The role of epithelial–mesenchymal transition drivers <scp>ZEB</scp>1 and <scp>ZEB</scp>2 in mediating docetaxel‐resistant prostate cancer

Hanrahan, Karen; O’Neill, Amanda; Prencipe, Maria; Bugler, Jane; Murphy, Lisa; Fabre, Aurélie; Puhr, Martin; Čulig, Zoran; Murphy, Keefe; Watson, R. William G.

doi:10.1002/1878-0261.12030

Cited by 109 publications

(83 citation statements)

References 58 publications

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“…Regulation by miRs is also to consider as certain miRs, found to be downregulated in resistant cells, directly suppress EMT-TF expression, while increasing chemosensitivity in cells with a more Epi phenotype (Nantajit et al, 2015). A deregulation of the miR-200 family/ZEBs axis appears to mediate docetaxel resistance of prostate cancer cells (Hanrahan et al, 2017;Puhr et al, 2012). miR-21, a well-known 'oncomir' (i.e., a miR with oncogenic properties), is associated with EMT, resistance to trastuzumab, as well as to chemotherapy (paclitaxel or doxorubicin) through the PTEN/AKT pathway in HER2-positive breast cancer cells (De Mattos-Arruda et al, 2015).…”

Section: Emt and Resistance To Chemotherapy And Radiotherapymentioning

confidence: 99%

New insights into the role of EMT in tumor immune escape

et al. 2017

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Novel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree of nonresponders, and in some cases the emergence of resistance in patients who do initially respond, represents a significant challenge in the field of cancer immunotherapy. These issues prompt much more extensive studies to better understand how cancer cells escape immune surveillance and resist immune attacks. Here, we review the current knowledge of how cellular heterogeneity and plasticity could be involved in shaping the tumor microenvironment (TME) and in controlling antitumor immunity. Indeed, recent findings have led to increased interest in the mechanisms by which cancer cells undergoing epithelial‐mesenchymal transition (EMT), or oscillating within the EMT spectrum, might contribute to immune escape through multiple routes. This includes shaping of the TME and decreased susceptibility to immune effector cells. Although much remains to be learned on the mechanisms at play, cancer cell clones with mesenchymal features emerging from the TME seem to be primed to face immune attacks by specialized killer cells of the immune system, the natural killer cells, and the cytotoxic T lymphocytes. Recent studies investigating patient tumors have suggested EMT as a candidate predictive marker to be explored for immunotherapy outcome. Promising data also exist on the potential utility of targeting these cancer cell populations to at least partly overcome such resistance. Research is now underway which may lead to considerable progress in optimization of treatments.

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Section: Emt and Resistance To Chemotherapy And Radiotherapymentioning

confidence: 99%

New insights into the role of EMT in tumor immune escape

et al. 2017

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“…Nowadays, a growing body of evidence implicates intratumoral heterogeneity, EMT, and increased ZEB1 levels as among the main drivers of therapy resistance, exemplified by EMTinduced docetaxel resistance in prostate cancer (Hanrahan et al, 2017), gemcitabine resistance in pancreatic cancer (Wang et al, 2017), and multiple types of resistance within various malignancies (Shibue and Weinberg, 2017;Cui et al, 2018;Zhang et al, 2018;Orellana-Serradell et al, 2019). Besides being a key contributor to the regulation of cancer cell differentiation and metastasis, the potential role of ZEB1 in the modulation of tumor chemoresistance is not yet fully understood.…”

Section: Mechanisms Of Zeb1-trigged Therapy Resistancementioning

confidence: 99%

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

Drápela

Bouchal

Jolly

et al. 2020

Front. Mol. Biosci.

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127

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The predominant way in which conventional chemotherapy kills rapidly proliferating cancer cells is the induction of DNA damage. However, chemoresistance remains the main obstacle to therapy effectivity. An increasing number of studies suggest that epithelial-to-mesenchymal transition (EMT) represents a critical process affecting the sensitivity of cancer cells to chemotherapy. Zinc finger E-box binding homeobox 1 (ZEB1) is a prime element of a network of transcription factors controlling EMT and has been identified as an important molecule in the regulation of DNA damage, cancer cell differentiation, and metastasis. Recent studies have considered upregulation of ZEB1 as a potential modulator of chemoresistance. It has been hypothesized that cancer cells undergoing EMT acquire unique properties that resemble those of cancer stem cells (CSCs). These stem-like cells manifest enhanced DNA damage response (DDR) and DNA repair capacity, self-renewal, or chemoresistance. In contrast, functional experiments have shown that ZEB1 induces chemoresistance regardless of whether other EMT-related changes occur. ZEB1 has also been identified as an important regulator of DDR by the formation of a ZEB1/p300/PCAF complex and direct interaction with ATM kinase, which has been linked to radioresistance. Moreover, ATM can directly phosphorylate ZEB1 and enhance its stability. Downregulation of ZEB1 has also been shown to reduce the abundance of CHK1, an effector kinase of DDR activated by ATR, and to induce its ubiquitin-dependent degradation. In this perspective, we focus on the role of ZEB1 in the regulation of DDR and describe the mechanisms of ZEB1-dependent chemoresistance.

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“…ZEB1 not only promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT), but it can also regulate therapeutic resistance via different mechanisms (11). ZEB1 is overexpressed in several types of cancer, such as gastric cancer, lung cancer and prostate cancer, and it plays an important role in inducing EMT in tumor cells (12)(13)(14). EMT, which describes the process by which tumor cells escape from one site to invade the adjacent matrix and transfer to a distant site, is a key event in the progression of malignant tumors.…”

Section: Vasculogenic Mimicry In Bladder Cancer and Its Association Wmentioning

confidence: 99%

Vasculogenic mimicry in bladder cancer and its association with the aberrant expression of ZEB1

Mao

Wang

et al. 2018

Oncol Lett

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Abstract. The aim of the present study was to investigate the associations between vasculogenic mimicry (VM) and zinc finger E-box binding homeobox 1 (ZEB1) in bladder cancer. VM structure and ZEB1 expression were analyzed by cluster of differentiation 34/periodic acid Schiff (PAS) double staining and immunohistochemical staining in 135 specimens from patients with bladder cancer, and a further 12 specimens from normal bladder tissues. Three-dimensional (3-D) culture was used to detect VM formation in the bladder transitional cancer cell lines UM-UC-3 and J82, and the immortalized human bladder epithelium cell line SV-HUC-1 in vitro. ZEB1 expression in these cell lines was compared by reverse transcription-quantitative polymerase chain reaction and western blot assays. In addition, small interfering RNA was used to inhibit ZEB1 in UM-UC-3 and J82 cells, followed by 3-D culturing of treated cell lines. As a result, VM was observed in 31.1% of specimens from bladder cancer tissues, and cases with high ZEB1 expression accounted for 60.0% of patients with bladder cancer. In addition, ZEB1 expression was closely associated with VM (r=0.189; P<0.05), and also increased as the grade and stage of the tumor developed. In an in vitro assay, UM-UC-3 and J82 cells exhibited VM formation, however, SV-HUC-1 did not. Furthermore, VM-forming cancer cell lines UM-UC-3 and J82 exhibited higher ZEB1 expression. Notably, VM formation was inhibited following knockdown of ZEB1. In conclusion, ZEB1 may be associated with VM in bladder cancer and serve an important role in the process of VM formation. However, its detailed mechanism requires further study.

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The role of epithelial–mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel‐resistant prostate cancer

Cited by 109 publications

References 58 publications

New insights into the role of EMT in tumor immune escape

New insights into the role of EMT in tumor immune escape

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

Vasculogenic mimicry in bladder cancer and its association with the aberrant expression of ZEB1

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