News Update on Bladder Cancer Research: April – 2019

LncRNA PVT1 regulates VEGFC through inhibiting miR‐128 in bladder cancer cells

Long noncoding ribonucleic acid PVT1 is taken into account to be Associate in Nursing transforming gene in multiple cancers. Our previous studies indicated that PVT1 levels were higher in bladder cancer tissue and related to with clinical progression and poor prognosis in bladder cancer patients. A bioinformatics analysis showed that PVT1 could regulate VEGFC expression through miR‐128 as a competitive  endogenous ribonucleic acid (ceRNA). during this study, we tend to incontestable  that PVT1 expression levels have an effect on the proliferation and migration ability of bladder cancer cells. Moreover, PVT1 knockdown considerably attenuate the proliferation capability of bladder cancer cells in nude mice. Luciferase assays and RNA‐binding macromolecule immunoprecipitation were performed to analyze the potential mechanism of ceRNAs within the regulation of PVT1 and VEGFC. The results showed that the enhanced range of PVT1 transcripts interacted directly with miR‐128 to decrease miR‐128 binding to the VEGFC 3′‐untranslated region. This result suppressed VEGFC mRNA degradation by miR‐128. last, these results indicated that PVT1 may play a important role in bladder cancer tumorigenesis via miR‐218 and VEGFC. Therefore, PVT1 can be a replacement biomarker for bladder cancer diagnosing and medical aid. [1]

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

Purpose: Chemoresistance and growth relapse are the leading reason behind deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) are reported  to contribute to those pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance stay mostly unknown. within the current study, a unique lncRNA termed Low expressed in Bladder Cancer Stem cells (lnc-LBCS) has been known and explored in BCSCs.

Experimental Design: foremost, we tend to establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical options of lnc-LBCS are analyzed in 3 freelance large-scale cohorts. The purposeful role and mechanism of lnc-LBCS are additional investigated by gain- and loss-of-function assays in vitro and in vivo.

Results: Lnc-LBCS is considerably downregulated in BCSCs and cancer tissues, and correlates with growth grade, therapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and growth initiation of BCSCs each in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and attention of zeste homolog two (EZH2), and is a scaffold to induce the formation of this complicated to repress SRY-box two (SOX2) transcription via mediating simple protein H3 essential amino acid twenty seven tri-methylation. SOX2 is important for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients.

Conclusions: As a unique regulator, lnc-LBCS plays a vital tumor-suppressor role in BCSCs’ self-renewal and chemoresistance, tributary to weak tumorigenesis and increased chemosensitivity. The lnc-LBCS–hnRNPK–EZH2–SOX2 restrictive axis could represent a therapeutic target for clinical intervention in chemoresistant bladder cancer. [2]

ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer

Purpose: DNA-damaging agents comprise the backbone of general treatment for several tumour types; but, few reliable prophetic  biomarkers are obtainable to guide use of those agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based therapy improves survival, nevertheless response varies wide among patients. Here, we tend to wanted to outline the role of the ester excision repair (NER) cistron ERCC2 as a biomarker prophetic  of response to cisplatin in MIBC.

Experimental Design: corporeal missense mutations in ERCC2 are related to improved response to cisplatin-based chemotherapy; but, clinically known ERCC2 mutations are distributed throughout the cistron, and therefore the impact of individual ERCC2 variants on NER capability and cisplatin sensitivity is unknown. we tend to developed a microscopy-based NER assay to profile ERCC2 mutations determined retrospectively in previous studies ANd prospectively among the context of an institution-wide tumour identification initiative. additionally, we tend to created the primary ERCC2-deficient bladder cancer diagnosis model for finding out the impact of ERCC2 loss of perform.

Results: we tend to used our useful assay to check the NER capability of clinically determined ERCC2 mutations and located that the majority ERCC2 helicase domain mutations cannot support NER. what is more, we tend to show that introducing AN ERCC2 mutation into a bladder neoplastic cell line abrogates NER activity and is decent to drive cisplatin sensitivity in an orthotopic heterograft model.

Conclusions: Our information support an immediate role for ERCC2 mutations in driving cisplatin response, outline the useful landscape of ERCC2 mutations in bladder cancer, and supply a chance to use combined genomic and useful approaches to prospectively guide medical aid choices in bladder cancer. [3]

Upregulation of NDRG1 predicts poor outcome and facilitates disease progression by influencing the EMT process in bladder cancer

N-myc downstream regulated factor one (NDRG1) is Associate in Nursing animate thing macromolecule concerned in cell differentiation and was recently rumored to exert numerous effects in many cancers. However, its expression and role in bladder cancer stay unclear. Our study listed a hundred bladder cancer patients to notice NDRG1 expression in tumor tissues by assay. Correlations between NDRG1 expression and clinical factors were analysed. Associate in Nursing NDRG1 overexpression cellular inclusion and NDRG1 siRNAs were transfected into bladder neoplastic cell lines. Cell biological behaviours were assessed by CCK-8, flow cytometry, wound healing and Transwell assays. in addition, the influence of NDRG1 on epithelial-mesenchymal transition (EMT) was investigated by western blotting and period PCR. NDRG1 expression in excreta from bladder cancer patients was examined by assay. NDRG1 macromolecule levels were considerably increased  in bladder cancer patients and related  with tumor stage (p = 0.025), lymphoid tissue metastasis (p = 0.034) and overall survival (p = 0.016). Patients with high NDRG1 expression had poorer outcomes than those with low NDRG1 expression. NDRG1 overexpression was related to increased  cell proliferation, migration, and invasion and weakened apoptotic cell numbers; NDRG1 knockdown resulted within the inverse effects. Moreover, upregulated NDRG1 expression was related to downregulated

Cytokeratin seven and Claudin-1 expression and upregulated N-cad, β-catenin and slug expression. Downregulated NDRG1 expression was related to the inverse effects. excreta macromolecule levels might distinguish bladder cancer patients from healthy controls, with a locality beneath the curve of zero.909. NDRG1 promoted EMT in bladder cancer and will be an efficient diagnostic and prognostic biomarker in bladder cancer patients. [4]

Differential Expression of Claudin-1, Claudin-3, and Claudin-4 in Bladder Lesions

Aims: Claudins are major transmembrane proteins of tight junctions. because the disruption of their perform have necessary impact on tumorogenesis, invasion and metastasis. Claudins became attention of interest for targeting therapies. though their expression profiles are studied in several organs, researches on Claudin expression in bladder are in restricted variety. The aim of this study is to gift the differential expression of Claudin-1, Claudin-3 and Claudin-4 in invasive and noninvasive urothelial lesions.

Study of Design: many teams of noninvasive and invasive urothelial lesions were stained immunohistochemically by Claudin-1, Claudin-3 and Claudin-4 and their expressions were evaluated.

Place and period of Study: Department of Pathology of Diskapi analysis and coaching Hospital, Ankara, between 2011-2013.

Methodology: eighty three cases (31 invasive urothelial carcinomas (IUCC) –further divided into: fifteen muscle invasive UCCs, sixteen UCCs with plate propria invasion-, seventeen noninvasive appendage urothelial carcinomas (NPUC), thirteen appendage urothelial neoplasms of low malignant potential (PUNLMP), seven cancer in place (CIS) and fifteen traditional freelance samples (CG). Sections from formalin-fixed paraffin embedded tissues were immunohistochemically stained with Claudin one, Claudin three and Claudin four.

Results: Claudin-1 expression is considerably lower in low grade noninvasive urotelial carcinomas compared to invasive carcinomas. Claudin-3 is extremely expressed in traditional urothelium and invasive lesions; however its expression is cut considerably all told non-invasive lesions. Claudin-4 expression seemed to decrease in muscle invasive UCC and CIS vs. others.

Conclusion: though higher expression of Claudin-4 in inferior and non-invasive lesions could also be used as a diagnostic tool, cut expression of Claudin-4 will indicate additional invasive capability of the neoplasm. In terms of Claudin-1 and -3, their cut expression in non-invasive lesions in comparison to manage cluster and their trend to point out additional exaggerated expression in IUCC must be studied additional in larger studies. [5]

Reference

[1] Yu, C., Longfei, L., Long, W., Feng, Z., Chen, J., Chao, L., Peihua, L., Xiongbing, Z. and Hequn, C., 2019. LncRNA PVT1 regulates VEGFC through inhibiting miR‐128 in bladder cancer cells. Journal of cellular physiology, 234(2), pp.1346-1353. (Web Link)

[2] Chen, X., Xie, R., Gu, P., Huang, M., Han, J., Dong, W., Xie, W., Wang, B., He, W., Zhong, G. and Chen, Z., 2019. Long noncoding RNA LBCS inhibits self-renewal and chemoresistance of bladder cancer stem cells through epigenetic silencing of SOX2. Clinical Cancer Research, 25(4), pp.1389-1403. (Web Link)

[3] Li, Q., Damish, A.W., Frazier, Z., Liu, D., Reznichenko, E., Kamburov, A., Bell, A., Zhao, H., Jordan, E.J., Gao, S.P. and Ma, J., 2019. ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer. Clinical Cancer Research, 25(3), pp.977-988. (Web Link)

[4] Upregulation of NDRG1 predicts poor outcome and facilitates disease progression by influencing the EMT process in bladder cancer

Aiwei Li, Xi Zhu, Chanjuan Wang, Shuo Yang, Yan Qiao, Rui Qiao & Jie Zhang

Scientific Reportsvolume 9, Article number: 5166 (2019) (Web Link)

[5] Dilay Kokenek-Unal, T., Coban, I., Selcen Oguz-Erdogan, A., Seneldir, H., Gurcay, N. and Alper, M. (2015) “Differential Expression of Claudin-1, Claudin-3, and Claudin-4 in Bladder Lesions”, Journal of Cancer and Tumor International, 2(3), pp. 117-127. doi: 10.9734/JCTI/2015/19336. (Web Link)