Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis

Furuya, Tatiane Katsue; Murta, Cláudio Bovolenta; Carrasco, Alexis Germán Murillo; Uno, Miyuki; Sichero, Laura; Villa, Luísa Lina; Cardilli, Leonardo; Coelho, Rafael F.; Guglielmetti, Giuliano; Cordeiro, Maurício; Leite, Kátia Ramos Moreira; Nahas, William Carlos; Chammas, Roger; Pontes, José

doi:10.3390/cancers13194745

Cited by 5 publications

(5 citation statements)

References 49 publications

(70 reference statements)

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“…At the analysis time, ten patients (41.7%) had died from any cause, and seven (29.2%) due to PeC. HPV DNA was detected in tumors from eight patients (33.3%) as described in our previous study [14].…”

Section: Description Of the Samplesupporting

confidence: 57%

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miRNA and mRNA Expression Profiles Associated with Lymph Node Metastasis and Prognosis in Penile Carcinoma

Murta

Furuya

Carrasco

et al. 2022

IJMS

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Penile cancer (PeC) is a rare disease, and no prognostic biomarkers have been adopted in clinical practice yet. The objective of the present study was to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) as potential biomarkers for lymph node metastasis and other prognostic factors in PeC. Tumor samples were prospectively obtained from 24 patients with squamous cell carcinoma of the penis. miRNA microarray analysis was performed comparing tumors from patients with inguinal lymph node metastatic and localized disease, and the results were validated by qRT-PCR. Eighty-three gene expression levels were also compared between groups through qRT-PCR. Moreover, DEmiRs and DEGs expression levels were correlated with clinicopathological variables, cancer-specific (CSS), and overall survival (OS). TAC software, TM4 MeV 4.9 software, SPSS v.25.0, and R software v.4.0.2 were used for statistical analyses. We identified 21 DEmiRs in microarray analysis, and seven were selected for validation. miR-744-5p and miR-421 were overexpressed in tissue samples of metastatic patients, and high expression of miR-421 was also associated with lower OS. We found seven DEGs (CCND1, EGFR, ENTPD5, HOXA10, IGF1R, MYC, and SNAI2) related to metastatic disease. A significant association was found between increased MMP1 expression and tumor size, grade, pathological T stage, and perineural invasion. Other genes were also associated with clinicopathological variables, CSS and OS. Finally, we found changes in mRNA–miRNA regulation that contribute to understanding the mechanisms involved in tumor progression. Therefore, we identified miRNA and mRNA expression profiles as potential biomarkers associated with lymph node metastasis and prognosis in PeC, in addition to disruption in mRNA–miRNA regulation during disease progression.

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Section: Description Of the Samplesupporting

confidence: 57%

“…Recently, epigenetic alterations have emerged to provide insights into the carcinogenesis of PeC, with a special focus on microRNAs (miRNAs) [8][9][10][11][12][13][14]. However, few studies have focused on the prognostic value of miRNA expression in PeC.…”

Section: Introductionmentioning

confidence: 99%

miRNA and mRNA Expression Profiles Associated with Lymph Node Metastasis and Prognosis in Penile Carcinoma

Murta

Furuya

Carrasco

et al. 2022

IJMS

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“…Although not all the cases presented with expression alterations in these genes, these results were recently corroborated by Furuya et al, who also described TP53 reduced expression levels in penile tumors. Compared to other cancers (Santos et al, 2018;Datta et al, 2019;Hussen et al, 2021;Liu et al, 2021), few studies have described epigenetic events in penile tumors, whether evaluating miRNAs (Zhang et al, 2015;Hartz et al, 2016;Kuasne et al, 2017;Peta et al, 2017;Ayoubian et al, 2021;Furuya et al, 2021) or by evaluating methylation patterns (Feber et al, 2015;Kuasne et al, 2015;Marchi et al, 2017). Changes by both mechanisms could justify the downregulation of TP53 and RB1, however only RB1 has been reported to be hypermethylated (Marchi et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, as most pathogenic variants of these genes have been described in coding regions, the mRNA downregulation of TP53 and RB1 does not appear to be due to mutations (Feber et al, 2016;Wang et al, 2019;Chahoud et al, 2021). Furthermore, few studies have evaluated patients' cohorts with a high incidence of HPV infection, remaining poorly known the impact of HPV infection in disrupting mRNA/miRNA networks in penile tumors (Zhang et al, 2015;Hartz et al, 2016;Kuasne et al, 2017;Ayoubian et al, 2021;Furuya et al, 2021). In the present study, our main goal was to determine whether altered miRNAs expression could be associated with the downregulation of the TP53 and RB1 expression in the etiopathogenesis of HPV-associated PeCa.…”

Section: Discussionmentioning

confidence: 99%

Upregulated miRNAs on the TP53 and RB1 Binding Seedless Regions in High-Risk HPV-Associated Penile Cancer

et al. 2022

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Cancer development by the human papillomavirus (HPV) infection can occur through the canonical HPV/p53/RB1 pathway mediated by the E2/E6/E7 viral oncoproteins. During the transformation process, HPV inserts its genetic material into host Integration Sites (IS), affecting coding genes and miRNAs. In penile cancer (PeCa) there is limited data on the miRNAs that regulate mRNA targets associated with HPV, such as the TP53 and RB1 genes. Considering the high frequency of HPV infection in PeCa patients in Northeast Brazil, global miRNA expression profiling was performed in high-risk HPV-associated PeCa that presented with TP53 and RB1 mRNA downregulated expression. The miRNA expression profile of 22 PeCa tissue samples and five non-tumor penile tissues showed 507 differentially expressed miRNAs: 494 downregulated and 13 upregulated (let-7a-5p, miR-130a-3p, miR-142-3p, miR-15b-5p miR-16-5p, miR-200c-3p, miR-205-5p, miR-21-5p, miR-223-3p, miR-22-3p, miR-25-3p, miR-31-5p and miR-93-5p), of which 11 were identified to be in HPV16-IS and targeting TP53 and RB1 genes. One hundred and thirty-one and 490 miRNA binding sites were observed for TP53 and RB1, respectively, most of which were in seedless regions. These findings suggest that up-regulation of miRNA expression can directly repress TP53 and RB1 expression by their binding sites in the non-canonical seedless regions.

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“…Using miRNA-mRNA tumor expression data, we identified deregulated miRNA that was validated in the regulatory networks of the four target genes. Some miRNAs found in our analysis that regulate MYOC , KCNQ5 , MUC1 , and F3 mRNAs has been also described in other cancers, such as colorectal cancer cells [ 103 ] and identified as biomarkers in lung cancer [ 104 ], osteosarcoma [ 105 ], ovarian cancer [ 106 ] and penile cancer [ 107 ].…”

Section: Discussionmentioning

confidence: 57%

Prostate Cancer Secretome and Membrane Proteome from Pten Conditional Knockout Mice Identify Potential Biomarkers for Disease Progression

Santos

Camargo

Carvalho

et al. 2022

IJMS

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Prostate cancer (PCa) is the second most common cause of mortality among men. Tumor secretome is a promising strategy for understanding the biology of tumor cells and providing markers for disease progression and patient outcomes. Here, transcriptomic-based secretome analysis was performed on the PCa tumor transcriptome of Genetically Engineered Mouse Model (GEMM) Pb-Cre4/Ptenf/f mice to identify potentially secreted and membrane proteins—PSPs and PMPs. We combined a selection of transcripts from the GSE 94574 dataset and a list of protein-coding genes of the secretome and membrane proteome datasets using the Human Protein Atlas Secretome. Notably, nine deregulated PMPs and PSPs were identified in PCa (DMPK, PLN, KCNQ5, KCNQ4, MYOC, WIF1, BMP7, F3, and MUC1). We verified the gene expression patterns of Differentially Expressed Genes (DEGs) in normal and tumoral human samples using the GEPIA tool. DMPK, KCNQ4, and WIF1 targets were downregulated in PCa samples and in the GSE dataset. A significant association between shorter survival and KCNQ4, PLN, WIF1, and F3 expression was detected in the MSKCC dataset. We further identified six validated miRNAs (mmu-miR-6962-3p, mmu-miR- 6989-3p, mmu-miR-6998-3p, mmu-miR-5627-5p, mmu-miR-15a-3p, and mmu-miR-6922-3p) interactions that target MYOC, KCNQ5, MUC1, and F3. We have characterized the PCa secretome and membrane proteome and have spotted new dysregulated target candidates in PCa.

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Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis

Cited by 5 publications

References 49 publications

miRNA and mRNA Expression Profiles Associated with Lymph Node Metastasis and Prognosis in Penile Carcinoma

miRNA and mRNA Expression Profiles Associated with Lymph Node Metastasis and Prognosis in Penile Carcinoma

Upregulated miRNAs on the TP53 and RB1 Binding Seedless Regions in High-Risk HPV-Associated Penile Cancer

Prostate Cancer Secretome and Membrane Proteome from Pten Conditional Knockout Mice Identify Potential Biomarkers for Disease Progression

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