Expression Profiles of PIWIL2 Short Isoforms Differ in Testicular Germ Cell Tumors of Various Differentiation Subtypes

Gainetdinov, Ildar; Skvortsova, Yulia V.; Stukacheva, E. A.; Bychenko, Oksana S.; Kondratieva, Sofia A.; Zinovieva, Marina V.; Azhikina, Tatyana

doi:10.1371/journal.pone.0112528

Cited by 18 publications

(29 citation statements)

References 88 publications

(101 reference statements)

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“…Importantly, PIWIL2 expression was upregulated in seminomas and downregulated in nonseminomas compared to the matched CIS samples (Figure 1C). Accordingly, PIWIL2 transcription level was higher in seminomas than in nonseminomas (Supplementary Data File 3) as in previous reports [24, 25]. This PIWIL2 expression pattern was also observed in The Cancer Genome Atlas cohort (Supplementary Data File 3).…”

Section: Resultssupporting

confidence: 86%

Distinguishing epigenetic features of preneoplastic testis tissues adjacent to seminomas and nonseminomas

et al. 2016

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PIWI pathway proteins are expressed during spermatogenesis where they play a key role in germ cell development. Epigenetic loss of PIWI proteins expression was previously demonstrated in testicular germ cell tumors (TGCTs), implying their involvement in TGCT development. In this work, apart from studying only normal testis and TGCT samples, we also analyzed an intermediate stage, i.e. preneoplastic testis tissues adjacent to TGCTs. Importantly, in this study, we minimized the contribution of patient-to-patient heterogeneity by using matched preneoplastic/TGCT samples. Surprisingly, expression of germ cell marker DDX4 suggests that spermatogenesis is retained in premalignant testis tissues adjacent to nonseminoma, but not those adjacent to seminoma. Moreover, this pattern is followed by expression of PIWI pathway genes, which impacts one of their functions: DNA methylation level over LINE-1 promoters is higher in preneoplastic testis tissues adjacent to nonseminomas than those adjacent to seminomas. This finding might imply distinct routes for development of the two types of TGCTs and could be used as a novel diagnostic marker, possibly, noninvasively. Finally, we studied the role of CpG island methylation in expression of PIWI genes in patient samples and using in vitro experiments in cell line models: a more complex interrelation between DNA methylation and expression of the corresponding genes was revealed.

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Section: Resultssupporting

confidence: 86%

Distinguishing epigenetic features of preneoplastic testis tissues adjacent to seminomas and nonseminomas

et al. 2016

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“…Interestingly, the enhanced expression of piwil2 was not seen in human testicular non-seminomas tumors, and the corresponding PIWIL2 isoform is PL2L60A, not PL2L80A [59]. This increased expression of piwil2 in various cancers suggests that PIWIL2 can be a useful prognostic factor with potential diagnostic and therapeutic applications.…”

Section: Piwis May Be Biomarkers For Cancer Diagnosis and Prognosismentioning

confidence: 99%

Emerging roles for PIWI proteins in cancer

Tan¹,

Liu²,

Liao³

et al. 2015

ABBS

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It is generally accepted that PIWI proteins are predominately expressed in the germline but absent in somatic tissues. Their best-characterized role is to suppress transposon expression, which ensures genomic stability in the germline. However, increasing evidence has suggested that PIWI proteins are linked to the hallmarks of cancer defined by Weinberg and Hanahan, such as cell proliferation, anti-apoptosis, genomic instability, invasion and metastasis. This provides new possibilities for anticancer therapies through the targeting of PIWI proteins, which may have fewer side effects due to their potential classification as a CTA (cancer/testis antigen). Furthermore, PIWI has been proposed to act as a diagnostic and prognostic marker for many types of cancer, and even to differentiate early-and late-stage cancers. We herein summarize the latest progress in this exciting field, hoping to encourage new investigations of PIWIs in cancer biology that will help to develop new therapeutics for clinical application.

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“…It plays crucial roles in self-renewal and maintenance of germline stem cells [ 3 , 14 ], transposon repression via methylation [ 15 , 16 ], chromatin remodeling [ 17 , 18 ], biogenesis of piwi-interacting RNA [ 19 ] and translational regulation [ 14 ] in various organisms during development. However, the expression of PIWIL2 has been observed in various types of primary cancers and tumor cell lines [ 1 , 11 ], including breast cancer [ 20 ], cervical cancer [ 21 ], gastric cancer [ 22 ],acute myeloid leukemia [ 23 ], colorectal cancer [ 24 ], colon cancer [ 24 , 25 ], ovarian cancer [ 26 ] and testicular germ cell tumors [ 11 , 27 ], etc.…”

Section: Introductionmentioning

confidence: 99%

“…We and others have found that PIWIL2 has multiple variants including PL2L80, PL2L80A, PL2L60, PL2L60A, PL2L50 and PL2L40. Some of the variants appear to be transcribed by intragenic promoters rather than a canonical promoter [ 1 , 2 , 27 ]. While full length PIWIL2 can mediate DNA repair acting as a barrier gene to the initiation of tumorigenesis and promote apoptotic cell death in tumor tissues [ 1 , 13 , 28 ], its variants such as PL2L60 [ 1 ] and PL2L60A [ 27 ] can promote tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Some of the variants appear to be transcribed by intragenic promoters rather than a canonical promoter [ 1 , 2 , 27 ]. While full length PIWIL2 can mediate DNA repair acting as a barrier gene to the initiation of tumorigenesis and promote apoptotic cell death in tumor tissues [ 1 , 13 , 28 ], its variants such as PL2L60 [ 1 ] and PL2L60A [ 27 ] can promote tumorigenesis. Interestingly, these variants appear not to be derived from canonical splicing of full length mRNAs of PIWIL2 gene rather being directly produced from short form of mRNAs transcribed by putative intragenic promoters in the host gene of PIWIL2 [ 1 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

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An unusual intragenic promoter ofPIWIL2contributes to aberrant activation of oncogenicPL2L60

Liu

et al. 2017

Oncotarget

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PIWIL2-like (PL2L) protein 60 (PL2L60), a product of aberrantly activated PIWIL2 gene, is widely expressed in various types of tumors and may promote tumorigenesis. However, the mechanisms underlying the activation of expression of PL2L60 remain unknown. In this study, an intragenic promoter responsible for the activation of PL2L60 within the human PIWIL2 gene has been identified, cloned and characterized. The promoter of PL2L60 is located in the intron 10 of the host gene PIWIL2. Bioinformatic and mutagenic analysis reveals that this intragenic promoter within the sequence of 50 nucleotides contains two closely arranged cis-acting elements specific for the hepatic leukemia factor (HLF) in the positive strand and signal transducer and activator of transcription 3 (STAT3) in the negative strand. Chromatin immunoprecipitation analysis demonstrates that both the HLF and polymerase II (Pol II), a hallmark of active promoters, directly bind to the sequence, although STAT3 does not. Knockdown of HLF and STAT3 alone or both by RNA interference significantly reduced both promoter activity and the PL2L60 protein expression, although there is no additive effect. The expression of PL2L60 proteins was enhanced when host gene Piwil2 was genetically disrupted in a murine cell model. Taken together, we have identified a PL2L60-specific intragenic promoter in the host gene of PIWIL2, which is interdependently activated by HLF and STAT3 through steric interaction. This activation is dependent on cellular milieu rather than the integrity of host gene PIWIL2, highlighting a novel, important mechanism for a cancer-causing gene to be activated during tumorigenesis.

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Expression Profiles of PIWIL2 Short Isoforms Differ in Testicular Germ Cell Tumors of Various Differentiation Subtypes

Cited by 18 publications

References 88 publications

Distinguishing epigenetic features of preneoplastic testis tissues adjacent to seminomas and nonseminomas

Distinguishing epigenetic features of preneoplastic testis tissues adjacent to seminomas and nonseminomas

Emerging roles for PIWI proteins in cancer

An unusual intragenic promoter ofPIWIL2contributes to aberrant activation of oncogenicPL2L60

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