The rise of testicular germ cell tumours: the search for causes, risk factors and novel therapeutic targets

McIver, Skye C; Roman, Shaun D.; Nixon, Brett; Loveland, Kate; McLaughlin, Eileen A.

doi:10.12688/f1000research.2-55.v1

Cited by 17 publications

(6 citation statements)

References 92 publications

(176 reference statements)

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“…Subsequently, several additional susceptibility loci have been reported, including three that overlap with the locations of KITLG , SPRY4 and BAK1 , involved in KIT signaling pathways regulating proliferation, survival and migration of primordial germ cells or TGCT development. 14 …”

mentioning

confidence: 99%

Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors

Özata

Lee

et al. 2017

Cell Death Dis

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Deregulation of microRNAs (miRNAs) contributes to the development and progression of many cancer types; however, their functions in the pathogenesis of testicular germ cell tumor (TGCT) remain unclear. Here, we determined miRNA expression profiles of TGCTs and normal testes using small RNA sequencing, and identified several deregulated miRNAs in TGCTs, including the miR-506~514 cluster. In functional studies in vitro we demonstrated that miR-514a-3p induced apoptosis through direct regulation of the paternally expressed gene 3 (PEG3), and ectopically expressed PEG3 could rescue the apoptotic effect of miR-514a-3p overexpression. Silencing of PEG3 or miR-514a-3p overexpression reduced nuclear accumulation of p50 and NF-κB reporter activity. Furthermore, PEG3 was co-immunoprecipitated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in TGCT cell lysates. We propose a model of PEG3-mediated activation of NF-κB in TGCT. Loss of miR-514a-3p expression in TGCT increases PEG3 expression that recruits TRAF2 and activates the NF-kappa B pathway, which protects germ cells from apoptosis. Importantly, we observed strong expression of PEG3 and nuclear p50 in the majority of TGCTs (83% and 78%, respectively). In conclusion, our study describes a novel function for miR-514a-3p in TGCT and highlights an unrecognized mechanism of PEG3 regulation and NF-κB activation in TGCT.

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mentioning

confidence: 99%

Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors

Özata

Lee

et al. 2017

Cell Death Dis

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“…[ 101,102 ] Another finding suggested that the c‐Kit receptor promotes cell survival via activation of Akt‐mediated phosphorylation of Bad on Ser136. [ 103 ] However, the precise molecular mechanism by which Akt activation induces Oct3/4 or c‐Kit overexpression is yet to be investigated in detail.…”

Section: Discussionmentioning

confidence: 99%

Sub‐chronic cadmium and lead compound exposure induces reproductive toxicity and development of testicular germ cell neoplasia in situ in murine model: Attenuative effects of resveratrol

Mitra

Patra

Saha

et al. 2022

J Biochem & Molecular Tox

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Cadmium and lead are widespread, nonbiodegradable heavy metals of perpetual environmental concerns. The present study aimed to evaluate whether sub‐chronic exposure to cadmium chloride (CdCl2) and lead acetate [Pb(CH3COO)2] induces reproductive toxicity and development of testicular germ cell neoplasia in situ (GCNIS) in swiss albino mice. The effects of resveratrol to reverse the metal‐induced toxicity were also analyzed. The mice were randomly divided into four groups for metal treatments and two groups received two different doses of each metal, CdCl2 (0.25 and 0.5 mg/kg) and Pb(CH3COO)2 (3 and 6 mg/kg). The fourth group received oral doses of 20 mg/kg resveratrol in combination with 0.5 mg/kg CdCl2 or 6 mg/kg Pb(CH3COO)2 for 16 weeks. Toxic effects of both metals were estimated qualitatively and quantitatively by the alterations in sperm parameters, oxidative stress markers, testicular histology, and protein expressions of the treated mice. Pronounced perturbation of sperm parameters, cellular redox balance were observed with severe distortion of testicular histo‐architecture in metal exposed mice. Significant overexpression of Akt cascade and testicular GCNIS marker proteins were recorded in tissues treated with CdCl2. Notable improvements were observed in all the evaluated parameters of resveratrol cotreated mice groups. Taken together, the findings of this study showed that long‐term exposure to Cd and Pb compounds, induced acute reproductive toxicity and initiation of GCNIS development in mice. Conversely, resveratrol consumption abrogated metal‐induced perturbation of spermatogenesis, testicular morphology, and the upregulation of Akt cascade proteins along with GCNIS markers, which could have induced the development of testicular cancer.

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“…Confounding this situation, three additional studies focusing on PFOA exposure and mortality from testicular cancer all failed to identify an association in occupationally exposed workers (87,96,97). Thus, whilst not universally demonstrated, the potential significance of these positive associations is highlighted by parallel correlations between the widespread increase in worldwide PFAS usage and the rising prevalence of testicular cancer; a pathology that has significantly increased in recent times to become the most common malignancy in young men aged 20-40 years (98)(99)(100)(101). Although the characterization of testicular cancer remains incomplete, there is speculation that environmental factors, as opposed to genetic factors, are a key contributor to the etiology of this form of cancer (98,102).…”

Section: Pfas Human Health Associationsmentioning

confidence: 99%

Assessment of the Emerging Threat Posed by Perfluoroalkyl and Polyfluoroalkyl Substances to Male Reproduction in Humans

et al. 2022

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Per-fluoroalkyl and polyfluoroalkyl substances (PFAS) are a diverse group of synthetic fluorinated chemicals used widely in industry and consumer products. Due to their extensive use and chemical stability, PFAS are ubiquitous environmental contaminants and as such, form an emerging risk factor for male reproductive health. The long half-lives of PFAS is of particular concern as the propensity to accumulate in biological systems prolong the time taken for excretion, taking years in many cases. Accordingly, there is mounting evidence supporting a negative association between PFAS exposure and an array of human health conditions. However, inconsistencies among epidemiological and experimental findings have hindered the ability to definitively link negative reproductive outcomes to specific PFAS exposure. This situation highlights the requirement for further investigation and the identification of reliable biological models that can inform health risks, allowing sensitive assessment of the spectrum of effects of PFAS exposure on humans. Here, we review the literature on the biological effects of PFAS exposure, with a specific focus on male reproduction, owing to its utility as a sentinel marker of general health. Indeed, male infertility has increasingly been shown to serve as an early indicator of a range of co-morbidities such as coronary, inflammatory, and metabolic diseases. It follows that adverse associations have been established between PFAS exposure and the incidence of testicular dysfunction, including pathologies such as testicular cancer and a reduction in semen quality. We also give consideration to the mechanisms that render the male reproductive tract vulnerable to PFAS mediated damage, and discuss novel remediation strategies to mitigate the negative impact of PFAS contamination and/or to ameliorate the PFAS load of exposed individuals.

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The rise of testicular germ cell tumours: the search for causes, risk factors and novel therapeutic targets

Cited by 17 publications

References 92 publications

Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors

Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors

Sub‐chronic cadmium and lead compound exposure induces reproductive toxicity and development of testicular germ cell neoplasia in situ in murine model: Attenuative effects of resveratrol

Assessment of the Emerging Threat Posed by Perfluoroalkyl and Polyfluoroalkyl Substances to Male Reproduction in Humans

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