Integrated Loss of miR-1/miR-101/miR-204 Discriminates Metastatic from Nonmetastatic Penile Carcinomas and Can Predict Patient Outcome

Hartz, Juliane M.; Engelmann, David; Fürst, Katharina; Marquardt, Stephan; Spitschak, Alf; Goody, Deborah; Protzel, Chris; Hakenberg, Oliver W.; Pützer, Brigitte M.

doi:10.1016/j.juro.2016.01.115

Cited by 27 publications

(24 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[45] showed that hsa-miR-145 overexpression altered MMP1 and MMP9 mRNA and protein levels, with subsequent inhibition of invasion, metastasis and angiogenesis in gastric cancer cells. Although some prognostic molecular makers have been reported in PeCa, the stratification of the patients is currently based on clinical and histopathological features [11, 31, 39, 46, 47]. In the present study, MMP1 showed superior performance in discriminate lymph node metastasis in PeCa compared with established clinical-pathological parameters.…”

Section: Discussionmentioning

confidence: 55%

“…The overall five-year survival in patients with lymph node metastasis is 27% [10]. Novel molecular markers in association with lymph node metastasis [11], disease free survival or overall survival [12–14], recurrence and perineural invasion [15] have been described in PeCa. However, to date, none of them are used in the clinical practice to predict lymph node metastasis and prognosis.…”

Section: Introductionmentioning

confidence: 99%

“…Hartz et al . [11] reported a miRNA-based signature associated with unfavorable prognosis in 24 PeCa and concomitant inguinal lymph node metastasis. Although these studies have contributed to our understanding of the disease, none have described an integrated analysis using miRNA and mRNA data in matched samples.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

et al. 2017

View full text Add to dashboard Cite

Penile carcinoma (PeCa) is an important public health issue in poor and developing countries, and has only recently been explored in terms of genetic and epigenetic studies. Integrative data analysis is a powerful method for the identification of molecular drivers involved in cancer development and progression. miRNA and mRNA expression profiles followed by integrative analysis were investigated in 23 PeCa and 12 non-neoplastic penile tissues (NPT). Expression levels of eight miRNAs and 10 mRNAs were evaluated in the same set of samples used for microarray and in a validation set of cases (PeCa = 36; NPT = 27). Eighty-one miRNAs and 2,697 mRNAs were identified as differentially expressed in PeCa. Integrative data analysis revealed 255 mRNAs potentially regulated by 68 miRNAs. Using RT-qPCR, eight miRNAs and nine transcripts were confirmed as altered in PeCa. We identified that MMP1, MMP12 and PPARG and hsa-miR-31-5p, hsa-miR-224-5p, and hsa-miR-223-3p were able to distinguish tumors from NPT with high sensitivity and specificity. Higher MMP1 expression was detected as a better predictor of lymph node metastasis than the clinical-pathological data. In addition, PPARG and EGFR were highlighted as potential pathways for targeted therapy in PeCa. The analysis based on HPV positivity (7 of 23 cases) revealed five miRNA and 13 mRNA differentially expressed. Although in a limited number of cases, HPV positive PeCa presented less aggressive phenotype in comparison with negative cases. Overall, an integrative analysis using mRNA and miRNA profiles revealed markers related with tumor development and progression. Furthermore, MMP1 expression level was a predictive marker for lymph node metastasis in patients with PeCa.

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

et al. 2017

View full text Add to dashboard Cite

show abstract

“…1,11,12 Other molecular mechanisms have been described, including new targets of E6 and E7 oncoproteins, which might interact or modulate the activity of proteins involved in the epigenetic regulation or in the differential expression of host cell miRNAs. [13][14][15][16][17] In parallel, the chronic inflammatory process has been investigated as a risk factor to PeCa, which can be triggered by phimosis, lichen sclerosus, and balanitis. [18][19][20][21] This process can provide a favorable microenvironment for malignant cell transformation and progression due to the release of reactive oxygen or nitrogen species, as well due to the extensive tissue damage and remodeling that is mediated by the immune system cells.…”

mentioning

confidence: 99%

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Macedo

Silva

Nogueira³

et al. 2020

Molecular Carcinogenesis

View full text Add to dashboard Cite

The incidence of penile cancer (PeCa) is increasing worldwide, however, the highest rates are reported in underdeveloped countries. The molecular mechanisms that underly the onset and progression of these tumors are still unclear. Therefore, our goal was to determine the genome-wide copy number alterations and the involvement of human papiloma virus (HPV) (TP53 and RB1), inflammatory (COX2 and EGFR), and PI3K/AKT pathway (AKT1, AKT2, EGFR, ERBB3, ERBB4, PIK3CA, and PTEN) associated genes in patients with PeCa from a high incidence region in Brazil (Maranhão). HPV genotyping was performed by nest-PCR and genome sequencing, copy number alterations (CNAs) by array comparative genomic hybridization and gene copy number status, gene, and protein expression by quantitative polymerase chain reaction, reverse transcriptasequantitative polymerase chain reaction, and immunohistochemistry, respectively.HPV genotyping revealed one of the highest frequencies of HPV reported in PeCa, affecting 96.4% of the cases. The most common CNAs observed were located at the HPV integration sites, such as 2p12-p11.2 and 14q32.33, where Abbreviations: aCGH, array comparative genomic hybridization; CNA, copy number alteration; Cq, quantification cycle; FFPE, formalin-fixed paraffin-embedded; HPV, human papiloma virus;HrHPV, High risk HPV; IHCi, mmunohistochemistry; PCR, polymerase chain reaction; PeCa, penile cancer; qPCR, quantitative polymerase chain reaction; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction; TMA, tissue microarray. ADAM 6, KIAA0125, LINC00226, LINC00221, and miR7641-2, are mapped. Increased copy number of ERBB3 and EGFR genes were observed in association with COX2 and EGFR overexpression, reinforcing the role of the inflammatory pathway in PeCa, and suggesting anti-EGFR and anti-COX2 inhibitors as promising therapies for PeCa. Additionally, TP53 and RB1 messenger RNA downregulation was observed, suggesting the occurrence of other mechanisms for repression of these oncoproteins, in addition to the canonical HPV/TP53/RB1 signaling pathway. Our data reinforce the role of epigenetic events in abnormal gene expression in HPV-associated carcinomas and suggest the pivotal role of HPV driving CNAs and controlling gene expression in PeCa. K E Y W O R D Scarcinoma of the penis, genomic alterations, human papillomavirus, molecular markers

show abstract

“…Molecular alterations in PeCa have been described only recently by our group and others [19,[21][22][23][24][25][26][27][28][29][30]. Interestingly, contrary to the findings described in breast and prostate cancers, AR mRNA is down-expressed in PeCa [19].…”

Section: Introductionmentioning

confidence: 63%

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

et al. 2018

View full text Add to dashboard Cite

Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.

show abstract

Integrated Loss of miR-1/miR-101/miR-204 Discriminates Metastatic from Nonmetastatic Penile Carcinomas and Can Predict Patient Outcome

Cited by 27 publications

References 30 publications

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

Contact Info

Product

Resources

About