Side Population in Human Non-Muscle Invasive Bladder Cancer Enriches for Cancer Stem Cells That Are Maintained by MAPK Signalling

Hepburn, Anastasia C.; Veeratterapillay, Rajan; Williamson, Stuart C.; El-Sherif, A; Neha, Sahay; Thomas, Huw D.; Mantilla, Alejandra; Pickard, Robert; Robson, Craig; Heer, Rakesh

doi:10.1371/journal.pone.0050690

Cited by 42 publications

(40 citation statements)

References 47 publications

(52 reference statements)

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“…We examined the ERK pathway and found that pERK was upregulated in our NP-siGP130-treated bladder tumors, indicating that this downstream pathway was still active and may be responsible in preventing complete abrogation of the bladder tumor. Hepburn and colleagues demonstrated that activation of the ERK pathway supported a role for cancer stem cell self-renewal and tumorigenicity (29).…”

Section: Discussionmentioning

confidence: 99%

Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target

Martín

Shen

Steinbach-Rankins

et al. 2019

Molecular Cancer Therapeutics

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Predicting bladder cancer progression is important in selecting the optimal treatment for bladder cancer. Because current diagnostic factors regarding progression are lacking, new factors are needed to further stratify the curative potential of bladder cancer. Glycoprotein-130 (GP130), a transmembrane protein, is central to a number of signal transduction pathways involved in tumor aggressiveness, making it an attractive target. We hypothesize that if GP130 is found in an aggressive population of bladder tumors, then blocking GP130 expression may inhibit bladder cancer growth. Herein, we quantitatively show, using 11 patient samples and four bladder cancer cell lines, that GP130 is expressed in the aggressive human bladder tumors and in high-grade bladder cancer cell lines. Moreover, GP130 is significantly correlated with tumor grade, node category, tumor category, and patient outcome. We demonstrated a tumor-specific GP130 effect by blocking GP130 expression in bladder tumor cells, which resulted in decreased cell viability and reduced cell migration. Furthermore, we reduced tumor volume by approximately 70% compared with controls by downregulating GP130 expression using chitosan-functionalized nanoparticles encapsulating GP130 siRNA in an in vivo bladder cancer xenograft mouse model. Our results indicate that GP130 expression is linked to the aggressiveness of bladder tumors, and blocking GP130 has therapeutic potential in controlling tumor growth.

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Section: Discussionmentioning

confidence: 99%

Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target

Martín

Shen

Steinbach-Rankins

et al. 2019

Molecular Cancer Therapeutics

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“…Recent research has focused on recurrence in CSCs, a small subpopulation of tumor cells that are tumor‐initiating and drive the production of cancer cells. Progress in this field has highlighted the necessity of targeting these cells as they strongly determine the response to treatment [25]. An important relationship between c‐MYB and CSCs was recently reported, with important implications for breast cancer cell invasion and metastasis [26].…”

Section: Discussionmentioning

confidence: 99%

c‐MYB regulates cell growth and DNA damage repair through modulating MiR‐143

Wang¹,

Wu²,

Shi³

et al. 2015

FEBS Letters

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a b s t r a c tRadiotherapy is the most successful nonsurgical treatment for nasopharyngeal carcinoma (NCP). Although NPCs initially respond well to a full course of radiation, recurrence and metastasis are frequent. In this study, we found that down-regulated c-MYB expression was associated with increased radiation resistance and DNA damage repair ability. Interestingly, c-MYB was over-expressed in cancer tissues but not in the adjacent tissues. Down-regulation of c-MYB expression inhibited cell proliferation, and led to cell cycle arrest at the M phase in NPC cells. Luciferase and chromatin immunoprecipitation assays demonstrated that c-MYB transactivated miR-143 through direct binding to its promoter. Based on these results, c-MYB might target miR-143 in order to regulate stem cell properties, cell growth, apoptosis, and DNA damage repair.

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“…EMT is linked to MAPK signaling, since activity of that pathway has previously been shown to be required for transforming growth factor beta (TGFβ)-induced EMT and is associated with invasiveness of urothelial carcinoma cells[43], [44]. Moreover, high MAPK activity has been linked to the maintenance of bladder cancer stem cell characteristics[45].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of p16INK4a in Urothelial Carcinoma In Situ Is a Marker for MAPK-Mediated Epithelial-Mesenchymal Transition but Is Not Related to Human Papillomavirus Infection

et al. 2013

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BackgroundThe role of human papillomavirus (HPV) in bladder carcinogenesis remains controversial. Overexpression of p16INK4a, a surrogate marker for infection with oncogenic HPV in other tumours, has been described for urothelial carcinoma in situ (UCIS). Our goal was therefore to evaluate whether overexpression of p16INK4a is associated with HPV infection and to identify mechanisms of p16INK4a upregulation in UCIS.Materials and MethodsIn 60 tissue specimens from a total of 45 patients (UCIS and controls), we performed p16INK4a immunohistochemistry followed by detection and subclassification of HPV DNA. In a subset of samples, we tested for gene amplification of p16INK4a applying fluorescence in situ hybridization (FISH). RAS/MAPK signalling and epithelial-mesenchymal transition (EMT) was assessed using immunohistochemistry. Finally, we transfected urothelial carcinoma cells with KRAS and examined the expression of p16INK4a as well as markers of EMT.ResultsWe found overexpression of p16INK4a in 92.6% of UCIS and in all cervical intraepithelial neoplasia (CIN) controls. In contrast, we detected high-risk HPV DNA in 80% of CIN, but none in UCIS. There was no gene amplification of p16INK4a. High levels of phosphorylated kinases and urokinase plasminogen activator (uPA) and loss of membraneous E-cadherin were detected in UCIS. KRAS transfection of urothelial carcinoma cells led to upregulation of p16INK4a and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib.ConclusionsOur results show that overexpression of p16INK4a in UCIS is neither associated with HPV infection nor p16INK4a gene amplification but is a consequence of enhanced RAS/MAPK signalling that promotes EMT, possibly due to Sorafenib-sensitive paracrine secretion of the EMT activator uPA. These findings might open a novel therapeutic option for localized but aggressive urothelial cancer.

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Side Population in Human Non-Muscle Invasive Bladder Cancer Enriches for Cancer Stem Cells That Are Maintained by MAPK Signalling

Cited by 42 publications

References 47 publications

Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target

Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target

c‐MYB regulates cell growth and DNA damage repair through modulating MiR‐143

Overexpression of p16INK4a in Urothelial Carcinoma In Situ Is a Marker for MAPK-Mediated Epithelial-Mesenchymal Transition but Is Not Related to Human Papillomavirus Infection

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