<scp>FOXM</scp>1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage <scp>pT</scp>1 non‐muscle‐invasive bladder cancer

Breyer, Johannes; Wirtz, Ralph M.; Erben, Philipp; Rinaldetti, Sébastien; Worst, Thomas; Stoehr, Robert; Eckstein, Markus; Sikic, Danijel; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt; Otto, Wolfgang

doi:10.1111/bju.14525

Cited by 18 publications

(17 citation statements)

References 33 publications

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“…FOXM1 facilitated to cell viability, migration and invasion of bladder cancer cells through reducing p27 level and increasing VEGF expression (23). High expression of FOXM1 was associated with adverse clinical features, including pathological grade, TNM stage, concomitant carcinoma in situ and multifocal tumors, and predicted a risk of luminal subtype with worse outcomes in patients with stage pT1 NMIBC (24). Emerging evidence supports the hypothesis that inflammation is one of the hallmark characteristics of cancer development and progression.…”

Section: Discussionmentioning

confidence: 81%

Identification of a 13‑mRNA signature for predicting disease progression and prognosis in patients with bladder cancer

et al. 2019

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There are no reliable criteria to assess risk of progression of non-muscle invasive bladder cancer to muscle invasive bladder cancer. The aim of the present study was to identify potential markers based on gene expression profiling to improve predictive power of disease progression and prognosis in patients with bladder cancer. In the present study, we screened seventy-three differentially expressed genes by analyzing bladder cancer samples with or without progression. Forty-seven prognosis-related genes were screened, 13 of which were identified to build a progression-associated gene signature using the LASSO regression method. Based on this 13-mRNA signature, patients were divided into high-and low-risk groups, with different prognostic outcomes. The gene signature was an independent prognostic factor for overall survival. Receiver operating characteristic analysis suggested that the signature performed well in the validation cohort and its predictive power outperformed other several published signatures. CTHRC1, MMP11, AEBP1, SNCAIP, COL1A1 and S100A8 were identified as hub genes and their expression levels were detected using reverse transcriptase-quantitative polymerase chain reaction. The expression of CTHRC1 was elevated in aggressive bladder cancer compared with non-invasive type, which suggests CTHRC1 may be a valuable biomarker for prediction of prognosis and progression of bladder cancer. Collectively, this 13-mRNA signature may be useful in predicting disease progression and prognosis, thereby contributing to individualized management of patients with bladder cancer.

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Section: Discussionmentioning

confidence: 81%

Identification of a 13‑mRNA signature for predicting disease progression and prognosis in patients with bladder cancer

et al. 2019

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“…As a transcription factor, FOXM1 crosstalk with multiple proteins including PLK1, Cyclin B1 and Aurora B, and thus plays a central role in tumor aggressiveness. Overexpression of FOXM1 has been found in a variety of human malignancies including ESCC (42)(43)(44)(45). High expression levels of FOXM1 was positively correlated with large tumor size, poor differentiation degree, deep invasion, and low survival rate and might serve as an independent prognostic indicator for determining prognosis of ESCC patients (42,43).…”

Section: Discussionmentioning

confidence: 99%

Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma

Chen

Wei

et al. 2020

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy and is one of the most important cause of cancer related mortalities in the world. However, there is no clinically effective targeted therapeutic drugs for ESCC due to lack of valuable molecular therapeutic targets. In the present study, we investigated the biological function and molecular mechanisms of maternal embryonic leucine zipper kinase (MELK) in ESCC. The expression of MELK mRNA and protein was determined in cell lines and clinical samples of ESCC. MTT, focus formation and soft agar assays were carried out to measure cell proliferation and colony formation. Wound healing and transwell assays were used to assess the capacity of tumor cell migration and invasion. Nude mice models of subcutaneous tumor growth and lung metastasis were performed to examine the function of MELK in tumorigenecity and metastasis of ESCC cells. High expression of MELK was observed in ESCC cell line and human samples, especially in the metastatic tumor tissues. Moreover, overexpression of MELK promoted cell proliferation, colony formation, migration and invasion, and increased the expression and enzyme activity of MMP-2 and MMP-9 in ESCC cells. More importantly, enhanced expression of MELK greatly accelerated tumor growth and lung metastasis of ESCC cells in vivo. In contrast, knockdown of MELK by lentiviral shRNA resulted in an opposite effect both in vitro and in animal models. Mechanistically, MELK facilitated the phosphorylation of FOXM1, leading to activation of its downstream targets (PLK1, Cyclin B1, and Aurora B), and thereby promoted tumorigenesis and metastasis of ESCC cells. In conclusion, MELK enhances tumorigenesis, migration, invasion and metastasis of ESCC cells via activation of FOXM1 signaling pathway, suggesting MELK is a potential therapeutic target for ESCC patients, even those in an advanced stage.

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“…Unfortunately, we did not perform any sub‐analysis of those populations. Furthermore, we did not use any stratification of risk by using biomarkers or molecular characterization 28 . Yang et al investigated the predictive role of Ribonucleotide reductase subunit M1 (RRM1) mRNA in patients who received gemcitabine 29 .…”

Section: Discussionmentioning

confidence: 99%

Intravesical gemcitabine as bladder‐preserving treatment for BCG unresponsive non‐muscle‐invasive bladder cancer. Results from a single‐arm, open‐label study

et al. 2020

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Background There is an unmet alternative medical therapy for BCG unresponsive patients. Objective To report efficacy of intravesical gemcitabine in NMIBC patients, who failed a previous course of BCG, or intolerant, and unwilling to undergo radical cystectomy (RC). Material and methods This is an open‐label, single‐arm study, which enrolled patients showing a failure or were intolerant to BCG and unwilling to undergo the RC. Intravesical gemcitabine was administered once a week for six consecutive weeks and once a month for 12 months. The primary outcome was DFS defined as the lack of a tumor on cystoscopy and negative urine cytology. Secondary endpoint was safety defined according a grading of side effects. OS, PFS, and DFS were described with Kaplan–Meier method at 12 and 24 months. Results and limitations Overall 36 patients were enrolled. The median follow‐up was 27 months. The DFS was 68.75% at the end of induction phase and 44.44% and 31.66% at 12 and 24 months of, respectively. The PFS was 43.75%. The OS and CSS were 77.9% (95% CI 58.78%‐88.92%) and 80.68% (95% CI 61.49%‐90.96%), respectively. There was no life threatening event or treatment‐related death (grade 4 or 5). The most common mild and moderate adverse events reported were urinary symptoms (LUTS) and fatigue (G1‐G2). Conclusion Patients who presented an unresponsive‐BCG recurrent NMIBC and unwilling to receive a RC, could benefit from intravesical gemcitabine as salvage organ‐sparing treatment.

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FOXM1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage pT1 non‐muscle‐invasive bladder cancer

Abstract: High FOXM1 expression was associated with adverse clinical and pathological features and worse outcomes, and predicted response to intravesical instillation therapy in patients with stage pT1 NMIBC.

Cited by 18 publications

References 33 publications

Identification of a 13‑mRNA signature for predicting disease progression and prognosis in patients with bladder cancer

Identification of a 13‑mRNA signature for predicting disease progression and prognosis in patients with bladder cancer

Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma

Intravesical gemcitabine as bladder‐preserving treatment for BCG unresponsive non‐muscle‐invasive bladder cancer. Results from a single‐arm, open‐label study

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