Testicular germ cell tumor: a comprehensive review

Batool, Aisha; Karimi, Najmeh; Wu, Xiangnan; Chen, Su‐Ren; Liu, Yi‐Xun

doi:10.1007/s00018-019-03022-7

Cited by 117 publications

(102 citation statements)

References 189 publications

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“…16,18 Disruption of this equilibrium might be one of the major factors underlying cisplatin resistance, as MDM2-p53 pathway alterations are reported to be more common among cisplatinresistant TGCTs than in sensitive ones. 29,30 In our work, we found a significant, albeit moderate, positive correlation between p53 and MDM2 expression values in primary tumors, which is in agreement with previous works on the topic, 16 possibly reflecting the balance between the two players. Other studies, however, have reported that wt-p53 expression did not relate to MDM2 expression, although accumulation of the latter is still the simplest explanation for wt-p53 overexpression tolerance in tumors.…”

Section: Discussionsupporting

confidence: 92%

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p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

et al. 2020

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Background Testicular germ cell tumors (TGCTs) are highly sensitive to platinum‐based chemotherapy, and wild‐type p53 seems to play a pivotal role in this susceptibility. On the other hand, overexpression of MDM2 seems to entail treatment resistance and unfavorable prognosis. Objectives We aimed to describe p53 and MDM2 immunoexpression in a well‐characterized cohort of primary and metastatic TGCTs and evaluate associations with clinicopathological and prognostic variables, including survival. Materials and methods 237 primary tumor samples and 12 metastases were evaluated for p53 and MDM2 immunoexpression using digital image analysis. Clinical records of all patients were reviewed for baseline clinical/pathologic characteristics and follow‐up. Results A significant positive correlation between p53 and MDM2 H‐scores was found (rs = 0.590, P < .0001). Non‐seminomas showed significantly higher expression levels of both p53 and MDM2 (P = .0002, P < .0001), which peaked in embryonal carcinomas and choriocarcinomas. Percentage of immunoexpressing cells and H‐score were significantly higher in chemo‐treated metastases compared with chemo‐naïve primary tumors for MDM2 (P ≤ .0001 for both), but not for p53 (P = .919 and P = .703, respectively). Cases with higher MDM2 immunoexpression showed a statistically significant trend for association with poorer prognosis (P = .043). Relapse/progression‐free survival at 12 months post‐diagnosis was lower in the “MDM2‐high” (≥P50) vs. the “MDM2‐low” (

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Section: Discussionsupporting

confidence: 92%

“…Median age at diagnosis was 30 years (interquartile range-IQR:[25][26][27][28][29][30][31][32][33][34][35][36], and median follow-up time was 69.0 months (95% CI 57.3-80.7). 52.2% of TGCT patients disclosed pure SE, followed by 37.9% having mixed tumors, in accordance with literature 23.…”

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confidence: 99%

p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

et al. 2020

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“…However, in a subset of young men, the incidence of testicular cancers is increasing, with 3 to 10 new cases diagnosed per 100,000 males/per year in industrialized countries [34]. The vast majority (90%-95%) of TCs are classified as testicular germ cell tumors (TGCTs), which are the most common malignancies diagnosed in males aged 15 to 44 years [35,36]. TGCTs develop from cells of germ cell neoplasia in situ (GCNIS), which originate from gonocytes that fail to undergo physiological spermatogenic differentiation [35].…”

Section: Testicular Cancermentioning

confidence: 99%

“…The vast majority (90%-95%) of TCs are classified as testicular germ cell tumors (TGCTs), which are the most common malignancies diagnosed in males aged 15 to 44 years [35,36]. TGCTs develop from cells of germ cell neoplasia in situ (GCNIS), which originate from gonocytes that fail to undergo physiological spermatogenic differentiation [35]. They are commonly further divided into seminomas and non-seminoma tumors based on their histology and radiosensitivity [5].…”

Section: Testicular Cancermentioning

confidence: 99%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

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“…The precise regulation of proliferation, apoptosis and cell cycle is crucial for germ cell development, and dysregulation of those processes may lead to infertility or cancer. TCam-2 cells, while representing human male germ cells, originate from a type of the most frequent type of human TGCT, the seminoma (for review see (Batool et al, 2019)). TGCTs are the most common solid tumours in young men, and their incidence is on the rise (Rosen et al, 2011).…”

Section: Knockdown Of Kif18a Caused Tcam-2 Cell Cycle Arrest In G2/m mentioning

confidence: 99%

Kinesin KIF18A is a novel PUM regulated target promoting mitotic progression and survival of human male germ cell line - TCam-2

Smialek

Kuczyńska

Ilaslan

et al. 2019

Preprint

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Regulation of proliferation, apoptosis and cell cycle is crucial for the physiology of germ cells. Their malfunction contributes to infertility and germ cell tumours. Kinesin KIF18A is an important germ cell specific regulator which downregulates apoptosis while promoting cell proliferation in animal models. Whereas regulation of KIF18A expression was studied at the transcriptional level, its posttranscriptional regulation has not been extensively explored. Due to the presence of two PUM Binding Elements (PBEs) within 3'UTR, KIF18A mRNA is a potential target of PUMs, well known RNA-binding proteins involved in posttranscriptional gene regulation (PTGR). We investigated that possibility in TCam-2 cells originating from seminoma, representing human male germ cells. We conducted RNA co-immunoprecipitation combined with RT-qPCR, as well as luciferase reporter assay by applying appropriate luciferase construct encoding the wild type KIF18A 3'UTR, upon PUM1 and PUM2 overexpression or knockdown. We found that KIF18A is repressed by PUM1 and PUM2. To study how this regulation influences KIF18A function in TCam-2 cells, MTS proliferation assay, apoptosis and cell cycle, analysis using flow cytometry was performed upon KIF18A siRNA knockdown. We uncovered that KIF18A significantly influences proliferation, apoptosis and cell cycle, these effects being opposite to PUM effects in TCam-2 cells. We propose that repression by PUM proteins may represent one of mechanisms influencing KIF18A level in controlling proliferation, cell cycle and apoptosis in TCam-2 cells. To the best of our knowledge, this paper identifies the first mammalian functionally germ cell specific gene that is regulated by Pum proteins via 3'UTR.

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Testicular germ cell tumor: a comprehensive review

Cited by 117 publications

References 189 publications

p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

TGF-β and microRNA Interplay in Genitourinary Cancers

Kinesin KIF18A is a novel PUM regulated target promoting mitotic progression and survival of human male germ cell line - TCam-2

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