A case of ganglioglioma grade 3 with H3 K27M mutation arising in the medial temporal lobe in an elderly patient.

The mutation p.K27M in H3F3A (H3 K27M mutation) is mainly detected in diffuse midline glioma. However, recent studies have demonstrated that H3 K27M mutation could also be observed in a subset of gangliogliomas. Importantly, most H3 K27-mutated ganglioglioma cases also harbor BRAF V600E mutation. Herein, we report a rare case of H3 K27M-mutated ganglioglioma grade 3 without BRAF mutation arising in the medial temporal lobe in an elderly man. A small biopsy specimen was sampled. The pathological diagnosis was diffuse astrocytoma. The tumor progressed gradually during an 18-month follow-up period. Gadolinium enhancement on magnetic resonance imaging was noted 36 months after the biopsy. The patient was referred to a hospital for tumor resection. Histological analysis of resected specimens led to a diagnosis of ganglioglioma grade 3 with H3 K27M mutation. The patient underwent concurrent temozolomide chemotherapy with radiotherapy. Although the patient's condition deteriorated after chemotherapy due to disease progression, he survived for more than 23 months after tumor resection. We present this rare case and discuss the involvement of H3 K27M mutation in ganglioglioma grade 3.

Downregulation of lncRNA PVT1 inhibits proliferation and migration of mesothelioma cells by targeting FOXM1.

Malignant mesothelioma is a highly aggressive tumor, and an effective strategy for its treatment is not yet available. Long non­coding RNAs (lncRNAs) have been reported to be associated with various biological processes, including the regulation of gene expression of cancer­related pathways. Among various lncRNAs, plasmacytoma variant translocation 1 (PVT1) acts as a tumor promoter in several human cancers, but its mechanism of action has not yet been elucidated. Increased PVT1 expression was identified in ACC­MESO­1, ACC­MESO­4, CRL­5915, and CRL­5946 mesothelioma cell lines. PVT1 expression was investigated in mesothelioma cell lines by reverse transcription­quantitative polymerase chain reaction and its functional analysis by cell proliferation, cell cycle, cell migration, and cell invasion assays, as well as western blot analysis of downstream target genes. Knockdown of PVT1 expression in these cell lines by small interfering RNA transfection resulted in decreased cell proliferation and migration and increased the proportion of cells in the G2/M phase. The results of reverse transcription­quantitative polymerase chain reaction analysis revealed that PVT1 knockdown in mesothelioma cell lines caused the downregulation of Forkhead box M1 (FOXM1) expression, while the results of western blot analysis revealed that this knockdown reduced FOXM1 expression at the protein level. In addition, combined knockdown of PVT1 and FOXM1 decreased the proliferation of mesothelioma cell lines. In conclusion, PVT1 and FOXM1 were involved in the proliferation of cancer cells. Therefore, PVT1­FOXM1 pathways may be considered as candidate targets for the treatment of malignant mesothelioma.

Downregulation of FTL decreases proliferation of malignant mesothelioma cells by inducing G1 cell cycle arrest.

Pleural malignant mesothelioma is a malignant tumor with a poor prognosis that is strongly associated with asbestos exposure during its development. Because there is no adequate treatment for malignant mesothelioma, investigation of its molecular mechanism is important. The ferritin light chain (FTL) is a subunit of ferritin, and its high expression in malignant tumors, including malignant mesothelioma, has recently been reported; however, its role in malignant mesothelioma is unclear. The purpose of the present study was to clarify the function of FTL in malignant mesothelioma. The expression levels of FTL in malignant mesothelioma were examined using the Cancer Cell Line Encyclopedia database and our previous data. The short interfering (si)RNA against FTL was transfected into two mesothelioma cell lines, ACC-MESO-1 and CRL-5915, and functional analysis was performed. Expression of p21, p27, cyclin-dependent kinase 2 (CDK2) and phosphorylated retinoblastoma protein (pRb) associated with the cell cycle were examined as candidate genes associated with FTL. The expression levels of the FTL mRNA were higher in malignant mesothelioma compared with other tumors in the Cancer Cell Line Encyclopedia database, and among other genes in our previous study. Reverse transcription-quantitative PCR and western blotting demonstrated suppression of FTL expression in two cell lines transfected with FTL siRNA compared with cells transfected with negative control (NC) siRNA. In the two cell lines transfected with FTL siRNA, proliferation was significantly suppressed, and cell cycle arrest was observed in the G1 phase. The levels of p21 and p27 were increased, while those of CDK2 and pRb were decreased compared with NC. However, no significant differences in invasion and migration ability were revealed between FTL siRNA-transfected cells and NC. In conclusion, FTL may increase the proliferative capacity of malignant mesothelioma cells by affecting p21, p27, CDK2 and pRb, and promoting the cell cycle at the G1 phase.

Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1.

Malignant mesothelioma is a tumor with a poor prognosis, mainly caused by asbestos exposure and with no adequate treatment yet. To develop future therapeutic targets, we analyzed the microarray dataset GSE 29370 of malignant mesothelioma and reactive mesothelial hyperplasia, downloaded from the Gene Expression Omnibus (GEO) database. We identified insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) as one of the significantly upregulated genes in malignant mesothelioma. IGF2BP3 functions as an oncoprotein in many human cancers; however, to our knowledge, this is the first study on the biological function of IGF2BP3 in malignant mesothelioma cells. The knockdown of IGF2BP3 in malignant mesothelioma cells resulted in the suppression of cell proliferation with an increase in the proportion of cells in the G1 phase of the cell cycle. Furthermore, knockdown of IGF2BP3 inhibited cell migration and invasion. We focused on the cell cycle assay to investigate the role of IGF2BP3 in cell proliferation in malignant mesothelioma. Among the various proteins involved in cell cycle regulation, the expression of p27 Kip1 (p27) increased significantly upon IGF2BP3 knockdown. Next, p27 siRNA was added to suppress the increased expression of p27. The results showed that p27 knockdown attenuated the effects of IGF2BP3 knockdown on cell proliferation and G1 phase arrest. In conclusion, we found that IGF2BP3 promotes cell proliferation, a critical step in tumorigenesis, by suppressing the expression of p27 in malignant mesothelioma.

Glypican-1 is a novel immunohistochemical marker to differentiate poorly differentiated squamous cell carcinoma from solid predominant adenocarcinoma of the lung.

BACKGROUND: The histological classification of non-small cell lung cancer (NSCLC) is essential in determining new cancer-specific targeted therapies. However, the accurate typing of poorly differentiated is difficult, particularly for poorly differentiated squamous cell carcinoma and adenocarcinoma of the lung with limited immunohistochemical markers. Thus, novel immunohistochemical markers are required. We assumed the possibility of the immunohistochemical expression of glypican-1 in lung squamous cell carcinoma. METHODS: The microarray dataset GSE43580 from Gene Expression Omnibus database were analyzed for confirming the gene expression of glypican-1 in lung squamous cell carcinoma. We immunohistochemically investigated the use of glypican-1 as a novel positive diagnostic marker for lung squamous cell carcinoma. Glypican-1 expression in 63 cases of poorly differentiated lung squamous cell carcinoma and 60 cases of solid predominant lung adenocarcinoma was investigated by immunohistochemistry. Additionally, we compared glypican-1 expression with the expressions of p40, cytokeratin 5/6, thyroid transcription factor-1 (TTF-1), and napsin A. RESULTS: All 63 cases of lung squamous cell carcinoma showed glypican-1 expression. In contrast, only 2 cases of lung adenocarcinoma showed glypican-1 expression. The sensitivity, specificity, and diagnostic accuracy of glypican-1 expression for differentiating lung squamous cell carcinoma from lung adenocarcinoma were 100%, 96.7%, and 98.4%, respectively. These were similar to those of p40 and significantly better than those of CK 5/6. CONCLUSIONS: We recommend the use of glypican-1 as an additional positive marker of lung squamous cell carcinoma.

Inhibition of miR-18a-3p reduces proliferation of mesothelioma cells and sensitizes them to cisplatin.

Malignant pleural mesothelioma is a notorious human malignancy. Despite combination chemotherapy with cisplatin and pemetrexed, the majority of patients with advanced malignant pleural mesothelioma have a poor prognosis. MicroRNAs (miRNAs/miRs) are short non-coding RNAs that regulate various biological processes by binding to the 3'-untranslated region of target gene mRNAs and suppressing their expression. Since abnormal expression patterns of miRNAs are a common feature in human malignancies, a number of them have been researched as potential therapeutic targets. Our previous study demonstrated that microRNA-18a (miR-18a) is upregulated in mesothelioma cell lines compared with in non-neoplastic mesothelial tissues, but its function remains unclear. In the present study, miRNA inhibitor was transfected into mesothelioma cell lines and then analyzed various cellular functions. Mesothelioma cells transfected with the miR-18a inhibitor exhibited lower proliferation and migration rates compared with cells transfected with a negative control inhibitor in proliferation and wound scratch assays, respectively. Additionally, the present study revealed that downregulation of miR-18a increased mesothelioma cell apoptosis. In a chemosensitivity assay, transfection of the miR-18a inhibitor significantly increased the sensitivity of mesothelioma cells to cisplatin but not to pemetrexed. Therefore, miR-18a may be a potential therapeutic target for mesothelioma resistant to cisplatin.

SOX6 is a Novel Immunohistochemical Marker for Differential Diagnosis of Epithelioid Mesothelioma From Lung Adenocarcinoma.

The differential diagnosis of epithelioid mesothelioma from lung adenocarcinoma using immunohistochemistry is improving. However, immunohistochemical markers with high sensitivity and specificity have yet to be identified. In this study, we investigated the utility of sex-determining region Y box 6 (SOX6) as a novel immunohistochemical marker, identified by analyzing previous gene expression data. Immunohistochemically, SOX6 expression was present in 53 of 54 (98%) cases of epithelioid mesothelioma, compared with its expression in only 5 of 69 (7%) cases of lung adenocarcinoma. The sensitivity and specificity of SOX6 expression for differentiating epithelioid mesothelioma and lung adenocarcinoma were 98% and 93%, respectively. SOX6 expression showed similar sensitivity and far better specificity than those of calretinin or podoplanin (D2-40). In addition, SOX6 expression was more sensitive than Wilms' tumor 1 expression. The combination of SOX6 with other markers showed comparable or better sensitivity and specificity relative to other combinations. In particular, the sensitivity of positivity for both SOX6 and calretinin (96%) and the specificity of positivity for both SOX6 and Wilms' tumor 1 (93%) were higher than those of the other combinations. In conclusion, SOX6 is a novel candidate immunohistochemical marker for differentiating epithelioid mesothelioma from lung adenocarcinoma.