Dysregulated miR-671-5p / CDR1-AS / CDR1 / VSNL1 axis is involved in glioblastoma multiforme.

MiR-671-5p is encoded by a gene localized at 7q36.1, a region amplified in human glioblastoma multiforme (GBM), the most malignant brain cancer. To investigate whether expression of miR-671-5p were altered in GBM, we analyzed biopsies from a cohort of forty-five GBM patients and from five GBM cell lines. Our data show significant overexpression of miR-671-5p in both biopsies and cell lines. By exploiting specific miRNA mimics and inhibitors, we demonstrated that miR-671-5p overexpression significantly increases migration and to a less extent proliferation rates of GBM cells. Through a combined in silico and in vitro approach, we identified CDR1-AS, CDR1, VSNL1 as downstream miR-671-5p targets in GBM. Expression of these genes significantly decreased both in GBM biopsies and cell lines and negatively correlated with that of miR-671-5p. Based on our data, we propose that the axis miR-671-5p / CDR1-AS / CDR1 / VSNL1 is functionally altered in GBM cells and is involved in the modification of their biopathological profile.

Extragastrointestinal stromal tumor of lesser omentum: a challenging radiological and histological diagnosis.

Extragastrointestinal stromal tumors (EGISTs) are a rare subgroup of gastrointestinal stromal tumors (GISTs), arising from outside the walls of gastrointestinal tubular organs. We report a case of an EGIST of the lesser omentum that represented a diagnostic challenge. Due to its atypical radiologic findings, it was preoperatively mistaken for pedunculated hepatic hemangioma. Histopathologically, it showed epithelioid structure and c-kit negative, very uncommon for GIST. Only a few cases of EGISTs have been previously reported. We discuss imaging and histological features, emphasizing potential pitfalls.

Wilms tumor 1 (WT1) protein: Diagnostic utility in pediatric tumors.

Despite Wilms tumor 1 (WT1) protein was originally considered as a specific immunomarker of Wilms tumor, with the increasing use of immunohistochemistry, there is evidence that other tumors may share WT1 protein expression. This review focuses on the immunohistochemical profile of WT1 protein in the most common malignant tumors of children and adolescents. The variable expression and distribution patterns (nuclear vs cytoplasmic) in the different tumors, dependent on the antibodies used (anti-C or N-terminus WT1 protein), will be emphasized by providing explicative illustrations. Potential diagnostic pitfalls from unexpected WT1 protein expression in some tumors will be discussed in order to avoid diagnostic errors, especially when dealing with small biopsies.

Immunolocalization of Wilms' Tumor protein (WT1) in developing human peripheral sympathetic and gastroenteric nervous system.

Developmental expression of Wilms' tumor gene (WT1) and protein is crucial for cell proliferation, apoptosis, differentiation and cytoskeletal architecture regulation. Recently, a potential role of WT1 has been suggested in the development of neural tissue and in neurodegenerative disorders. We have investigated immunohistochemically the developmentally regulated expression and distribution of WT1 in the human fetal peripheral sympathetic nervous system (PSNS) and the gastro-enteric nervous system (GENS) from weeks 8 to 28 gestational age. WT1 expression was restricted to the cytoplasm of sympathetic neuroblasts, while it progressively disappeared with advancing morphologic differentiation of these cells along both ganglionic and chromaffin cell lineages. In adult tissues, both ganglion and chromaffin cells lacked any WT1 expression. These findings show that WT1 is a reliable marker of human sympathetic neuroblasts, which can be used routinely in formalin-fixed, paraffin-embedded tissues. The progressive loss of WT1 in both ganglion and chromaffin cells, suggests its potential repressor role of differentiation in a precise temporal window during the development of the human PSNS and GENS.

Human ß-defensin 4 expression in Gianotti-Crosti.

The Gianotti-Crosti syndrome is a relatively common children dermatosis characterized by a monomorphous erythematous papular rash limited to the face and extensor surface of the arms and legs. Although the pathogenesis is still unclear, infections are considered as the most important factor. Human ß-defensins are cationic antimicrobial peptides closely related to bacterial and viral infections of many epithelia. We herein report a case of Gianotti-Crosti syndrome in a 7-year-old Caucasian girl presented with prominent eruption consisting of dome-shaped lichenoid papules on her upper and lower extremities, with spontaneous resolution. Skin biopsy revealed a dense lichenoid lymphohistiocytic infiltrate and showed strong cytoplasmic immunopositivity for human ß-defensin-4 in the stratum corneum, stratum granulosum, and stratum spinosum. Considering that ß-defensins have been described to be induced by infections, we investigated the expression of human ß-defensin-4 by immunohistochemistry in a case of Gianotti-Crosti syndrome, in order to demonstrate that it represents a cutaneous response to skin infections.

Expression of BMI1 and p16 in laryngeal squamous cell carcinoma.

BACKGROUND: The clinical evolution of laryngeal squamous cell carcinoma (SCC) is undetectable with the current staging criteria. To more completely understand the biology of laryngeal SCC, we assessed the expression of the proteins B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and p16. METHODS: We assessed immunohistochemically the expression of BMI1 and p16 in 25 laryngeal SCCs at different stages. RESULTS: High BMI1 expression was detected in 11.7% of glottic tumors and in 50% of supraglottic tumors. No significant differences were observed in the patients' clinical data after they were stratified by the tumor expression of p16. The expression of nuclear BMI1 in the absence of p16 immunoreactivity correlated significantly with the pN status of the primary tumors. CONCLUSION: Nuclear BMI1 expression in the absence of p16 expression seems to characterize a subset of patients with a high risk of developing lymph node metastasis.

Nuclear BMI-1 expression in laryngeal carcinoma correlates with lymph node pathological status.

BACKGROUND: The main cause of treatment failure and death in laryngeal squamous cell carcinoma is metastasis to the regional lymph nodes. The current clinical staging criteria fail to differentiate patients with occult metastasis from patients without metastasis. Identifying molecular markers of the disease might improve our understanding of the molecular mechanisms underlying the pathogenesis and development of laryngeal carcinoma and may help improve clinical staging and treatment. METHODS: Sixty-four previously untreated patients who underwent surgical excision of laryngeal squamous cell carcinoma with neck dissection were included in this study. The expression of B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) was examined immunohistochemically on formalin-fixed paraffin-embedded primary tissue specimens. RESULTS: Nuclear expression of BMI-1 (nBMI-1) was detected in 32 of the 64 tumors (50%), cytoplasmic expression of BMI-1 (cBMI-1) was detected in 22 (34.4%), and 10 tumors (15.6%) showed no BMI-1 immunoreactivity. High nBMI-1 expression levels (≥ 10) were detected in 28 of the 32 (87.5%) nBMI-1-positive patients. Multivariate analysis including age at diagnosis, grade, tumor location, TNM status, and nBMI-1 expression showed that a high nBMI-1 expression level was an independent prognostic factor for lymph node metastasis. CONCLUSION: The expression of BMI-1 in patients with laryngeal carcinoma seems to correlate with lymph node metastasis.

Specific alterations of the microRNA transcriptome and global network structure in colorectal cancer after treatment with MAPK/ERK inhibitors.

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has a master control role in various cancer-related biological processes as cell growth, proliferation, differentiation, migration, and apoptosis. It also regulates many transcription factors that control microRNAs (miRNAs) and their biosynthetic machinery. To investigate on the still poorly characterised global involvement of miRNAs within the pathway, we profiled the expression of 745 miRNAs in three colorectal cancer (CRC) cell lines after blocking the pathway with three different inhibitors. This allowed the identification of two classes of post-treatment differentially expressed (DE) miRNAs: (1) common DE miRNAs in all CRC lines after treatment with a specific inhibitor (class A); (2) DE miRNAs in a single CRC line after treatment with all three inhibitors (class B). By determining the molecular targets, biological roles, network position of chosen miRNAs from class A (miR-372, miR-663b, miR-1226*) and class B (miR-92a-1*, miR-135b*, miR-720), we experimentally demonstrated that they are involved in cell proliferation, migration, apoptosis, and globally affect the regulation circuits centred on MAPK/ERK signaling. Interestingly, the levels of miR-92a-1*, miR-135b*, miR-372, miR-720 are significantly higher in biopsies from CRC patients than in normal controls; they also are significantly higher in CRC patients with mutated KRAS than in those with wild-type genotypes (Wilcoxon test, p < 0.05): the latter could be a downstream effect of ERK pathway overactivation, triggered by KRAS mutations. Finally, our functional data strongly suggest the following miRNA/target pairs: miR-92a-1*/PTEN-SOCS5; miR-135b*/LATS2; miR-372/TXNIP; miR-663b/CCND2. Altogether, these results contribute to deepen current knowledge on still uncharacterized features of MAPK/ERK pathway, pinpointing new oncomiRs in CRC and allowing their translation into clinical practice and CRC therapy.

Unusual clinical and pathological features in pemphigus vulgaris: a potential diagnostic pitfall.

We describe the case of a 67-year-old woman affected by pemphigus vulgaris with a dry whitish scaly lesion in the upper lip. Clinically, this lesion resembled an actinic keratosis. Although histological examination revealed a focal acantholysis, the finding of a moderate-to-severe dysplastic epithelium was consistent with the diagnosis of acantholytic actinic keratosis with moderate/severe dysplasia. Nevertheless, the complete resolution of the lip lesion after systemic therapy for pemphigus vulgaris led us to reconsider the possibility that we were dealing with a pemphigus vulgaris with unusual clinical and histological features. The previously reported cytological dysplasia was better regarded reactive rather than neoplastic, likely as the result to the inflammatory injury.

Post-traumatic inflammatory pseudotumor of the breast with atypical morphological features: A potential diagnostic pitfall. Report of a case and a critical review of the literature.

Although inflammatory pseudotumor (IPT) and inflammatory myofibroblastic tumor (IMT) may share a common morphology, they are distinct clinico-pathologic entities. Unfortunately, the terms IMT and IPT are still used interchangeably, especially when lesions occur in unusual sites, including breast. All the cases of IMT/IPT involving the breast have raised spontaneously without any apparent prior injury. We herein report the first case of a post-traumatic IPT of the breast parenchyma in a 22-year-old male. Histologically, the lesion was highly cellular and composed of spindle cells arranged in a predominant fascicular pattern. Notably, mono- or multi-nucleated large pleomorphic cells were observed. Inflammatory cells, especially plasma cells and lymphocytes, were closely admixed with the spindle cell proliferation. The overall picture was reminiscent of an "IMT with atypical features", typically seen in lung, abdomen, pelvis, and retroperitoneum of children. Immunohistochemically, the spindle-shaped and large pleomorphic cells were immunoreactive to vimentin, α-smooth muscle actin, and desmin. No immunoreactivity was obtained with ALK-1 protein. The present case contributes to widening the morphological spectrum of IPT of the breast, emphasizing the possibility that a reactive lesion may contain large pleomorphic cells that may represent a potential diagnostic pitfall. Lastly, we suggest that the diagnosis of IMT of the breast should be rendered with caution when dealing with ALK-negative spindle cell lesions in adult patients, and alternative diagnoses, including IPT, should be seriously considered.

Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment.

The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.