Abstract
BackgroundUncontrolled proliferation is thought to be the most fundamental characteristic of cancer. Detailed knowledge of cancer cell proliferation mechanisms would not only benefit understanding of cancer progression, but may also provide new clues for developing novel therapeutic strategies.MethodsIn vitro function of MNX1 (Motor neuron and pancreas homeobox 1) in bladder cancer cell was evaluated using MTT assay, colony formation assay, and bromodeoxyuridine incorporation assay. Real-time PCR and western blotting were performed to detect MNX1 and CCNE1/2 expressions. In vivo tumor growth was conducted in BALB/c-nu mice.ResultsWe reported that MNX1 is responsible for sustaining bladder cancer cell proliferation. Abnormal MNX1 upregulation in bladder cancer cell lines and 167 human tissue specimens; high MNX1 expression levels correlated significantly with shorter 5-year overall and relapse-free survival in the bladder cancer patients. Furthermore, MNX1 overexpression accelerated bladder cancer cell proliferation and tumorigenicity both in vitro and in vivo, whereas MNX1 downregulation arrested it. In addition, MNX1 transcriptionally upregulated CCNE1 and CCNE2 by directly bounding to their promoters, which promoted G1–S transition in the bladder cancer cells.ConclusionThese findings reveal an oncogenic role and novel regulatory mechanism of MNX1 in bladder cancer progression and suggest that MNX1 is a potential prognostic biomarker and therapeutic target.
Highlights
Uncontrolled proliferation is thought to be the most fundamental characteristic of cancer
Motor neuron and pancreas homeobox 1 (MNX1) was markedly upregulated in bladder cancer To investigate the spectrum of MNX1 expression in bladder cancer, we first analyzed MNX1 expression in publicly available human bladder cancer datasets from The Cancer Genome Atlas (TCGA) [24] and Gene Expression Omnibus (GEO) [25]
Western blotting and real-time PCR showed that MNX1 mRNA and protein expression, respectively, were markedly upregulated in all bladder cancer cell lines compared to primary normal urethral epithelial cells (Fig. 1c, d)
Summary
Uncontrolled proliferation is thought to be the most fundamental characteristic of cancer. Detailed knowledge of cancer cell proliferation mechanisms would benefit understanding of cancer progression, but may provide new clues for developing novel therapeutic strategies. Bladder cancer is a primary cause of morbidity and mortality, with 429,700 estimated new cases each year and 165,000 deaths worldwide [1]. Treatment for bladder cancer has improved greatly in recent decades, many patients especially those at the advanced stages of the disease, succumb to it. Patients with advanced bladder cancer mostly receive radiotherapy or chemotherapy, but the therapeutic. The vital feature of cancer is thought to be sustained proliferation [3]. Dysregulation in cell cycle progression results in the release of proliferative signals in cancer cells, disrupting cell number homeostasis and causing uncontrolled cell proliferation. Phosphorylation of the retinoblastoma (Rb) family members leads to the release of E2F-containing repressor complexes from E2F-regulated
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