Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours

Rudolph, Christiane; Melau, Cecilie; Nielsen, John; Jensen, Kristina Vile; Liu, Dekang; Peña-Dı́az, Javier; Meyts, Ewa Rajpert‐De; Rasmussen, Lene Juel; Jørgensen, Anne

doi:10.1007/s13402-017-0326-8

Cited by 29 publications

(25 citation statements)

References 55 publications

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“…Despite the general understanding that expression of pluripotency factors is a hallmark of GCNIS and the majority of TGCTs, the underlying molecular mechanisms responsible for the maintenance or re-activation of pluripotency factor expression in these malignant germ cells are not well understood. Several independent studies have implicated the Nodal signalling pathway in the pathogenesis of TGCTs [12,[14][15][16][17][18][19]. Recently, we found that stimulation of the Nodal pathway in human fetal testes prolonged the expression of OCT4 in gonocytes, thus directly implicating the pathway in the regulation of the gonocyte to pre-spermatogonia transition during human fetal testis development [19] and involvement in regulating pluripotency factor expression in fetal germ cells (reviewed in [20]).…”

Section: Introductionmentioning

confidence: 85%

“…Recently, we found that stimulation of the Nodal pathway in human fetal testes prolonged the expression of OCT4 in gonocytes, thus directly implicating the pathway in the regulation of the gonocyte to pre-spermatogonia transition during human fetal testis development [19] and involvement in regulating pluripotency factor expression in fetal germ cells (reviewed in [20]). Furthermore, high expression of the Nodal signalling factors NODAL, LEFTY1 and CRIPTO has been reported in GCNIS cells, TGCTs and TGCTderived cell lines [12,16,17], and several studies have found co-expression of Nodal signalling and pluripotency factors in NTera2 cells [12,15]. Also, heterogeneous expression of the co-receptor CRIPTO was found in NTera2 cells, with highest expression in the subpopulation of cells displaying the most tumorigenic potential [15].…”

Section: Introductionmentioning

confidence: 99%

“…The relationship between expression of pluripotency factors and cisplatin-sensitivity has also been examined in a TGCT-derived EC cell line, in which loss of pluripotency factor expression by siRNAmediated knockdown of OCT4, resulted in decreased sensitivity to cisplatin [9]. Moreover, treatment with retinoic acid to induce differentiation of the EC-derived NTera2 cell line along the neuroectodermal lineage, resulted in decreased expression of the pluripotency factor OCT4 and increased cisplatin-resistance [10][11][12], thus supporting the association between pluripotency factor expression and cisplatin-sensitivity. Although cisplatin-based chemotherapy has provided high cure rates for TGCTs, the treatment regimen is associated with long-term complications, including cardiovascular side effects and infertility as well as relapse [5,13].…”

Section: Introductionmentioning

confidence: 99%

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Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours

et al. 2020

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Background: Testicular germ cell tumours (TGCTs) are characterised by an overall high cisplatin-sensitivity which has been linked to their continued expression of pluripotency factors. Recently, the Nodal signalling pathway has been implicated in the regulation of pluripotency factor expression in fetal germ cells, and the pathway could therefore also be involved in regulating expression of pluripotency factors in malignant germ cells, and hence cisplatin-sensitivity in TGCTs. Methods:We used in vitro culture of the TGCT-derived cell line NTera2, ex vivo tissue culture of primary TGCT specimens and xenografting of NTera2 cells into nude mice in order to investigate the consequences of manipulating Nodal and Activin signalling on pluripotency factor expression, apoptosis, proliferation and cisplatinsensitivity.Results: The Nodal signalling factors were markedly expressed concomitantly with the pluripotency factor OCT4 in GCNIS cells, seminomas and embryonal carcinomas. Despite this, inhibition of Nodal and Activin signalling either alone or simultaneously did not affect proliferation or apoptosis in malignant germ cells in vitro or ex vivo. Interestingly, inhibition of Nodal signalling in vitro reduced the expression of pluripotency factors and Nodal pathway genes, while stimulation of the pathway increased their expression. However, cisplatin-sensitivity was not affected following pharmacological inhibition of Nodal/Activin signalling or siRNA-mediated knockdown of the obligate co-receptor CRIPTO in NTera2 cells in vitro or in a xenograft model. Conclusion: Our findings suggest that the Nodal signalling pathway may be involved in regulating pluripotency factor expression in malignant germ cells, but manipulation of the pathway does not appear to affect cisplatinsensitivity or tumour cell proliferation.

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Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours

et al. 2020

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“…A number of studies explored cisplatin, an efficient spectrum drug against cancer that is frequently applied in the treatment of various cancers in the place of lung, breast, bladder and brain, etc 6, 7. Cisplatin triggers cancer cell death by cross‐linking with the DNAs to suppress replication and transcription 8. However, extended records of administrating cisplatin caused great drug fastness in those cisplatin‐applied tumour cells 9, 10.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 Cisplatin triggers cancer cell death by cross-linking with the DNAs to suppress replication and transcription. 8 However, extended records of administrating cisplatin caused great drug fastness in those cisplatin-applied tumour cells. 9,10 In order to keep the effectiveness of the cisplatin treatment, it is imperative for lung cancer cells to maintain a steady level of sensitivity against it.…”

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confidence: 99%

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

Zhang

Sun

et al. 2018

Cell Biochemistry & Function

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More and more studies indicate the relevance of miRNAs in inducing certain drug resistance. Our study aimed to investigate whether microRNA‐130b‐3p (miR‐130b) mediates the chemoresistance as well as proliferation of lung cancer (LC) cells. MTS assay and apoptosis analysis were conducted to determine cell proliferation and apoptosis, respectively. Binding sites were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT‐PCR and immunoblot, respectively. Mouse xenograft model was used to evaluate the role of miR‐130b in cisplatin resistance in vivo. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. We identified PTEN as miR‐130b's major target and inversely correlated with miR‐130b expression in LC. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. Suppression of miR‐130b enhanced drug cytotoxicity and reduced proliferation of A549/CR cells both internally and externally. Particularly, miR‐130b mediated Wnt/β‐catenin signalling pathway activities, chemoresistance and proliferation in LC cell, which was partially blocked following knockdown of PTEN. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway.

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Evaluation of Chemotherapeutic Drugs for Treatment of (Cisplatin-Resistant) Germ Cell Cancer Cell Lines

Skowron

Hoffmann

Watolla

et al. 2020

Methods in Molecular Biology

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Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours

Cited by 29 publications

References 55 publications

Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours

Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

Evaluation of Chemotherapeutic Drugs for Treatment of (Cisplatin-Resistant) Germ Cell Cancer Cell Lines

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