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Several studies have demonstrated that the p75NTR low-affinity receptor of Nerve Growth Factor (NGF), is produced in abnormally large amounts in several human cancer types. However, the role of p75NTR varies substantially depending on cell context, so that a dual role of this receptor protein in tumor cell survival and invasion, as well as cell death, has been supported in recent studies. Herein we explored for the first time the expression of p75NTR in human specimens (nr = 40) from testicular germ cell tumors (TGCTs), mostly seminomas. Nuclear overexpression of p75NTR was detected by immunohistochemistry in seminoma tissue as compared to normal tissue, whereas neither NGF nor its high-affinity TrkA receptor was detected. An increased nuclear staining of phospho-JNK, belonging to the p75NTR signaling pathway and its pro-apoptotic target gene, p53, was concomitantly observed. Interestingly, our analysis revealed that decreased expression frequency of p75NTR, p-JNK and p53 was related to staging progression, thus suggesting that p75NTR may represent a specific marker for seminoma and staging in TGCTs.

Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still open questions. Herein, we investigated the functional significance of the oncogenic lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in MM. Our study demonstrates that NEAT1 expression level is higher in MM than in the majority of hematological malignancies. NEAT1 silencing by novel LNA-gapmeR antisense oligonucleotide inhibits MM cell proliferation and triggers apoptosis in vitro and in vivo murine MM model as well. By transcriptome analyses, we found that NEAT1 targeting downregulates genes involved in DNA repair processes including the Homologous Recombination pathway, which in turn results in massive DNA damage. These findings may explain the synergistic impact on apoptosis observed in MM cell lines co-treated with inhibitors of both NEAT1 and PARP. The translational significance of NEAT1 targeting is further underlined by its synergistic effects with the most common drugs administered for MM treatment, including bortezomib, carfilzomib, and melphalan. Overall, NEAT1 silencing is associated with a chemo-sensitizing effect of both conventional and novel therapies, and its targeting could therefore represent a promising strategy for novel anti-MM therapeutic options.

Lung cancer is the leading cause of cancer-related mortality around the world (Molina et al. 2008), but many problems concerning its therapy and diagnosis are at present unsolved. A series of reports have focused attention on the potential role of the ubiquitin-mediated proteolysis and ubiquitin- conjugating enzyme (UbcH10) in cell cycle regulation and malignant transformation (Wagner et al. 2004; Pallante et al. 2005; Berlingieri, Pallante, Sboner, et al. 2007; Berlingieri, Pallante, Guida, et al. 2007; Donato et al. 2008). Pulmonary tumors are among neoplasms believed to be triggered and regulated in their growth from high levels of UbcH10 (van Ree et al. 2010). Recently, proteasome inhibitors have been developed as therapeutic agents in cancer therapy (Rossi et al. 2005; Orlowski and Kuhn 2008; Testa 2009; Crawford et al. 2011), and several phase I and phase II clinical trials in non–small cell and small cell lung cancer are in progress (Bunn 2004; Li et al. 2010; Escobar et al. 2011). Paradoxically, the role of UbcH10 in human lung cancer is not yet well explored, and very little is known regarding the histopathological and immunohistochemical pattern of UbcH10 in the most important subtypes of lung cancer. To extend the knowledge about the relationship between lung cancer and UbcH10 and to better define the diagnostic and prognostic potentials of UbcH10 on histologic and/or cytologic specimens, we have evaluated the expression profile of the enzyme in normal lung tissue, low-grade and high-grade lung carcinomas, and pleural effusions. We suggest that a tailored lung cancer treatment might require, in the future, a preliminary study of the expression of UbcH10 by a simple immunohistochemical or immunocytochemical analysis.

Myxomas are the most frequent primary cardiac neoplasms. They have an abundant extracellular matrix rich in proteoglycans. Interactions between cells and matrix are very important in the development of tumors, but data about myxomas in this setting are scarce because of the rarity of such neoplasms. The expression of tenascin-c and hyaluran receptors in cardiac myxoma has never been investigated. Moreover, it is now well recognized that cells of cardiac myxoma differentiate along endothelial lines.We have analyzed left atrial myxomas from 13 consecutive patients (six male and seven female, surgically treated), via immunohistochemical methods for the expression of molecules also implicated in angiogenesis in normal and pathological conditions, like tenascin-c and hyaluran receptors CD44s, CD44v5 and CD44v6.Our data suggest that tenascin-c and CD44s play a synergic and perhaps complementary role in development of cardiac myxomas. In particular, tenascin-c seems to promote aggregation of cells and differentiation in vascular structures, whereas CD44s receptors might be important for cellular motility. Cell proliferation rate in such tumors was very low (MIB-1 labeling index1%) and uniform in all the areas of the neoplasms regardless of the presence of characteristic structures such as cords and rings of multinucleated cells or the expression of tenascin-c and CD44 receptors.This study shows that cardiac myxomas express in the extracellular matrix tenascin-c and on the cellular membranes of neoplastic cells the hyaluran receptor CD44s. Such molecules take part in the mechanism of development of the myxomas and might be in the future the target of nonsurgical treatments.

Previous studies suggest the expression of UbcH10 gene, that codes for a protein belonging to the ubiquitin-conjugating enzyme family, as a valid indicator of the proliferative and aggressive status of tumors of different origin. Therefore, to look for possible tools to be used as diagnostic markers in astrocytic neoplasias, we investigated UbcH10 expression in normal brain, gliosis and low-grade and high-grade astrocytic tumors by immunohistochemistry. UbcH10 expression was observed in low-grade astrocytoma and in glioblastoma. Our data indicate a clear correlation between UbcH10 expression and the histological grade of the astrocytic tumors. Moreover, the analysis of UbcH10 expression allows the differentiation between gliotic and malignant tissues. Finally, since proteasome inhibitors have recently been considered as possible drugs in the chemotherapy of various tumors, our results would suggest new perspectives for the treatment of brain malignancies based on the suppression of the UbcH10 function.

Glioblastoma is one of the most aggressive tumors in mankind with 50% of patients dying within the 1st year of diagnosis, and being refractory to conventional therapies. The aim of our work has been to analyse the expression of the HMGA1 proteins in human astrocytomas and glioblastomas in order to verify whether the detection of these proteins might be of some help in the diagnosis of these neoplasias. Here we report the analysis of 27 cases, including 12 astrocytomas and 15 glioblastomas, for HMGA1 expression. All the neoplastic samples showed positive staining even though the number of positive cells and the staining intensity was higher in glioblastomas compared to astrocytomas. Conversely, HMGA1 proteins were not detected in normal brain. Accordingly, expression of the hmga1 gene, analysed by RT-PCR, was higher in glioblastomas than in astrocytomas.

Recent studies suggest that in patients with carpal tunnel syndrome, pathological changes occur in the subsynovial connective tissue. Such changes are non-inflammatory synovial fibrosis and vascular proliferation. Thickening of the tendon sheet may cause an increase of canal pressure and damages to the median nerve in the wrist; however, the causes of such events still remain to be clarified. We examined synovial specimens from 26 patients operated on for idiopathic carpal tunnel syndrome. Analysis included histological, ultrastructural and immunohistochemical examination in order to establish a pathological underlying pattern. An explanation for the pathogenesis of the found changes suggested. Our data confirm the presence of a non-inflammatory fibrosis with irregular bundles of collagen. De novo blood vessel formation was also noted. Interestingly the neo-angiogenesis consists of anomalous vessels and may be triggered from various cell types secreting vascular endothelial growth factor (VEGF), including macrophage-like elements similar to endothelial progenitor cells. Therefore, we believe that in the future a non-surgical management of carpal tunnel syndrome might be conjecturable via anti-VEGF drugs.