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Abnormal gametogenesis induced by p53 deficiency promotes tumor progression and drug resistance.

ABSTRACT: The century-old embryonal/gametogenesis hypothesis of tumors could link diverse tumors' malignant features together likely representing the real "stemness" of tumors. However, the genetic evidence to validate abnormal gametogenesis in tumors remains lacking. Here we show that p53 deficiency elicits abnormal gametogenesis from primordial germ cell-like stage to late oocyte-like stage and subsequent parthenogenetic activation. The similar upregulation of abnormal gametogenesis by p53 deficiency is observed both in p53^-/- mouse model and cultured cancer cells. Notably, germ cell-like cells isolated from distinct tumors from p53^-/- mice and cancer cell lines display potent tumorigenicity potential. Abnormal oogenesis induced by p53 deficiency and then spontaneous parthenogenetic activation endow tumors with imitated embryonic development, life cycle, and therapeutic resistance. Our study establishes the genetic evidence to support embryonal/gametogenesis theory of tumors and reveals a pivotal role of p53 in restricting abnormal gametogenesis that may represent a novel aspect for p53's tumor suppression.

SUBMITTER: Liu C

PROVIDER: S-EPMC6167385 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Abnormal gametogenesis induced by p53 deficiency promotes tumor progression and drug resistance.

Liu Chunfang C Cai Zhen Z Jin Guoxiang G Peng Danni D Pan Bo-Syong BS Zhang Xian X Han Fei F Xu Xiaohong X Lin Hui-Kuan HK

Cell discovery 20181002

The century-old embryonal/gametogenesis hypothesis of tumors could link diverse tumors' malignant features together likely representing the real "stemness" of tumors. However, the genetic evidence to validate abnormal gametogenesis in tumors remains lacking. Here we show that p53 deficiency elicits abnormal gametogenesis from primordial germ cell-like stage to late oocyte-like stage and subsequent parthenogenetic activation. The similar upregulation of abnormal gametogenesis by p53 deficiency is ...[more]

PMID: 30302273

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Project description:Background: Wilms tumor (WT) is the most common renal tumor in children with diffusely anaplastic or unfavorable histology, indicative of a poor prognosis. Heterogeneous nuclear ribonucleoprotein L (hnRNPL) is an RNA-binding protein (RBP) and a regulator of alternative RNA splicing that plays an important role in the occurrence and development of several cancers. Methods: Next generation sequencing technologies was used to discovery differentially expressed genes between WT and adjacent nontumors. The gene ontology (GO) analysis was performed to uncover the biological functions of differentially expressed genes, and the kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was applied to find out the related signal pathways. Expression levelsof hnRNPL with WT tissues and cells were determined by RT-qPCR.After silencing hnRNPL, the expression of hnRNPL, p53 and Bcl-2 were detected by RT-qPCR and Western blot in WT cell line. The regulatory effects of hnRNPLon proliferative and apoptotic potentials of WT cells were evaluated by MTT and flow cytometry, respectively. RNA-binding protein immuno-precipitation was used to confirm the direct interaction of hnRNPL with p53 mRNA. Mouse xenograft models ofhnRNPL knockdown were established to test the functions in the growth of WT in vivo. Results: High levels of hnRNPL were expressed in WT tissues and cells. Functional analysis revealed that hnRNPL silencing suppressed cell proliferation and promoted cell apoptosis in WT. Molecular mechanism exploration indicated that hnRNPL directly targeted p53. Moreover, knockdown of hnRNPL inhibited the expression of p53 and Bcl2 in WT. Additionally, hnRNPL silencing inhibited the growth of xenograft tumors in vivo. Conclusion: HnRNPL act as p53 mRNA-binding protein, which plays an important role in the proliferation and apoptosis of WT through p53 and Bcl2 pathways and these findings provide new insights into the mechanism of WT pathogenesis.

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Abnormal gametogenesis induced by p53 deficiency promotes tumor progression and drug resistance.

Publications

Abnormal gametogenesis induced by p53 deficiency promotes tumor progression and drug resistance.

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