Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract

Inoue, Satoshi; Ide, Hiroki; Fujita, Kazutoshi; Mizushima, Taichi; Jiang, Guiyang; Kawahara, Takashi; Yamaguchi, Seiji; Fushimi, Hiroaki; Nonomura, Norio; Miyamoto, Hiroshi

doi:10.3390/ijms19030777

Cited by 8 publications

(9 citation statements)

References 24 publications

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“…ELK1 functions through phosphorylation and can be regulated by the mitogen‐activated protein kinase (MAPK) pathway 10,11 . Interestingly, ELK1 is highly expressed and hyperactivated in some cancers, including gastric cancer, 12 urothelial carcinoma, 13 hepatocarcinoma, 14 and cervical and endometrial carcinomas 15 . A global analysis of TFs suggested that ELK1 is an important TF, involved in CRC progression, and might be a potential biomarker for CRC treatment 16 .…”

Section: Introductionmentioning

confidence: 99%

c‐KIT‐ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression

Liu

Chen

et al. 2020

Cancer Science

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Carcinoembryonic antigen (CEA) is highly expressed in embryo and colorectal cancer (CRC) and has been widely used as a marker for CRC. Emerging evidence has demonstrated that elevated CEA levels promote CRC progression. However, the mechanism of the increased CEA expression in patients with primary and recurrent CRC is still an open question. In this study, we showed that c‐KIT, ELK1, and CEA were hyperexpressed in patients with CRC, especially patients with recurrent disease. From bioinformatics analysis, we picked ELK1 as a candidate transcription factor (TF) for CEA; the binding site of ELK1 within the CEA promoter was confirmed by chromatin immunoprecipitation and dual luciferase reporter assays. Overexpression of ELK1 increased CEA expression in vitro, while knockdown of ELK1 decreased CEA. Upregulated ELK1 promoted the adhesion, migration, and invasion of CRC cells, however knockdown of CEA blocked the activities of ELK1‐overexpressed CRC cells. Furthermore, we explored the role of c‐KIT‐ERK1/2 signaling in activation of ELK1. Blocking c‐KIT signaling using Imatinib or ISCK03 reduced p‐ELK1 expression and consequently decreased CEA levels in CRC cells, as did blocking the ERK1/2 pathway by U0126. Compared with wild type littermates, the c‐kit loss‐of‐functional Wadsm/m mice showed lowered c‐KIT, ELK1, and CEA expression. In conclusion, our study revealed that ELK1, which was activated by c‐KIT‐ERK1/2 signaling, was a key TF for CEA expression. Blocking ELK1 or its upstream signaling could be an alternative way to decelerate CRC progression. Besides being a biomarker for CRC, CEA could be used for guiding targeted therapy.

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Section: Introductionmentioning

confidence: 99%

c‐KIT‐ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression

Liu

Chen

et al. 2020

Cancer Science

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“…We demonstrated, using SVHUC cells with carcinogen challenge, that knockdown of ELK1 or treatment with a selective α 1 -blocker silodosin, which could inactivate ELK1, prevented the MCA-induced neoplastic formation of SVHUC-AR cells [35], indicating the oncogenic role of ELK1 in urothelial cancer. Our immunohistochemical studies in bladder [76] and UUT [77] specimens showed significant up-regulation of the expression of ELK1 and/or its activated form phospho-ELK1 in tumors, compared with non-neoplastic urothelial tissues. In addition, phospho-ELK1 positivity in non-muscle-invasive bladder tumors was associated with a significantly higher risk of disease recurrence [76].…”

Section: Elk1mentioning

confidence: 59%

The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis

Ide

Miyamoto

2020

Cancers

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Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis.

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“…Using the identical UUTUC TMA, we previously determined the expression status of various transcription factors (20,(23)(24)(25)(26). Notably, the positive rates of 6 transcription factors, including AR (20), ERβ (20), GATA-binding protein 3 (GATA3) (23), zinc finger with KRAB and SCAN domains 3 (ZKSCAN3) (24), nuclear factor of activated T-cells 1 (NFATc1) (25) and a phosphorylated form of ELK1 (p-ELK1) (26), were significantly (P<0.05; GATA3, ZKSCAN3) or insignificantly (0.05≤P<0.1; AR, ERβ, NFATc1, p-ELK1) different between renal pelvic and ureteral tumor samples, although the underlying reasons remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Forkhead box O1 as an indicator of prognosis is inactivated in urothelial carcinoma of the upper urinary tract

et al. 2018

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The transcription factor forkhead box O1 (FOXO1) can be inactivated via its phosphorylation, resulting in suppression of apoptosis. Using immunohistochemistry, the expression of a phosphorylated form of FOXO1 was assessed in upper urinary tract urothelial carcinoma (UUTUC) specimens. Overall, phospho-FOXO1 (p-FOXO1) was immunoreactive in all 99 UUTUC specimens [12 (12.1%) weak (1+), 46 (46.5%) moderate (2+) and 41 (41.4%) strong (3+)], which was significantly (P= 0.018) increased, compared with benign urothelium specimens [77/82 (93.9%): 18 (22.0%) 1+, 41 (50.0%) 2+ and 18 (22.0%) 3+]. Muscle invasion (P= 0.031) and lymphovascular invasion (P= 0.025) were observed more frequently in p-FOXO1(2+/3+) tumor samples compared with p-FOXO1(1+) tumor samples. No statistically significant associations between p-FOXO1 expression and tumor grade or presence of concurrent carcinoma in situ, hydronephrosis or lymph node metastasis were observed. Furthermore, the levels of p-FOXO1 and estrogen receptor-β expression were significantly (P<0.05) correlated in UUTUC samples [correlation coefficient (CC)= 0.244], particularly in tumor samples from male patients (CC= 0.330). Additionally, patients with p-FOXO1(3+) tumors had a significantly increased risk of cancer-specific mortality (P= 0.043), compared with those with p-FOXO1(1+/2+) tumors. Multivariate analysis further demonstrated a notable, albeit not significant, association between p-FOXO1 expression and cancer-specific survival (hazard ratio=2.204; P=0.053). These findings indicate that FOXO1 is inactivated in UUTUC specimens and p-FOXO1 overexpression may serve as a predictor of poor patient outcomes.

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Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract

Cited by 8 publications

References 24 publications

c‐KIT‐ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression

c‐KIT‐ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression

The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis

Forkhead box O1 as an indicator of prognosis is inactivated in urothelial carcinoma of the upper urinary tract

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