cyclin-d1 and Small-Cell-Lung-Carcinoma

Large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC) of lung encompass high-grade neuroendocrine tumour category and share several fundamental features. As both tumours may respond to different treatment modalities and show unique molecular alterations distinction between the two is clinically relevant, but can be challenging due to sampling and fixation issues and shared morphological features.. Surgically resected primary SCLC (n = 129) and LCNEC (n = 27) were immunohistochemically stained with Rb1, cyclin D1 and p16 using tissue microarray (TMA), and expression patterns of the proteins were compared between the two to identify the discriminatory pattern.. All markers had high diagnostic accuracy; Rb1 was the highest followed by p16 and cyclin D1. The majority of SCLC had the pattern Rb1-/p16+/cyclin D1- and more than half of LCNEC had Rb1+/p16-/cyclin D1+. Overall, the expression pattern Rb1- and cyclin D1- was strongly associated with the diagnosis of SCLC, while the pattern Rb1+ and/or cyclin D1+ was strongly associated with LCNEC. The use of this simplified expression pattern leads to a diagnostic accuracy of 97.3%. p16 did not add to further discrimination. The heterogeneity in Rb1, cyclin D1 and p16 expression was insignificant in SCLCs compared with LCNECs.. Use of Rb1, cyclin D1 and p16 immunohistochemistry can distinguish the two with high accuracy. Notably, the Rb1-/cyclin D1- pattern in given tumour sample would confirm the diagnosis of SCLC. Our results could be extrapolated and applied to routine diagnostic samples such as biopsies and cytology samples.

Topics: Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cyclin D1; Genes, p16; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Retinoblastoma Binding Proteins; Small Cell Lung Carcinoma; Ubiquitin-Protein Ligases

The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population.. The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models.. The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03).. Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Case-Control Studies; Cyclin D1; Female; Genetic Predisposition to Disease; Genotype; Humans; India; Lung Neoplasms; Male; Middle Aged; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Risk; Small Cell Lung Carcinoma; Young Adult

Ubiquitin specific protease 32 (USP32) is a highly conserved but uncharacterized gene, which has been reported to be associated with growth of breast cancer cells. However, the role of USP32 in human small cell lung cancer (SCLC) has not been uncovered. The aim of this study was to investigate and evaluate the clinical significance of USP32 in patients with SCLC.. Expression of USP32 was firstly investigated using public online data sets and then determined in SCLC tissues and cell lines using quantitative real-time PCR, Western blotting and immunohistochemical staining. SCLC cells were transfected with a small-interfering RNA targeting USP32 mRNA and analysed for cell viability, proliferation ability, cell cycle distribution, apoptosis and invasion.. USP32 was found to be overexpressed in SCLC tissues compared with normal tissues. High USP32 expression was significantly correlated with disease stage and invasion. In vitro experiments demonstrated that silencing of USP32 caused a significant decrease in the proliferation and migration rate of cells. Furthermore, USP32 silencing arrested cell cycle progression at G0/G1 phase via decreasing CDK4/Cyclin D1 complex and elevating p21. In addition, downregulation of USP32 significantly induced cell apoptosis by activating cleaved caspase-3 and cleaved PARP, as well as inhibiting cell invasiveness via altering epithelial mesenchymal transition expression.. Our results suggest for the first time that USP32 is important for SCLC progression and might be a potential target for molecular therapy of SCLC.

Topics: Aged; Caspase 3; Cell Movement; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Female; G1 Phase Cell Cycle Checkpoints; Humans; Immunohistochemistry; Lung Neoplasms; Male; Poly(ADP-ribose) Polymerases; RNA Interference; RNA, Messenger; RNA, Small Interfering; Small Cell Lung Carcinoma; Tumor Cells, Cultured; Ubiquitin Thiolesterase

Insulinoma associated-1 (INSM1) gene is expressed exclusively in early embryonic neuroendocrine tissues, but has been found highly re-activated in most of the neuroendocrine tumors including small cell lung carcinoma.. In order to elucidate the functional effects of INSM1 in normal lung development, we used a conditional lung-specific INSM1 transgenic mouse model. Transgenic (Tet-on system) CMV-INSM1 responder mice were bred with the lung-specific, club cell secretory protein (CCSP) promoter-rtTA activator mice to produce bi-transgenic progeny carrying both alleles, CCSP-rtTA and Tet-on-INSM1. Mice were fed with doxycycline containing food at the initial mating day to the postnatal day 21. Lung samples were collected at embryonic day 17.5, newborn, and postnatal day 21 for analyses.. Northern blot, RT-PCR, and immunohistochemical analyses revealed that doxycycline induced respiratory epithelium-specific INSM1 expression in bi-transgenic mice. Samples from postnatal day 21 mice revealed a larger lung size in the bi-transgenic mouse as compared to the single-transgenic or wild-type littermates. The histopathology results showed that the alveolar space in the bi-transgenic mice were 4 times larger than those in the single transgenic or wild-type littermates. In contrast, the size was not significantly different in the lungs collected at E17.5 or newborn among the bi-transgenic, single transgenic, or wild type mice. The respiratory epithelium with INSM1 ectopic expression suppressed cyclin D1 signal. Further in vitro studies revealed that the ectopic expression of INSM1 suppresses cyclin D1 expression and delays cell cycle progression.. The current study suggests that CCSP promoter-driven INSM1 ectopic expression impairs normal lung development especially in postnatal alveologenesis.

Topics: Animals; Blotting, Northern; Blotting, Western; Bronchi; Case-Control Studies; Cell Line; Cyclin D1; DNA-Binding Proteins; Ectopic Gene Expression; Epithelial Cells; Flow Cytometry; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Mice; Mice, Transgenic; Pulmonary Alveoli; Repressor Proteins; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; Small Cell Lung Carcinoma; Transcription Factors

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

Topics: Alleles; Animals; Cell Line, Tumor; Chromosome Breakpoints; Cyclin D1; Disease Models, Animal; DNA-Binding Proteins; Female; Gene Expression Profiling; Genome, Human; Genomics; Humans; Lung Neoplasms; Male; Mice; Mutation; Neurosecretory Systems; Nuclear Proteins; Receptors, Notch; Retinoblastoma Protein; Signal Transduction; Small Cell Lung Carcinoma; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59)Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.

Topics: Administration, Oral; Animals; Antigens, CD; Antineoplastic Agents; Apoptosis; Benzoates; Cell Cycle; Cell Line, Tumor; Copper; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Deferasirox; Female; Humans; Iron; Iron Chelating Agents; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neuroectodermal Tumors, Primitive, Peripheral; Protein Serine-Threonine Kinases; Receptors, Transferrin; Small Cell Lung Carcinoma; Transplantation, Heterologous; Triazoles; Zinc

Described herein is an unusual case of mantle cell lymphoma (MCL) histologically mimicking marginal zone lymphoma (MZL). An 83-year-old man presented with multiple adenopathies and a hilar mass encroaching on the right lung. A transbronchial biopsy showed small blue cells suspicious for small cell carcinoma. On further analysis the cells were predominantly small cleaved and CD20 positive, suggesting follicular lymphoma, grade 2. An axillary lymph node biopsy showed germinal centers surrounded by monocytoid B cells. Flow cytometry was negative for CD5 and CD23 and the diagnosis of MZL was considered. Because of the aggressive clinical behavior, including extensive necrosis on imaging studies, immunohistochemistry for cyclin D-1 was performed and was positive. Bone marrow was extensively involved and it showed t(11;14), in addition to other complex cytogenetic abnormalities. Differentiating MCL from MZL has prognostic and therapeutic implications, particularly when considering the potential role of targeted therapy and cell cycle modulators.

Topics: Aged, 80 and over; Biomarkers, Tumor; CD5 Antigens; Cyclin D1; Diagnosis, Differential; Flow Cytometry; Humans; Immunohistochemistry; Lung Neoplasms; Lymph Nodes; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Mantle-Cell; Male; Small Cell Lung Carcinoma