microRNA Portraits in Human Vulvar Carcinoma

Maia, Beatriz de Melo; Lavorato-Rocha, André Mourão; Rodrigues, Lara Sant Ana; Coutinho‐Camillo, Cláudia Malheiros; Baiocchi, Glauco; Stiepcich, Monica Maria; Puga, Renato; Lima, Leandro; Soares, Fernando Augusto

doi:10.1158/1940-6207.capr-13-0121

Cited by 24 publications

(27 citation statements)

References 38 publications

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“…Nevertheless, many of the miR expression changes detected in HPV16 E6/E7-expressing HFKs were also observed in HPV + head and neck squamous cell carcinoma cell lines (44) and tumors (45). We also observed changes in miR expression that have been detected in HPV + anal carcinomas (46), vulvar cancers (47), and penile squamous cell carcinoma (48). A comparison of our data to miR expression in HPV-associated human biopsy specimens are detailed in Tables S8 and S9.…”

Section: Discussionsupporting

confidence: 53%

Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

Harden

Prasad

Griffiths

et al. 2017

mBio

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The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects the expression of cellular noncoding RNAs. The goal of our study was to investigate HPV16 E6/E7 modulation of cellular microRNA (miR) levels and to determine the potential consequences for cellular gene expression. We performed deep sequencing of small and large cellular RNAs in primary undifferentiated cultures of human foreskin keratinocytes (HFKs) with stable expression of HPV16 E6/E7 or a control vector. After integration of the two data sets, we identified 51 differentially expressed cellular miRs associated with the modulation of 1,456 potential target mRNAs in HPV16 E6/E7-expressing HFKs. We discovered that the degree of differential miR expression in HFKs expressing HPV16 E6/E7 was not necessarily predictive of the number of corresponding mRNA targets or the potential impact on gene expression. Additional analyses of the identified miR-mRNA pairs suggest modulation of specific biological activities and biochemical pathways. Overall, our study supports the model that perturbation of cellular miR expression by HPV16 E6/E7 importantly contributes to the rewiring of cellular regulatory circuits by the high-risk HPV E6 and E7 proteins that contribute to oncogenic transformation.

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Section: Discussionsupporting

confidence: 53%

Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

Harden

Prasad

Griffiths

et al. 2017

mBio

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“…The first mention of microRNA differential expression in vulvar cancer was provided by our group on a previous study [18] and miR-223-5p appeared as an important microRNA associated with metastasis in HPV negative vulvar samples. In fact, miR-223 arose as a recognized tumor invasiveness and metastasis predictor in several tumor types: its expression was correlated with metastasis in breast [19], gastric [20], colorectal [24] and hepatocellular [25] carcinomas, and osteosarcoma [26].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, our group demonstrated that altered expression of miR-223-5p was associated to the presence of nodal metastasis in patients with vulvar cancer [18]. In fact, this microRNA has emerged as a putative predictor of tumor invasiveness and metastasis, [19–21] as well as recurrence [22, 23] in many tumor types.…”

Section: Introductionmentioning

confidence: 99%

MiR-223-5p works as an oncomiR in vulvar carcinoma byTP63suppression

et al. 2016

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MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation (p < 0.01) and migration (p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified (p < 0.004). In silico search indicated that miR-223-5p targets TP63, member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients (p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion (p = 0.0491) and lower patient overall survival (p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.

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“…While miRNA 133a has been suggested as a marker in cardiac disease [29], in most studies it was analyzed in malignant tumors (ovary [30]; vulvar carcinoma [31]; breast [32]). Here, conflicting results were reported, associating miRNA 133a as either a tumor suppressor [30] or a tumor promoter [31]. …”

Section: Discussionmentioning

confidence: 99%

ET-1 Induced Downregulation of MRP2 via miRNA 133a - A Marker for Tubular Nephrotoxicity?

Löser¹,

Brandenstein²,

Herschung³

et al. 2015

Am J Nephrol

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Background: Multiple drug resistance (MDR), known from treating malignant tumors with chemotherapy, increases the efflux of reabsorbed reagents in tumor cells. This mechanism has been reported in the renal proximal tubule and may prevent therapeutic tubular protection in proteinuria. Since endothelin-1 (ET-1), a major component in the urine of proteinuric patients, stimulates proximal tubules, its influence on MDR was analyzed with emphasis on the multidrug resistance-associated protein 2 (MRP2), a prominent transporter in the human proximal tubule and microRNA (miRNA) 133a. Methods: ET-1 stimulated, cultured human renal proximal tubule cells (RPTECs), were analyzed via Western blot for the expression of MRP2 and via qRT-PCR for miRNA 133a. For direct interaction between the miRNA 133a and the 3′UTR of MRP2, an immunoprecipitation was performed using FITC-labelled miRNA 133a as capture, followed by MRP2 PCR analysis and Sanger sequencing. Murine Adriamycin nephropathic model and human proteinuric samples showed high levels of miRNA 133a but low levels of MRP2. The increasing miRNA 133a levels were detectable in urine samples of humans and animals. Results: ET-1 activates the miRNA 133a, which can bind to the 3′UTR of MRP2 and is therefore responsible for the detectable decrease of MRP2. Conclusion: This is the first report to analyze the correlation between ET-1-induced miRNA 133a overexpression in proteinuria resulting in MRP2 downregulation, which is a contributing factor for renal cytotoxicity. The detection of the miRNA 133a in urine samples can be possibly used as a monitor for cytotoxicity.

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microRNA Portraits in Human Vulvar Carcinoma

Cited by 24 publications

References 38 publications

Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

MiR-223-5p works as an oncomiR in vulvar carcinoma byTP63suppression

ET-1 Induced Downregulation of MRP2 via miRNA 133a - A Marker for Tubular Nephrotoxicity?

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