Tibial tubercle avulsion fracture following preexisting Osgood-Schlatter disease in an adolescent: a case report.

Tibial tubercle avulsion fractures (TTAFs) are rare but typical in children and adolescents and Osgood-Schlatter disease (OSD) may be involved in their pathogenesis. However, few publications have reported the relationship between OSD and TTAF. A 16-year-old healthy male adolescent presented with pain, swelling and limited range of motion of the right knee following sudden acceleration while running. Based on the radiographic evidence, the patient was diagnosed with an avulsion fracture of the right tibial tubercle and OSD. Open reduction and internal fixation were performed using two cannulated screws and two Kirschner wires. The patient returned to preinjury activity levels at the 12-month follow-up postoperatively. This case report aimed to highlight this unique injury pattern. For patients with TTAFs, not only should the fracture be treated, but the cause of the fracture, such as OSD, should also be given appropriate treatment.

[Retracted] MicroRNA­379 acts as a tumor suppressor in non­small cell lung cancer by targeting the IGF­1R­mediated AKT and ERK pathways.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the cell migration and invasion assay data shown in Figs. 2F, 5D and 6D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 38: 1857­1866, 2017; DOI: 10.3892/or.2017.5835].

The oncogenic role of HIF-1α/miR-182-5p/ZFP36L1 signaling pathway in nasopharyngeal carcinoma.

BACKGROUND: Accumulating evidence indicates that dysregulation of miR-182-5p can serve as diagnostic and prognostic biomarkers for some cancers, whereas the role of miR-182-5p has not been explored in nasopharyngeal carcinoma (NPC). Our study aims to elucidate the biological function of miR-182-5p in NPC and the potential molecular mechanism involved. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine miR-182-5p expression in NPC primary tissues and cell lines. Immunohistochemistry (IHC) for ZFP36L1 was conducted in NPC samples. Western blot was used to evaluate protein expression in cell lines. A series of functional assays were carried out to evaluate the roles of miR-182-5p and ZFP36L1 in tumor development and progression of NPC. Bioinformatics tools and luciferase reporter assays were utilized to identify the potential mechanisms of action. Moreover, rescue experiments were applied to explore whether ZFP36L1 mediated the effects of miR-182-5p in NPC. RESULTS: Up-regulation of miR-182-5p was significantly associated with tumor development and poor prognosis in patients with NPC. Functional study demonstrated that miR-182-5p overexpression enhanced, whereas suppression of miR-182-5p impeded NPC cell proliferation, migration, tumorigenesis and metastasis. Mechanistically, miR-182-5p interacted with ZFP36L1 at two sites in its 3' un-translated region (UTR) and repressed ZFP36L1 expression in NPC. Consistently, an inverse correlation was observed between the expression levels of miR-182-5p and ZFP36L1 using clinical NPC tissues, and down-regulation of ZFP36L1 in NPC predicts poor survival. Furthermore, overexpression of miR-182-5p in NPC was partly attributable to the transcriptional activation effect induced by hypoxia-inducible factor 1α (HIF-1α). CONCLUSIONS: Our data suggests that miR-182-5p facilitates cell proliferation and migration in NPC through its ability to down-regulate ZFP36L1 expression, and that the HIF-1α/miR-182-5p/ZFP36L1 axis may serve as a novel therapeutic target in the management of NPC.

Comprehensive analysis of gene expression and DNA methylation data identifies potential biomarkers and functional epigenetic modules for lung adenocarcinoma.

Lung cancer has one of the highest mortality rates of malignant neoplasms. Lung adenocarcinoma (LUAD) is one of the most common types of lung cancer. DNA methylation is more stable than gene expression and could be used as a biomarker for early tumor diagnosis. This study is aimed to screen potential DNA methylation signatures to facilitate the diagnosis and prognosis of LUAD and integrate gene expression and DNA methylation data of LUAD to identify functional epigenetic modules. We systematically integrated gene expression and DNA methylation data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), bioinformatic models and algorithms were implemented to identify signatures and functional modules for LUAD. Three promising diagnostic and five potential prognostic signatures for LUAD were screened by rigorous filtration, and our tumor-normal classifier and prognostic model were validated in two separate data sets. Additionally, we identified functional epigenetic modules in the TCGA LUAD dataset and GEO independent validation data set. Interestingly, the MUC1 module was identified in both datasets. The potential biomarkers for the diagnosis and prognosis of LUAD are expected to be further verified in clinical practice to aid in the diagnosis and treatment of LUAD.

Quinalizarin, a specific CK2 inhibitor, can reduce icotinib resistance in human lung adenocarcinoma cell lines.

The abnormal activation of the downstream signaling pathways of epidermal growth factor receptor (EGFR) that are independent of EGFR, contribute to the acquisition of EGFR­tyrosine kinase inhibitor (TKI) resistance in non­small cell lung cancer (NSCLC). The serine/threonine protein kinase casein kinase II (CK2) phosphorylates and modulates several members of the EGFR downstream signaling pathways. Thus, the purpose of the current study was to investigate the effects of the addition of quinalizarin (a specific CK2 inhibitor) to icotinib (an EGFR­TKI) on the proliferation and apoptosis of four NSCLC cell lines and its underlying mechanisms. The human lung adenocarcinoma cell lines HCC827, A549, H1650 and H1975 were employed to represent the EGFR­TKI­sensitive EGFR (EGFR­sensitive) mutation, wild­type EGFR and the EGFR­TKI­resistant EGFR (EGFR­resistant) mutations. The cell viability was determined by the MTT assay. Cell apoptosis was detected by flow cytometry using the Annexin V­enhanced green fluorescent protein Apoptosis Detection kit. The level of proteins in the EGFR downstream pathway was observed using a western blot assay. The results showed that the cells with the EGFR­sensitive mutation (HCC827, EGFR E716­A750del) were more sensitive to icotinib compared with those possessing the EGFR wild­type (A549) and the EGFR­resistant mutations (H1650, EGFR E716­A750del and PTEN lost; H1975, EGFR L858R+T790M). Quinalizarin inhibited proliferation and promoted apoptosis in the cells with the EGFR wild­type and resistant mutations, and the addition of quinalizarin to icotinib partially restored their sensitivity to icotinib. Quinalizarin and/or icotinib increased the apoptotic rates in the EGFR­TKI resistant cells, and the combination of these reduced the level of protein downstream of EGFR, including phosphorylated (p­AKT) and p­(ERK). In conclusion, quinalizarin may partially sensitize cells to icotinib by inhibiting proliferation and promoting apoptosis mediated by AKT and ERK in EGFR­TKI resistant NSCLC cell lines.

Inhibition of hepatocellular carcinoma cell proliferation, migration, and invasion by a disintegrin and metalloproteinase-17 inhibitor TNF484.

BACKGROUND: The aim of this study was to test the effect of TNF484 on cell proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. MATERIALS AND METHODS: Various doses (0, 1, 10, 50, and 100 nM) of TNF484 were applied to the HepG2 and Bel7402 cells, and cell proliferation was measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay after 72 h. Cell migration rate was measured using the xCELLigence system, and the cell invasion ability was examined by the three-dimensional spheroid BME cell invasion assay. The expression level of ADAM17 was also measured with RT-PCR. RESULTS: With the treatment of TNF484, the cell proliferation of HepG2 and Bel7402 cells was inhibited in a dose-dependent manner. Moreover, under TNF484 treatment, the cell migration rate as well as cell invasion ability of the HepG2 and Bel7402 cells were suppressed. CONCLUSION: TNF484 could inhibit the cell proliferation, migration, and invasion of some HCC cell lines, making it a potential therapeutic option for liver cancer treatment.

Endothelial progenitor cells contribute to neovascularization of non-small cell lung cancer via histone deacetylase 7-mediated cytoskeleton regulation and angiogenic genes transcription.

To supply tumor tissues with nutrients and oxygen, endothelial progenitor cells (EPCs) home to tumor sites and contribute to neovascularization. Although the precise mechanism of EPCs-induced neovascularization remains poorly understood in non-small cell lung cancer (NSCLC), histone deacetylase 7 (HDAC7) is considered as a critical regulator. To explore the function of HDAC7 in neovascularization induced by EPCs, tube formation assay, immunofluorescence, microarray, Western blot analysis and animal models were performed. In vitro, HDAC7 abrogation led to the activation of Rho-associated coiled-coil containing protein kinase/myosin light chain 2 pathway concomitant with ERK dephosphorylation, causing the instability of cytoskeleton and collapse of tube formation. In vivo, absence of HDAC7 impaired the vascular lumen integrity and decreased the functional blood perfusion, inhibiting the growth of tumor. At the level of transcription, HDAC7 silencing upregulated antiangiogenic genes and suppressed proangiogenic genes collectively, turning off the angiogenic switch during vessel formation. Taken together, HDAC7 plays a dual role in maintaining the structural and nonstructural functions of EPCs. Our work demonstrates the molecular mechanism by which HDAC7 contributes to the angiogenic property of EPCs and provides a rational basis for specific targeting of antiangiogenic strategies in lung cancer.

Pharmacological targeting of BET proteins attenuates radiation-induced lung fibrosis.

Radiation-induced lung injury has restricted radiotherapy for thoracic cancer. The purpose of this study was to investigate the radioprotective effects of bromodomain and extra terminal (BET) inhibitor JQ1 in a murine model of pulmonary damage. Chest computed tomography (CT) was performed in a rat model after 20 Gy radiation of the right thorax. And histological evaluation and protein expressions of irradiated tissue were analyzed to confirm the potential anti-fibrosis effect of JQ1 and its underlying mechanisms. Moreover, colony formation assays were used to explore the effects of JQ1 on esophageal cancer Eca109 and breast cancer MCF7. JQ1 attenuated radiologic and histologic presentations of radiation-induced fibrosis, inflammatory reaction and pulmonary structural changes and the increase of Hounsfield units (HU) density and hydroxyproline content after radiation. Additionally, JQ1 suppressed BRD4, c-MYC, Collagen I, TGF-ß, p-NF-κB p65, p-Smad2 and p-Smad3 expressions after irradiation, repressed proliferation and transdifferentiation of lung fibroblasts, and impaired clonogenic survival of thoracic cancer cells. Collectively, our study demonstrated for the first time that BET Bromodomain inhibitor JQ1 protected normal lung tissue after radiation, and exerted a radiosensitizing effect in thoracic cancer cells.

Antitumor effects of histone deacetylase inhibitor suberoylanilide hydroxamic acid in epidermal growth factor receptor-mutant non-small-cell lung cancer lines in vitro and in vivo.

Histone acetylation is one of the most abundant post-translational modifications in eukaryotic cells; aberrant histone acetylation is related to a range of cancer types because of the dysregulation of histone deacetylases (HDACs). Inhibition of HDACs leads to suppression of tumor growth in multiple cancers, whereas the inhibitory effects of HDAC inhibitors remain incompletely understood in epidermal growth factor receptor (EGFR)-mutant lung cancers. In this study, the antitumor effects of HDACs inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) were examined in EGFR-mutant lung cancer cell lines. The results of the present work showed that SAHA markedly inhibited cell viability and proliferation, induced cell apoptosis by arresting the cell cycle in the G2/M phase, and significantly reduced tumor growth in a xenograft model. Further study confirmed that the suppression function of SAHA might be mediated by regulating the ERK-dependent and/or the AKT-dependent pathway; meanwhile, angiogenesis abrogation induced by SAHA exerted effects on tumor regression in vivo. Taken together, our results identify the antitumor effects of HDACs inhibitor SAHA as an alternative therapeutic application for the epigenetic treatment of EGFR-mutant non-small-cell lung cancer.

Association of protein kinase CK2 inhibition with cellular radiosensitivity of non-small cell lung cancer.

Protein kinase CK2 is a highly conserved protein Ser/Thr protein kinase and plays important roles in cell proliferation, protein translation and cell survival. This study investigated the possibility of using CK2 inhibition as a new approach for increasing the efficacy of radiotherapy in non-small cell lung cancer (NSCLC) and its underlying mechanisms. Kinase inhibition of CK2 was attempted either by using the specific CK2 inhibitor, Quinalizarin or by applying siRNA interference technology to silence the expression of the catalytic subunit of CK2 in A549 and H460 cells. The results showed that CK2α knockdown or Quinalizarin significantly enhanced the radiosensitivity of various NSCLC cells. The notable findings we observed after exposure to both CK2 inhibition and ionizing radiation (IR) were a prolonged delay in radiation-induced DNA double-strand breaks (DSB) repair, robust G2/M checkpoint arrest and increased apoptosis. In vivo studies further demonstrated that compared with each treatment alone, CK2 inhibition combined with IR reduced tumor growth in the H460 cell xenograft model. In conclusion, CK2 is a promising target for the enhancement of radiosensitivity in NSCLC.

MicroRNA-379 acts as a tumor suppressor in non-small cell lung cancer by targeting the IGF­1R-mediated AKT and ERK pathways.

Lung cancer is one of the most common types of malignancy in humans and is a leading cause of cancer-related deaths among men and women worldwide. Aberrantly expressed microRNAs in non-small cell lung cancer (NSCLC) contribute to tumor occurrence and development as either tumor suppressors or promoters. MicroRNA-379 (miR­379) is dysregulated in several types of human cancer. However, its expression pattern, role and underlying mechanism in NSCLC progression and metastasis are poorly understood. In this study, assay of reverse transcription-quantitative polymerase chain reaction showed that miR­379 was downregulated in both NSCLC tissue and cell lines. Low miR­379 expression in NSCLC tissues was significantly correlated with TNM stage and lymph node metastasis. In addition, functional experiments revealed that restoring the expression of miR­379 inhibited cell proliferation, migration and invasion of NSCLC. The insulin-like growth factor receptor-1 (IGF­1R) was identified as a direct target of miR­379 in NSCLC. IGF­1R was highly expressed in NSCLC tissues and inversely correlated with miR­379 expression. Downregulation of IGF­1R had tumor suppressive roles similar to that of miR­379 overexpression on NSCLC cell proliferation, migration and invasion. Moreover, the upregulation of IGF­1R effectively rescued the tumor suppressive roles induced by miR­379 overexpression in NSCLC. The resumption of the expression of miR­379 inhibited the activation of AKT and ERK signaling pathways in NSCLC. These findings suggested that miR­379 acts as a tumor suppressor in NSCLC by directly targeting IGF­1R and indirectly regulating AKT and ERK signaling pathways. miR­379 provides novel therapeutic targets for the treatment of patients with this disease.

MicroRNA-378g enhanced radiosensitivity of NPC cells partially by targeting protein tyrosine phosphatase SHP-1.

PURPOSE: To investigate the influence of microRNA-378g (miR-378g) on radiosensitivity and metastasis of nasopharyngeal carcinoma cells and study how miR-378g regulated Src homology region 2 domain-containing phosphatase-1 (SHP-1) expression. MATERIALS AND METHODS: Polymerase chain reaction (PCR) was used to detect the expression level of miR-378g and SHP-1 mRNA in different nasopharyngeal carcinoma (NPC) cell lines. MiR-378g mimics were transfected into NPC cells and radiosensitivity was determined by colony formation assay. Cell apoptotic rate was determined by flow cytometry analysis. Cell invasion was examined by transwell assay. SHP-1 transcriptional activity was examined by luciferase assay. SHP-1 expression level was determined by Western blot. Lentivirus containing SHP-1 gene and miR-378g mimics were co-transfected into NPC cells and radiosensitivity and metastasis were detected by colony formation assay and transwell assay again. RESULTS: Expression of miR-378g and SHP-1 mRNA was negatively correlated in NPC cell lines. MiR-378g mimics enhanced radiosensitivity, promoted apoptosis and decreased invasion in NPC cells. SHP-1 expression was inhibited by miR-378g mimics. Luciferase reporter assay showed that miR-378g directly targeted SHP-1 by binding to 3' untranslated region (3'UTR) of SHP-1 mRNA. Overexpression of SHP-1 partially inversed the effect of miR-378g mimics on radiosensitivity, but had no effect on cell invasion. CONCLUSION: MiR-378g enhanced radiosensitivity partially by targeting SHP-1 in NPC cells. Cell invasion was also partially inhibited by miR-378g, but the effect was not mediated by SHP-1.

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling.

Determining the molecular phenotype is a key to understanding and predicting the metastatic potential and the prognosis for patients with lung cancer. Our previous study demonstrated that increased expression of cyclin­dependent kinase 5 (CDK5) in patients with non­small cell lung cancer (NSCLC) is associated with a poorer prognosis. The present study aimed to further investigate the underlying mechanism of CDK5 in vitro and in vivo using the A549 human NSCLC cell line. A 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay was used to quantify the proliferation of the A549 cells; migration assay and invasiveness assays were performed using Transwell chambers and wound healing assays were used to assess cell motility, which was assessed by measuring the movement of cells. Inhibition of CDK5 by roscovitine and small interfering (si)RNA was used to investigate the mechanism of CDK5 in the process of A549 lung cancer cell proliferation, migration and invasion. The results demonstrated that functional inhibition of CDK5 using roscovitine and siRNA markedly suppressed the proliferation of A549 cells and resulted in a reduced tumor mass in vivo. In addition, the hinhibition of CDK5 reduced the migration and invasiveness of the A549 cells in vitro and in vivo. Notably, CDK5 inhibition also impaired tumor cell cytoskeletal remodeling and led to loss of cell polarity, which may partially explain the reduction of A549 cell mobility and invasiveness. The results of the present study revealed that CDK5 may be important in the regulation of migration and invasiveness in NSCLC through its effects on cytoskeletal remodeling.