The c-MYC transcription factor conduces to resistance to cisplatin by regulating MMS19 in bladder cancer cells.

Chemoresistance is one of the dominant causes for tumor progression and recurrence of bladder cancer (BC). This paper investigated the effects of transcription factor c-MYC through promoting MMS19 expression on proliferation, metastasis and cisplatin (DDP) resistance in BC cells. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were applied to acquire the needed BC gene data. The mRNA and protein levels of c-MYC and MMS19 were verified with q-PCR or Western blot assay. MTT and Transwell assays were utilized to detect cell viability and metastasis. Chromatin Immunoprecipitation (ChIP) assay and Luciferase reporter assay were exerted to confirm the relationship between c-MYC and MMS19. TCGA and GEO BC datasets results implied MMS19 could be an independent indicator for BC patients' prognosis. MMS19 expression was dramatically augmented in BC cell lines. Overexpression of MMS19 conduced to accelerate BC cells proliferation, metastasis and increase DDP resistance. c-MYC was positively correlated with MMS19 and acted as a transcription activator for MMS19 in BC cell lines and activated MMS19 expression. Overexpression of c-MYC facilitated BC cells proliferation, metastasis and DDP resistance. In conclusions, c-MYC gene was a transcriptional regulator of MMS19. Up-regulation of c-MYC facilitated BC cells proliferation, metastasis and DDP resistance by motivating MMS19 expression. This molecular mechanism between c-MYC and MMS19 exerts a crucial mission in BC tumorigenesis and DDP resistance, and may contribute to the diagnosis and therapy of BC for the time to come.

The YTHDC1/GLUT3/RNF183 axis forms a positive feedback loop that modulates glucose metabolism and bladder cancer progression.

Aberrant glucose metabolism is a characteristic of bladder cancer. Hyperglycemia contributes to the development and progression of bladder cancer. However, the underlying mechanism by which hyperglycemia promotes the aggressiveness of cancers, especially bladder cancer, is still incompletely understood. N6-methyladenosine (m6A) modification is a kind of methylation modification occurring at the N6 position of adenosine that is important for the pathogenesis of urological tumors. Recently, it was found that the m6A reader YTHDC1 is regulated by high-glucose conditions. In our study, we revealed that YTHDC1 is not only regulated by high-glucose conditions but is also downregulated in bladder cancer tissue and associated with the prognosis of cancer. We also showed that YTHDC1 suppresses the malignant progression of and the glycolytic process in bladder cancer cells in an m6A-dependent manner and determined that this effect is partially mediated by GLUT3. Moreover, GLUT3 was found to destabilize YTHDC1 by upregulating RNF183 expression. In summary, we identified a novel YTHDC1/GLUT3/RNF183 feedback loop that regulates disease progression and glucose metabolism in bladder cancer. Collectively, this study provides new insight regarding the pathogenesis of bladder cancer under hyperglycemic conditions and might reveal ideal candidates for the development of drugs for bladder cancer.

AGAP2-AS1/miR-628-5p/FOXP2 feedback loop facilitates the growth of prostate cancer via activating WNT pathway.

Increasing studies have indicated the critical roles of long non-coding RNAs (lncRNAs) in the tumorigenesis of cancers. LncRNA AGAP2 antisense RNA 1 (AGAP2-AS1) can serve as an oncogenic role in some cancers, including prostate cancer (PCa). However, the underling mechanism of such lncRNA in PCa has not been fully studied. Therefore, it is meaningful to investigate the role and underlying mechanism of AGAP2-AS1 in PCa. AGAP2-AS1 was confirmed to be highly expressed in PCa cells. Functionally, AGAP2-AS1 silencing inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition process and induced apoptosis. According to mechanism assays, AGAP2-AS1 sponged miR-628-5p, which was found to restrain PCa cell growth. Besides, FOXP2 was identified as a target gene of miR-628-5p, and its expression was negatively regulated by miR-628-5p and positively modulated by AGAP2-AS1. Importantly, we found that FOXP2 could function as the upstream gene of AGAP2-AS1. Through rescue experiments, we discovered that FOXP2 up-regulation countered AGAP2-AS1 knockdown-mediated inhibition on PCa cell growth. Finally, it was found that AGAP2-AS1 could activate WNT pathway, and LiCl could reverse the influence of AGAP2-AS1 on PCa biological behaviors. To conclude, AGAP2-AS1/miR-628-5p/FOXP2 feedback loop facilitated PCa cell growth via activating WNT pathway.

The oncogenic role of the cerebral endothelial cell adhesion molecule (CERCAM) in bladder cancer cells in vitro and in vivo.

Bladder cancer is a menace to global health worldwide due to its high recurrence rate and its progression to invasive muscular complications. Cell adhesion molecules play an intricate role in cancer migration, growth, and invasion. Therefore, through bioinformatics analysis, it was found that the higher cerebral endothelial cell adhesion molecule (CERCAM) predicted lower chance in bladder cancer patient survival; subsequently, in vitro and in vivo investigations were performed to evaluate the specific effects of CERCAM on bladder cancer cell phenotypes and tumor growth in mice model. The PCR-based analysis revealed an aberrant upregulation of CERCAM in bladder carcinoma tissues and cells when compared with normal controls. In vitro, functional experiments such as MTT, EdU, and Transwell assays showed that CERCAM overexpression markedly enhanced bladder cancer cell viability, DNA synthesis, and cell invasion. In contrast, CERCAM silencing suppressed bladder cancer cell viability, DNA synthesis, and cell invasion. CERCAM overexpression significantly increased PCNA, Vimentin, Twist, and N-cadherin proteins but decreased E-cadherin and cleaved-caspase3, whereas CERCAM silencing exerted opposite effects on these markers. In vivo, subcutaneous implant model experiments in nude mice showed that CERCAM silencing suppressed the growth of subcutaneously implanted tumors. CERCAM altered the phosphorylation process of AKT. The PI3K inhibitor LY294002 treatment manifested similar effects as CERCAM silencing on bladder cancer cell behaviors and partially impaired the promotive functions of CERCAM overexpression upon the capacity of bladder cancer cells to proliferate and invade. When taken together, the cell adhesion molecule CERCAM is overexpressed in bladder cancer tissues. In vitro, CERCAM overexpression significantly promoted bladder cancer cell viability, DNA synthesis, and cell invasion and alters the cleaved-caspase3, E-cadherin, and N-cadherin expression pattern; in vivo, CERCAM silencing suppressed tumor growth in nude mice. The PI3K/AKT signaling is suspected of interfering participate in the functions of CERCAM in bladder carcinoma.