1) reduces cell motility, when re-expressed in colorectal cancer (CRC). We aimed to understand any potential interplay between MTA1 and 15-LOX-1 in CRC metastasis. Materials and methods: ALOX15 and MTA1 expression in tumour and normal samples were analysed from TCGA RNA-seq data, microarray data sets and a human CRC cDNA array. Western blots, chromatin immunoprecipitation (ChIP), luciferase assays and electrophoretic mobility shift assays (EMSA) were carried out in HT-29 and LoVo cells re-expressing 15-LOX-1 to determine NF- κB activity at the MTA1 promoter. Functional assays in cells ectopically expressing either 15-LOX-1, MTA-1 or both, were carried out to determine adhesion and cell motility. Results: Significantly higher expression of MTA1 was observed in tumours compared to normal tissues; MTA1 overexpression resulted in reduced adhesion in CRC cell lines. Re-expression of 15-LOX-1 in the CRC cell lines reduced expression of endogenous MTA1, corroborated by negative correlation between the two genes in two independent human CRC microarray data sets, with greater significance in specific subsets of patients. DNA binding and transcriptional activity of NF-κB at the MTA1 promoter was significantly lower in cells re-expressing 15-LOX-1. Functionally, the same cells had reduced motility, which was rescued when they overexpressed MTA1, and further corroborated by expressions of E-cadherin and vimentin. Conclusions: Expression of MTA1 and 15-LOX-1 negatively correlated in specific subsets of CRC. Mechanistically, this is at least in part through reduced recruitment of NF-κB to the MTA1 promoter.
Open Access
Metastasis suppressor proteins in cutaneous squamous cell carcinoma
(Elsevier, 2016-07) Bozdogan, O.; Vargel, I.; Cavusoglu, T.; Karabulut, A. A.; Karahan, G.; Sayar, N.; Atasoy, P.; Yulug, I. G.
Cutaneous squamous cell carcinomas (cSCCs) are common human carcinomas. Despite having metastasizing capacities, they usually show less aggressive progression compared to squamous cell carcinoma (SCC) of other organs. Metastasis suppressor proteins (MSPs) are a group of proteins that control and slow-down the metastatic process. In this study, we established the importance of seven well-defined MSPs including NDRG1, NM23-H1, RhoGDI2, E-cadherin, CD82/KAI1, MKK4, and AKAP12 in cSCCs. Protein expression levels of the selected MSPs were detected in 32 cSCCs, 6 in situ SCCs, and two skin cell lines (HaCaT, A-431) by immunohistochemistry. The results were evaluated semi-quantitatively using the HSCORE system. In addition, mRNA expression levels were detected by qRT-PCR in the cell lines. The HSCOREs of NM23-H1 were similar in cSCCs and normal skin tissues, while RGHOGDI2, E-cadherin and AKAP12 were significantly downregulated in cSCCs compared to normal skin. The levels of MKK4, NDRG1 and CD82 were partially conserved in cSCCs. In stage I SCCs, nuclear staining of NM23-H1 (NM23-H1nuc) was significantly lower than in stage II/III SCCs. Only nuclear staining of MKK4 (MKK4nuc) showed significantly higher scores in in situ carcinomas compared to invasive SCCs. In conclusion, similar to other human tumors, we have demonstrated complex differential expression patterns for the MSPs in in-situ and invasive cSCCs. This complex MSP signature warrants further biological and experimental pathway research.
Open Access
miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance
(Springer Verlag, 2016-06) Mutlu, M.; Raza, U.; Saatci, Ö.; Eyüpoğlu, E.; Yurdusev, E.; Şahin, Ö.
MicroRNAs (miRNAs) are 20–22-nucleotide small endogenous non-coding RNAs which regulate gene expression at post-transcriptional level. In the last two decades, identification of almost 2600 miRNAs in human and their potential to be modulated opened a new avenue to target almost all hallmarks of cancer. miRNAs have been classified as tumor suppressors or oncogenes depending on the phenotype they induce, the targets they modulate, and the tissue where they function. miR-200c, an illustrious tumor suppressor, is one of the highly studied miRNAs in terms of development, stemness, proliferation, epithelial-mesenchymal transition (EMT), therapy resistance, and metastasis. In this review, we first focus on the regulation of miR-200c expression and its role in regulating EMT in a ZEB1/E-cadherin axis-dependent and ZEB1/E-cadherin axis-independent manner. We then describe the role of miR-200c in therapy resistance in terms of multidrug resistance, chemoresistance, targeted therapy resistance, and radiotherapy resistance in various cancer types. We highlight the importance of miR-200c at the intersection of EMT and chemoresistance. Furthermore, we show how miR-200c coordinates several important signaling cascades such as TGF-β signaling, PI3K/Akt signaling, Notch signaling, VEGF signaling, and NF-κB signaling. Finally, we discuss miR-200c as a potential prognostic/diagnostic biomarker in several diseases, but mainly focusing on cancer and its potential application in future therapeutics.
Open Access
SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer
(National Academy of Sciences, 2009) Sayan, A. E.; Griffiths, T. R.; Pal, R.; Browne G. J.; Ruddick, A.; Yagci, T.; Edwards, R.; Mayer, N. J.; Qazi, H.; Goyal, S.; Fernandez, S.; Straatman, K.; Jones G. D. D.; Bowman, K. J.; Colquhoun, A.; Mellon, J. K.; Kriajevska, M.; Tulchinsky, E.
The epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Two ZEB family members, ZEB1 and ZEB2(SIP1), inhibit transcription of the E-cadherin gene and induce EMT in vitro. However, their relevance to human cancer is insufficiently studied. Here, we performed a comparative study of SIP1 and ZEB1 proteins in cancer cell lines and in one form of human malignancy, carcinoma of the bladder. Whereas ZEB1 protein was expressed in all E-cadherin-negative carcinoma cell lines, being in part responsible for the high motility of bladder cancer cells, SIP1 was hardly ever detectable in carcinoma cells in culture. However, SIP1 represented an independent factor of poor prognosis (P = 0.005) in a series of bladder cancer specimens obtained from patients treated with radiotherapy. In contrast, ZEB1 was rarely expressed in tumor tissues; and E-cadherin status did not correlate with the patients' survival. SIP1 protected cells from UV- and cisplatin-induced apoptosis in vitro but had no effect on the level of DNA damage. The anti-apoptotic effect of SIP1 was independent of either cell cycle arrest or loss of cell-cell adhesion and was associated with reduced phosphorylation of ATM/ATR targets in UV-treated cells. The prognostic value of SIP1 and its role in DNA damage response establish a link between genetic instability and metastasis and suggest a potential importance for this protein as a therapeutic target. In addition, we conclude that the nature of an EMT pathway rather than the deregulation of E-cadherin per se is critical for the progression of the disease and patients' survival.