Diagnostic value of FDG PET-CT in differentiating lung adenocarcinoma from squamous cell carcinoma.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. The combination of fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) and computed tomography (CT) has a major impact on the diagnosis, staging, treatment planning and follow-up of lung cancer patients. The maximum standardized uptake value (SUVmax) is an easily performed and most widely used semi-quantitative index for the analysis of FDG PET images and estimation of metabolic activity. This study aimed to investigate the role of PET/CT in differentiating adenocarcinoma (ADC), the most common lung cancer, from squamous cell carcinoma (SCC) by comparing FDG uptake measured as SUVmax. RESULTS: Between 2019 and 2022, 76 patients diagnosed with non-small cell lung cancer (NSCLC) at the Department of Pathology, Atatürk University Faculty of Medicine, with histopathologic evidence of adenocarcinoma or squamous cell carcinoma, underwent retrospective analysis using PET/CT scanning to measure PET parameters of the lesions and compare them with histopathology. Among 76 NSCLC patients included in the study, 43 (57%) were histopathologically diagnosed as ADC and 33 (43%) as SCC. SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) values of lesions in patients with SCC were statistically significantly higher than those in patients with ADC (p values 0.007, 0.009, 0.003 and 0.04, respectively). CONCLUSIONS: Lung SCC has higher metabolic uptake values than ADC, and PET/CT can be used to differentiate them.

SET-NUP214 and MLL cooperatively regulate the promoter activity of the HoxA10 gene.

SET-Nup214 is a recurrent fusion gene that is mainly observed in T-cell acute lymphoblastic leukemia (T-ALL). Dysregulation of homeobox (Hox) genes is frequently observed in patients with leukemia. Consistent with this, HoxA genes are upregulated in the SET-Nup214 + T-ALL cell line and patients. Although SET-Nup214 has been reported to be recruited to the promoter regions of HoxA genes, the detailed mechanisms of how SET-Nup214 specifically binds to HoxA gene promoters and regulates HoxA gene expression are not known. In this study, we demonstrated that SET-Nup214 interacts with MLL via the SET acidic region of SET-Nup214. SET-Nup214 and MLL cooperatively enhance the promoter activity of the HoxA10 gene. Neither the SET region alone nor the Nup214 region alone sufficiently enhanced the HoxA10 gene promoter. Our results indicated that the SET portion of the SET-Nup214-fusion protein is important for interactions with MLL and transcription enhancement of the HoxA10 gene. Thus, our study will contribute to the understanding of how SET-Nup214 and MLL disturb the expression of HoxA10 gene in leukemia.

NF-Ä¸ß upregulates ADAMTS5 expression by direct binding after TNF-α treatment in OUMS-27 chondrosarcoma cell line.

Inflammation caused-aggrecan degradation is a critical event in the pathogenesis of osteoarthritis (OA). The aggrecanases like a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) are assumed to be key players in the aggrecan destruction. To develop the comprehensive therapy method for OA, it is essential to elucidate the activation mechanism of ADAMTS5 gene after stimulation of inflammatory cytokines like tumor necrosis factor-α (TNF-α). The cell lines of human chondrosarcoma (OUMS-27) and embryonic kidney (HEK293T) were incubated with tumor necrosis factor-α (TNF-α) for certain time periods, and the expression level of ADAMTS5 was measured in both mRNA and protein levels. Tissue-specific ADAMTS5 activation was founded to be induced after TNF-α treatment. Then, the constructs for the promoter region of ADAMTS5 were prepared and luciferase assay was conducted to understand the involvement mechanism of nuclear factor-kappa beta (NF-ĸß) in ADAMTS5 activation. It was demonstrated that NF-Ä¸ß induces the ADAMTS5 expression level by directly binding the promoter region of ADAMTS5. Although the TNF-α blocker is used for OA treatment, the development of a more comprehensive treatment strategy is an urgent need. Our experimental data contributes in terms of selecting NF-Ä¸ß as a target molecule. Up to date, NF-Ä¸ß has been proven to involve in the ADAMTS5 up-regulation after several pro-inflammatory cytokines stimulation. In conclusion, our findings make important contributions to the knowledge about the roles of NF-Ä¸ß in ADAMTS5 activation under inflammatory conditions. So, NF-Ä¸ß could be considered to be a potential target for OA treatment.

Functional analysis of ESM1 by siRNA knockdown in primary and metastatic head and neck cancer cells.

BACKGROUND: Genetic factors play a large role in cancer, and thus, there is a great desire to understand the effects of different genes in cancer and to also develop gene therapy for better treatments. Therefore, the development of alternative diagnosis and therapy modalities is of utmost importance. The aim of our study was to illuminate the role of ESM1 (endothelial cell-specific molecule-1, also known as Endocan) in proliferation and migration of head and neck cancer, thus helping to pave the way for new treatment modalities and predictive biomarkers. METHODS: ESM1 expression was shown with immunofluorescence assay using confocal laser scanning microscope in primary and metastatic head and neck cancer cells. ESM1 expression was knocked down by RNA interference in head and neck cancer cells. Knockdown efficiency was evaluated by quantitative real-time RT-PCR and Western blot. Cell proliferation and migration assays were performed by xCELLigence real-time cell analysis system. RESULTS: Immunofluorescence assay showed nuclear localization and high expression of ESM1 in primary and metastatic head and neck cancer cells. ESM1 mRNA and protein levels were significantly decreased in ESM1-knockdown cells compared to control. ESM1-knockdown cells showed reduced proliferation and migration activity when compared to control cells. CONCLUSION: These findings suggest that ESM1 has roles on proliferation and migration of head and neck cancer cells.

Function of Nup98 subtypes and their fusion proteins, Nup98-TopIIß and Nup98-SETBP1 in nuclear-cytoplasmic transport.

Nup98 is a component of the nuclear pore complex. The nup98-fusion genes derived by chromosome translocations are involved in hematopoietic malignancies. Here, we investigated the functions of Nup98 isoforms and two unexamined Nup98-fusion proteins, Nup98-TopIIß and Nup98-SETBP1. We first demonstrated that two Nup98 isoforms are expressed in various mouse tissues and similarly localized in the nucleus and the nuclear envelope. We also showed that Nup98-TopIIß and Nup98-SETBP1 are localized in the nucleus and partially co-localized with full-length Nup98 and a nuclear export receptor XPO1. We demonstrated that Nup98-TopIIß and Nup98-SETBP1 negatively regulate the XPO1-mediated protein export. Our results will contribute to the understanding of the molecular mechanism by which the Nup98-fusion proteins induce tumorigenesis.

Suppression of bromodomain-containing protein 4 by shRNA: A new approach for cancer treatment.

PURPOSE: MYC is a transcription factor coding gene that is believed to control 15% of the genes in the entire human genome. The central role of c-MYC in cancer pathogenesis makes it a major therapeutic target in field of anticancer agent development. METHODS: We targeted the acetyl-lysine binding modules or bromodomains, which are associated with c-MYC transcriptional activation. RESULTS: Sequence specific inhibition of BET bromodomains with small hairpin RNAs (shRNAs) resulted in cessation of cellular proliferation in different cancer cell lines. Unlike previous studies on inhibition of bromodomains with selective small-molecule inhibitors, our study revealed the significant role of BET bromodomains in solid tumours and also highlighted the ease of RNA interference (RNAi) methodology for inhibition of bromodomain translation. CONCLUSION: The degree of influence of BET bromodomain inhibition on proliferation in five cancer cell lines established it as the major target in malignancies characterized by activation of c-MYC.

Investigation of MACC1 Gene Expression in Head and Neck Cancer and Cancer Stem Cells.

PURPOSE: By investigating the MACC1 gene (metastasis-associated in colon cancer 1) in cancer stem cells (CSC) resistant to chemotherapy and in cancer stem cells (CSC) resistant to chemotherapy and in cancer cells (CS) sensitive to chemotherapy we determineda steady expression in both types of cells in head and neck cancer. In conformity with the result we examined if this gene could be a competitor gene for chemotherapy. According to literature, the MACC1 gene shows a clear expression in head and neck cancer cells [1]. Here we examined MACC1 expression in CSC and investigated it as a possible biomarker. METHODS: Our experiments were performed in the UT -SCC -74 in primary head and neck cancer cell line. We examined the MACC -1 gene expression by Real Time PCR from both isolated CSC and CS. RESULTS: Expression of MACC -1 gene of cancer stem cells showed an two-fold increase compared with cancer cells. Based on the positive expression of MACC1 in both CS and CSC, this gene may serve as a potential biomarker in head and neck cancer. By comparing the results of this study with the novel features of MACC1, two important hypotheses could be examined. The first hypothesis is that MACC1 is a possible transcripton factor in colon cancer, which influences a high expression of CSC in head and neck and affects the expression of three biomarkers of the CSC control group biomarkers. The second hypothesisis is that the positive expression of MACC1 in patients with a malignant prognosis of tongue cancer, which belongs to head and neck cancer types, operates a faster development of CSC to cancer cells.

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway.

Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEK-Nup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-κB signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-κB-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IκB, in the nucleus. These results suggest that SET-Nup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system.