CCND1 G870A polymorphism interaction with cigarette smoking increases lung cancer risk: meta-analyses based on 5008 cases and 5214 controls.

Evidence indicates CCND1 G870A polymorphisms as a risk factor for a number of cancers. Increasing studies have been conducted on the association of CCND1 G870A polymorphism with lung cancer risk. However, the results were controversial. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses examining the association between CCND1 G870A polymorphism and lung cancer were performed. Subgroup analyses regarding ethnicity, smoking status, histological types and source of controls were also implemented. All eligible studies for the period up to May 2012 were identified. The overall data from ten case-control studies including 5,008 cases and 5,214 controls indicated that variant A allele may have an association with increased lung cancer risk (AA vs GG: OR = 1.21; 95 % CI = 1.08-1.36, dominant model: OR = 1.09; 95 % CI = 1.00-1.19, recessive model: OR = 1.23; 95 % CI = 1.01-1.49). In the subgroup analysis by ethnicity, A allele may elevate lung cancer risk among Asians but not Caucasians or Mixed ethnicities. In smoking status subgroup, A allele was shown to associate with increased lung cancer risk among smokers but not non-smokers. In the subgroup analysis by histological types, increased cancer risks were shown in adenocarcinoma but not squamous cell carcinoma, under the homozygote comparison and recessive models. Collectively, the results of the present study suggest that CCND1 G870A polymorphism might be a low-penetrant risk factor for lung cancer, particularly among Asians and smokers. Moreover, homozygous AA alleles might have a correlation with increased lung adenocarcinoma susceptibility.

Induction of palate epithelial mesenchymal transition by transforming growth factor ß3 signaling.

Transforming growth factor (TGFß)3 is essential for palate development, particularly during the late phase of palatogenesis when the disintegration of the palatal medial edge seam (MES) occurs resulting in mesenchymal confluence. The MES is composed of medial-edge epithelium (MEE) of opposite palatal shelves; its complete disintegration is essential for mediating correct craniofacial morphogenesis. This phenomenon is initiated by TGFß3 upon adherence of opposing palatal shelves, and subsequently epithelial-mesenchymal transition (EMT) instigates the loss of E-Cadherin, causing the MES to break into small epithelial islands forming confluent palatal mesenchyme; however, apoptosis and cell migration or in combination of all are other established mechanisms of seam disintegration. To investigate the molecular mechanisms that cause this E-Cadherin loss, we isolated and cultured murine embryonic primary MES cells from adhered palates and employed several biological approaches to explore the mechanism by which TGFß3 facilitates palatal seam disintegration. Here, we demonstrate that TGFß3 signals by activating both Smad-dependent and Smad-independent pathways. However, activation of the two most common EMT related transcription factors, Snail and SIP, was facilitated by Smad-independent pathways, contrary to the commonly accepted Smad-dependent pathway. Finally, we provide the first evidence that TGFß3-activated Snail and SIP1, combined with Smad4, bind to the E-Cadherin promoter to repress its transcription in response to TGFß3 signaling. These results suggest that TGFß3 uses multiple pathways to activate Snail and SIP1 and these transcription factors repress the cell-cell adhesion protein, E-Cadherin, to induce palatal epithelial seam EMT. Manipulation and intervention of the pathways stimulated by TGFß3 during palate development may have a significant therapeutic potential.

Transforming growth factor-ß activates c-Myc to promote palatal growth.

During palatogenesis, the palatal mesenchyme undergoes increased cell proliferation resulting in palatal growth, elevation and fusion of the two palatal shelves. Interestingly, the palatal mesenchyme expresses all three transforming growth factor (TGF) ß isoforms (1, 2, and 3) throughout these steps of palatogenesis. However, the role of TGFß in promoting proliferation of palatal mesenchymal cells has never been explored. The purpose of this study was to identify the effect of TGFß on human embryonic palatal mesenchymal (HEPM) cell proliferation. Our results showed that all isoforms of TGFß, especially TGFß3, increased HEPM cell proliferation by up-regulating the expression of cyclins and cyclin-dependent kinases as well as c-Myc oncogene. TGFß activated both Smad-dependent and Smad-independent pathways to induce c-Myc gene expression. Furthermore, TBE1 is the only functional Smad binding element (SBE) in the c-Myc promoter and Smad4, activated by TGFß, binds to the TBE1 to induce c-Myc gene activity. We conclude that HEPM proliferation is manifested by the induction of c-Myc in response to TGFß signaling, which is essential for complete palatal confluency. Our data highlights the potential role of TGFß as a therapeutic molecule to correct cleft palate by promoting growth.

Intradural disc herniation at L5 level mimicking an intradural spinal tumor.

Intradural lumbar disc herniation is a rare complication of disc disease. The reason for the tearing of the dura matter by a herniated disc is not clearly known. Intradural disc herniations usually occur at the disc levels and are often seen at L4-L5 level but have also been reported at other intervertebral disc levels. However, intradural disc herniation at mid-vertebral levels is rare in the literature and mimics an intradural extramedullary spinal tumor lesion in radiological evaluation. Although magnetic resonance imaging (MRI) with gadolinium is useful in the diagnosis of this condition, preoperative correct diagnosis is usually difficult and the definitive diagnosis must be made during surgery. We describe here a 50-year-old female patient who presented with pain in the lower back for 6 months and a sudden exacerbation of the pain that spread to the left leg as well as numbness in both legs for 2 weeks. MRI demonstrated an intradural mass at the level of L5. Laminectomy was performed, and subsequently durotomy was also performed. An intradural disc fragment was found and completely removed. The patient recovered fully in 3 months. Intradural lumbar disc herniation must be considered in the differential diagnosis of mass lesions in the spinal canal.

Mechanisms of palatal epithelial seam disintegration by transforming growth factor (TGF) beta3.

TGFbeta3 signaling initiates and completes sequential phases of cellular differentiation that is required for complete disintegration of the palatal medial edge seam, that progresses between 14 and 17 embryonic days in the murine system, which is necessary in establishing confluence of the palatal stroma. Understanding the cellular mechanism of palatal MES disintegration in response to TGFbeta3 signaling will result in new approaches to defining the causes of cleft palate and other facial clefts that may result from failure of seam disintegration. We have isolated MES primary cells to study the details of MES disintegration mechanism by TGFbeta3 during palate development using several biochemical and genetic approaches. Our results demonstrate a novel mechanism of MES disintegration where MES, independently yet sequentially, undergoes cell cycle arrest, cell migration and apoptosis to generate immaculate palatal confluency during palatogenesis in response to robust TGFbeta3 signaling. The results contribute to a missing fundamental element to our base knowledge of the diverse roles of TGFbeta3 in functional and morphological changes that MES undergo during palatal seam disintegration. We believe that our findings will lead to more effective treatment of facial clefting.

TGFbeta3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex.

Dissociation of medial-edge epithelium (MEE) during palate development is essential for mediating correct craniofacial morphogenesis. This phenomenon is initiated by TGFbeta3 upon adherence of opposing palatal shelves, because loss of E-cadherin causes the MEE seam to break into small epithelial islands. To investigate the molecular mechanisms that cause this E-cadherin loss, we isolated and cultured murine embryonic primary MEE cells from adhered or non-adhered palates. Here, we provide the first evidence that lymphoid enhancer factor 1 (LEF1), when functionally activated by phosphorylated Smad2 (Smad2-P) and Smad4 (rather than beta-catenin), binds with the promoter of the E-cadherin gene to repress its transcription in response to TGFbeta3 signaling. Furthermore, we found that TGFbeta3 signaling stimulates epithelial-mesenchymal transformation (EMT) and cell migration in these cells. LEF1 and Smad4 were found to be necessary for up-regulation of the mesenchymal markers vimentin and fibronectin, independently of beta-catenin. We proved that TGFbeta3 signaling induces EMT in MEE cells by forming activated transcription complexes of Smad2-P, Smad4 and LEF1 that directly inhibit E-cadherin gene expression.