Pleiotropic Biological Activities of Alternatively Spliced TMPRSS2/ERG Fusion Gene Transcripts

Wang, Jianghua; Cai, Yi; Yu, Wendong; Ren, Chengxi; Spencer, David M.; Ittmann, Michael

doi:10.1158/0008-5472.can-08-1147

Cited by 154 publications

(194 citation statements)

References 36 publications

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“…Due to the high frequency of such genetic rearrangements in PCa, patients carrying T/E fusions form the largest subgroup of PCas, and there is an urgent need to discover novel treatment options for this subgroup of patients. We have shown that knockdown of T/E fusion is a viable therapeutic approach [9,10]. But they do not completely eliminate the tumor growth, suggesting some A.…”

Section: Discussionmentioning

confidence: 98%

“…To further confirm the correlation of Ser536 phosphorylation with CCL2 expression, we also accessed their expression levels in VCaP xenograft tumor samples we collected previously [9]. As shown in Fig 5A, Fig.5B.…”

Section: Nf-kb Ser536 Phosphorylation Plays a Role In Regulating Ccl2mentioning

confidence: 95%

“…PNT1a and LNCaP cells were maintained in the RPMI with 10% fetal bovine serum (FBS) [9]. Human embryonic kidney-293 cell line 293t cells and 293-FT (Invitrogen) were cultured in the DMEM with 10% FBS.…”

Section: Cell Culturementioning

confidence: 99%

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Introducing, OncoTarget

Blagosklonny¹,

Gudkov²

2010

Oncotarget

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Majority of prostate cancer (PCa) patients carry TMPRSS2/ERG (T/E) fusiongenes and there has been tremendous interest in understanding how the T/E fusion may promote progression of PCa. We showed that T/E fusion can activate NFkB pathway by increasing phosphorylation of NF-kB p65 Ser536 (p536), but the function of p536 has never been studied in PCa. We report here that active p536 can significantly increase cell motility and transform PNT1a cells (an immortalized normal cell line), suggesting p536 plays a critical role in promoting PCa tumorigenesis.We have discovered a set of p536 regulated genes, among which we validated the regulation of CCL2 by p536. Based on all evidence, we favor that T/E fusion, NF-kB p536 and CCL2 form a signaling chain. Finally, PNT1a cells (not tumorigenic) can form tumors in SCID mice when overexpressing of either wild type or active p65 in the presence of activated AKT, demonstrating synergistic activities of NF-kB and AKT signals in promoting PCa tumorigenesis. These findings indicate that combination therapies targeting T/E fusion, NF-kB, CCL2 and/or AKT pathways may have efficacy in T/E fusion gene expressing PCa. If successful, such targeted therapy will benefit more than half of PCa patients who carry T/E fusions.

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Section: Discussionmentioning

confidence: 98%

Section: Nf-kb Ser536 Phosphorylation Plays a Role In Regulating Ccl2mentioning

confidence: 95%

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Introducing, OncoTarget

Blagosklonny¹,

Gudkov²

2010

Oncotarget

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“…The TMPRSS2-ERG gene fusion in PCa makes it a desirable therapeutic target. It was shown that knockdown of this gene fusion product inhibited primary tumor growth 101 . One recent study reported targeting the TMPRSS2-ERG gene fusion junction in vivo by specific siRNAs delivered via liposomal nanovectors.…”

Section: Discussionmentioning

confidence: 99%

TMPRSS2-ERG gene fusion in prostate cancer

Burdova

Bouchal²,

Tavandzis³

et al. 2014

BIOMED PAP

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aBackground. The TMPRSS2-ERG gene fusion is one of the most widely spread chromosomal rearrangements in carcinomas. Since its discovery, a number of studies have examined its diagnostic, prognostic and therapeutic implications for prostate cancer where suitable biomarkers are still lacking. The publication data are inconsistent. The aim of this review was to critically evaluate the current clinical impact of this gene fusion. Methods. The PubMed online database was used to search relevant reviews and original articles. Results. Although the TMPRSS2-ERG gene fusion appears to be a suitable diagnostic biomarker, the prognostic implications of this gene fusion are still unclear. Several new strategies for therapeutically targeting ETS fusions and their modulators have been identified and are currently being investigated. Conclusion. Due to the heterogeneity of prostate cancer, the combination of several biomarkers is necessary to accurately assess the presence of prostate cancer, predict its potential clinical outcome and decide on appropriate therapy (e.g. PARP inhibitors).

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“…Currently, there are many studies targeting at the TMPRSS2-ERG fusion and its downstream signaling. It was shown that knockdown of the TMPRSS2-ERG fusion in a cancer cell line can lead to primary tumour growth inhibition, which made TMPRSS2-ERG a potential therapeutic target [16]. There is also study showing that targeting the most common and clinically significant alternatively spliced isoforms of the TMPRSS2-ERG mRNA with specific siRNAs via liposomal nanovectors can be promising therapy for men with prostate cancer [17].…”

Section: Fusion Genes: Tumorgenesis Biomarker and Therapeutic Targetmentioning

confidence: 99%

Fusion Genes and their Detection through Next Generation Sequencing in Malignant Hematological Disease and Solid Tumors

Liu¹,

Weng²,

Ming³

et al. 2016

Diagn Pathol Open

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Fusion genes are neoplasia-associated mutations, which play a particularly significant role in tumorgenesis and exhibit great importance for clinical applications in malignant hematological diseases and solid tumors. Simultaneously with copy number variants (CNVs), gene fusions are resulting from balanced and unbalanced chromosomal rearrangements. Thus, understanding the mutagenesis and instability of CNV, as well as the underlying molecular mechanisms of chromosomal rearrangements will improve our comprehension of gene fusions. Recently, next generation sequencing (NGS), especially transcriptome sequencing or RNA-Sequencing (RNA-seq), has become a very useful tool to identify gene alterations in cancer and a powerful approach for investigating the tumorgenesis. However, we are still facing with the challenge of minimizing false positives in results of RNA-seq. Whole-genome sequencing (WGS) is also used for the fusion gene detection, which provides us a more comprehensive and integrative way to detect structural variants. WGS may correct the false-negative results from RNA-seq. Additionally; many computational tools with more sensitivity and specificity have been developed for the detection of fusion transcripts from NGS datas. In the future, multi-omics analysis, third-generation sequencing and liquid-biopsy technique all provide opportunities to comprehensively interpret gene fusions and understand the biology of cancer genomes.

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Pleiotropic Biological Activities of Alternatively Spliced TMPRSS2/ERG Fusion Gene Transcripts

Cited by 154 publications

References 36 publications

Introducing, OncoTarget

Introducing, OncoTarget

TMPRSS2-ERG gene fusion in prostate cancer

Fusion Genes and their Detection through Next Generation Sequencing in Malignant Hematological Disease and Solid Tumors

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