Gene Summary

Gene:COL1A1; collagen type I alpha 1 chain
Aliases: OI1, OI2, OI3, OI4, EDSC
Summary:This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:collagen alpha-1(I) chain
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: COL1A1 (cancer-related)

Ryu D, Lee C
Expression quantitative trait loci for PI3K/AKT pathway.
Medicine (Baltimore). 2017; 96(1):e5817 [PubMed] Free Access to Full Article Related Publications
A genome-wide association study (GWAS) was conducted to identify expression quantitative trait loci (eQTLs) for the genes involved in phosphatidylinositol-3-kinase/v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway.Data on mRNA expression of 341 genes in lymphoblastoid cell lines of 373 Europeans recruited by the 1000 Genomes Project using Illumina HiSeq2000 were utilized. We used their genotypes at 5,941,815 nucleotide variants obtained by Genome Analyzer II and SOLiD.The association analysis revealed 4166 nucleotide variants associated with expression of 85 genes (P < 5 × 10). A total of 73 eQTLs were identified as association signals for the expression of multiple genes. They included 9 eQTLs for both of the genes encoding collagen type I alpha 1 (COL1A1) and integrin alpha 11 (ITGA11), which synthesize a major complex of plasma membrane. They also included eQTLs for type IV collagen molecules; 13 eQTLs for both collagen type IV alpha 1 (COL4A1) and collagen type IV alpha 2 (COL4A2) and 18 eQTLs for both collagen type IV alpha 5 (COL4A5) and collagen type IV alpha 6 (COL4A6). Some genes expressed by the eQTLs might induce expression of the genes encoding type IV collagen. One eQTL (rs16871986) was located in the promoter of palladin (PALLD) gene which might synthesize collagen by activating fibroblasts through the PI3K/AKT pathway. Another eQTL (rs34845474) was located in an enhancer of cadherin related family member 3 (CDHR3) gene which can mediate cell adhesion.This study showed a profile of eQTLs for the genes involved in the PI3K/AKT pathway using a healthy population, revealing 73 eQTLs associated with expression of multiple genes. They might be candidates of common variants in predicting genetic susceptibility to cancer and in targeting cancer therapy. Further studies are required to examine their underlying mechanisms for regulating expression of the genes.

Esbona K, Inman D, Saha S, et al.
COX-2 modulates mammary tumor progression in response to collagen density.
Breast Cancer Res. 2016; 18(1):35 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: High breast density is linked to an increased risk of breast cancer, and correlates with changes in collagen. In a mouse model of mammary carcinoma in the context of increased collagen deposition, the MMTV-PyMT/Col1a1 (tm1jae) , there is accelerated mammary tumor formation and progression. Previous gene expression analysis suggests that increased collagen density elevates expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for cyclooxygenase-2 (COX-2).
METHODS: To understand the role of COX-2 in tumor progression within a collagen-dense microenvironment, we treated MMTV-PyMT or MMTV-PyMT/Col1a1 (tm1jae) tumors prior to and after tumor formation. Animals received treatment with celecoxib, a specific COX-2 inhibitor, or placebo. Mammary tumors were examined for COX-2, inflammatory and stromal cell components, and collagen deposition through immunohistochemical analysis, immunofluorescence, multiplex cytokine ELISA and tissue imaging techniques.
RESULTS: PyMT/Col1a1 (tm1jae) tumors were larger, more proliferative, and expressed higher levels of COX-2 and PGE2 than PyMT tumors in wild type (WT) mice. Treatment with celecoxib significantly decreased the induced tumor size and metastasis of the PyMT/Col1a1 tumors, such that their size was not different from the smaller PyMT tumors. Celecoxib had minimal effect on the PyMT tumors. Celecoxib decreased expression levels of COX-2, PGE2, and Ki-67. Several cytokines were over-expressed in PyMT/Col1a1 compared to PyMT, and celecoxib treatment prevented their over-expression. Furthermore, macrophage and neutrophil recruitment were enhanced in PyMT/Col1a1 tumors, and this effect was inhibited by celecoxib. Notably, COX-2 inhibition reduced overall collagen deposition. Finally, when celecoxib was used prior to tumor formation, PyMT/Col1a1 tumors were fewer and smaller than in untreated animals.
CONCLUSION: These findings suggest that COX-2 has a direct role in modulating tumor progression in tumors arising within collagen-dense microenvironments, and suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue and early-stage breast cancer.

Makino M, Sasaoka S, Nakanishi G, et al.
Congenital atrophic dermatofibrosarcoma protuberans detected by COL1A1-PDGFB rearrangement.
Diagn Pathol. 2016; 11:24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Atrophic variant of dermatofibrosarcoma protuberans (DFSP) is a distinct form of DFSP.
CASE PRESENTATION: Here, we report the case of a 19-year-old woman with a small congenital atrophic plaque on the right precordium. The lesion remained atrophic for more than 10 years. Several years earlier, a portion of the plaque became tuberous and enlarged. Physical examination revealed a 25 × 30 mm erythematous atrophic plaque surrounded by three hard, smooth, and orange-colored nodules of varying sizes on the right precordium, along with visible subcutaneous adipose tissue and cutaneous veins. Biopsy of the nodule and atrophic plaque revealed dense proliferation of spindle-shaped tumor cells from the dermis to the subcutaneous adipose tissue, and positive immunostaining for CD34 and vimentin in addition to negative staining for factor XIIIa and α-smooth muscle actin. Reverse transcription polymerase chain reaction (RT-PCR) of the tumor tissue revealed the presence of a COL1A1-PDGFB fusion gene. Thus, congenital atrophic dermatofibrosarcoma protuberans was diagnosed. No metastasis to the lungs or regional lymph nodes was found on magnetic resonance imaging. Wide local excision and split-thickness skin grafting was performed and neither recurrence nor metastasis has been observed for 5 years and 8 months since the surgery.
CONCLUSION: This case indicates that a congenital atrophic lesion could represent a quiescent phase of DFSP. Awareness of this rare condition can aid with early diagnosis and thereby improve the prognosis of DFSP.

Guimaraes TA, Farias LC, Fraga CA, et al.
Evaluation of the antineoplastic activity of gallic acid in oral squamous cell carcinoma under hypoxic conditions.
Anticancer Drugs. 2016; 27(5):407-16 [PubMed] Related Publications
The purpose of the current study was to develop and test a theoretical model that could explain the mechanism of action of gallic acid (GA) in the oral squamous cell carcinoma context for the first time. The theoretical model was developed using bioinformatics and interaction network analysis to evaluate the effect of GA on oral squamous cell carcinoma. In a second step to confirm theoretical results, migration, invasion, proliferation, and gene expression (Col1A1, E-cadherin, HIF-1α, and caspase-3) were performed under normoxic and hypoxic conditions. Our study indicated that treatment with GA resulted in the inhibition of cell proliferation, migration, and invasion in neoplastic cells. Observation of the molecular mechanism showed that GA upregulates E-cadherin expression and downregulates Col1A1 and HIF-1α expression, suggesting that GA might be a potential anticancer compound. In conclusion, the present study demonstrated that GA significantly reduces cell proliferation, invasion, and migration by increasing E-cadherin and repressing Col1A1.

Patel A, Malik M, Britten J, et al.
Mifepristone inhibits extracellular matrix formation in uterine leiomyoma.
Fertil Steril. 2016; 105(4):1102-10 [PubMed] Related Publications
OBJECTIVE: To characterize the efficacy of mifepristone treatment on extracellular matrix (ECM) production in leiomyomas.
DESIGN: Laboratory study.
SETTING: University research laboratory.
INTERVENTION(S): Treatment of human immortalized two-dimensional (2D) and three-dimensional (3D) leiomyoma and myometrial cells with mifepristone and the progestin promegestone (R5020).
MAIN OUTCOME MEASURE(S): Expression of COL1A1, fibronectin, versican variant V0, and dermatopontin in treated leiomyoma cells by Western blot analysis and confirmatory immunohistochemistry staining of treated 3D cultures.
RESULT(S): Treatment with progestin stimulated production of COL1A1, fibronectin, versican, and dermatopontin. Mifepristone treatment inhibited protein production of these genes, most notably with versican expression. Combination treatment with both the agonist and antagonist further inhibited protein expression of these genes. Immunohistochemistry performed on 3D cultures demonstrated generalized inhibition of ECM protein concentration.
CONCLUSION(S): Our study demonstrated that the progesterone agonist R5020 directly stimulated extracellular matrix components COL1A1, fibronectin, versican, and dermatopontin production in human leiomyoma cells. Progesterone antagonist mifepristone decreased protein production of these genes to levels comparable with untreated leiomyoma cells.

Qiu J, Zhang W, Xia Q, et al.
RNA sequencing identifies crucial genes in papillary thyroid carcinoma (PTC) progression.
Exp Mol Pathol. 2016; 100(1):151-9 [PubMed] Related Publications
PURPOSE: The study aims to uncover molecular mechanisms of PTC (papillary thyroid carcinoma) progression and provide therapeutic biomarkers.
METHODS: The paired tumor and control tissues were obtained from 5 PTC patients. RNA was extracted and cDNA libraries were constructed. RNA-sequencing (RNA-seq) was performed on the Illumina HiSeq2000 platform using paired-end method. After preprocessing of the RNA-seq data, gene expression value was calculated by RPKM. Then the differentially expressed genes (DEGs) were identified with edgeR. Functional enrichment and protein-protein interaction (PPI) network analyses were conducted for the DEGs. Module analysis of the PPI network was also performed. Transcription factors (TFs) of DEGs were predicted.
RESULTS: A cohort of 496 up-regulated DEGs mainly correlating with the ECM degradation pathways, and 440 down-regulated DEGs predominantly enriching in transmembrane transport process were identified. Hub nodes in the PPI network were RRM2 and a set of collagens (COL1A1, COL3A1 and COL5A1), which were also remarkable in module 3 and module 5, respectively. Genes in module 3 were associated with cell cycle pathways, while in module 5 were related to ECM degradation pathways. PLAU, PSG1 and EGR2 were the crucial TFs with higher transcriptional activity in PTC than in control.
CONCLUSION: Several genes including COL1A1, COL3A1, RRM2, PLAU, and EGR2 might be used as biomarkers of PTC therapy. Among them, COL1A1 and COL3A1 might exert their functions via involving in ECM degradation pathway, while RRM2 through cell cycle pathway. PLAU might be an active TF, whereas EGR2 might be a tumor suppressor.

Huang QX, Cui JY, Ma H, et al.
Screening of potential biomarkers for cholangiocarcinoma by integrated analysis of microarray data sets.
Cancer Gene Ther. 2016 Feb-Mar; 23(2-3):48-53 [PubMed] Related Publications
Cholangiocarcinoma (CCA) continues to harbor a difficult prognosis and it is difficult to diagnose in its early stages. The molecular mechanisms of CCA oncogenesis and progression are poorly understood. This study aimed to identify candidate biomarkers for CCA. Integrated analysis of microarray data sets was performed to identify differentially expressed genes (DEGs) between CCA and normal tissues. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to identify the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. The expressions of DEGs were validated in human CCA tissues by qRT-PCR. A set of 712 DEGs were identified in CCA compared with normal tissues, including 306 upregulated and 406 downregulated DEGs. It can be shown from the KEGG pathway analysis that some pathways may have important roles in pathology of CCA, including peroxisome proliferator-activated receptor signaling pathway, bile secretion, cell cycle, fat digestion and absorption. PPI network indicated that the significant hub proteins were PKM, SPP1 and TPM1. The abnormally overexpression PKM, SPP1 and TPM1 were closely related to oncogenesis and progression of CCA. PKM, SPP1, TPM1, COL1A1 and COL1A2 may serve as candidate biomarkers for diagnosis and prognosis of CCA.

Kopp S, Warnke E, Wehland M, et al.
Mechanisms of three-dimensional growth of thyroid cells during long-term simulated microgravity.
Sci Rep. 2015; 5:16691 [PubMed] Free Access to Full Article Related Publications
Three-dimensional multicellular spheroids (MCS) of human cells are important in cancer research. We investigated possible mechanisms of MCS formation of thyroid cells. Both, normal Nthy-ori 3-1 thyroid cells and the poorly differentiated follicular thyroid cancer cells FTC-133 formed MCS within 7 and 14 days of culturing on a Random Positioning Machine (RPM), while a part of the cells continued to grow adherently in each culture. The FTC-133 cancer cells formed larger and numerous MCS than the normal cells. In order to explain the different behaviour, we analyzed the gene expression of IL6, IL7, IL8, IL17, OPN, NGAL, VEGFA and enzymes associated cytoskeletal or membrane proteins (ACTB, TUBB, PFN1, CPNE1, TGM2, CD44, FLT1, FLK1, PKB, PKC, ERK1/2, Casp9, Col1A1) as well as the amount of secreted proteins (IL-6, IL-7, IL-8, IL-17, OPN, NGAL, VEGFA). Several of these components changed during RPM-exposure in each cell line. Striking differences between normal and malignant cells were observed in regards to the expression of genes of NGAL, VEGFA, OPN, IL6 and IL17 and to the secretion of VEGFA, IL-17, and IL-6. These results suggest several gravi-sensitive growth or angiogenesis factors being involved in 3D formation of thyroid cells cultured under simulated microgravity.

Singh V, Singh LC, Vasudevan M, et al.
Esophageal Cancer Epigenomics and Integrome Analysis of Genome-Wide Methylation and Expression in High Risk Northeast Indian Population.
OMICS. 2015; 19(11):688-99 [PubMed] Related Publications
Esophageal cancer is a major global health burden with a strong host-environment interaction component and epigenomics underpinnings that remain to be elucidated further. Certain populations such as the Northeast Indians suffer at a disproportionately higher rate from this devastating disease. Promoter methylation is correlated with transcriptional silencing of various genes in esophageal cancer. Very few studies on genome-wide methylation for esophageal cancer exist and yet, no one has carried out an integromics analysis of methylation and gene expression. In the present study, genome-wide methylation was measured in samples collected from the Northeast Indian population by Infinium 450k array, and integration of the methylation data was performed. To prepare a network of genes displaying enriched pathways, together with the list of genes exhibiting promoter hypermethylation or hypomethylation with inversely correlated expression, we performed an integrome analysis. We identified 23 Integrome network enriched genes with relevance to tumor progression and associated with the processes involved in metastasis such as cell adhesion, integrin signaling, cytoskeleton, and extracellular matrix organizations. These included four genes (PTK2, RND1, RND3, and UBL3) with promoter hypermethylation and downregulation, and 19 genes (SEMG2, CD97, CTNND2, CADM3, OMD, NEFM, FBN2, CTNNB1, DLX6, UGT2B4, CCDC80, PZP, SERPINA4, TNFSF13B, NPC1, COL1A1, TAC3, BMP8A, and IL22RA2) with promoter hypomethylation and upregulation. A Methylation Efficiency Index was further calculated for these genes; the top five gene with the highest index were COL1A1, TAC3, SERPINA4, TNFSF13B, and IL22RA2. In conclusion, we recommend that the circulatory proteins IL22RA2, TNFSF13B, SERPINA4, and TAC3 in serum of patients and disease-free healthy controls can be examined in the future as putative noninvasive biomarkers.

Smith EH, Lan TT, Jo VY, et al.
Dermatofibrosarcoma Protuberans in a Patient With Cowden Syndrome: Revisiting the PTEN and PDGF Pathways.
Am J Dermatopathol. 2016; 38(4):e40-3 [PubMed] Related Publications
PTEN hamartoma tumor syndrome, of which Cowden syndrome (CS) is the most recognized variant, is characterized by multiple benign and malignant tumors of ectodermal, mesodermal, and endodermal origins, secondary to germline mutation in the phosphatase and tensin homolog (PTEN) gene. Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive malignant fibroblastic/myofibroblastic tumor of the skin, characterized by the t(17:22)(q22:q13) translocation resulting in fusion of the COL1A1 and PDGFB genes. An association between CS and DFSP has not been reported in the literature to date. The authors have encountered a male patient with CS and a history of DFSP that developed adjacent to a sclerotic fibroma on the parietal scalp, both excised at age 7. He presented at age 21 with an enlarging pink nodule at the same site on the parietal scalp. Excision revealed a dermal and subcutaneous storiform spindle cell proliferation with fat entrapment and positive staining for CD34, consistent with DFSP. Fluorescence in situ hybridization confirmed PDGFB gene rearrangement. PTEN expression in the patient's recurrent DFSP was nearly absent when compared with that of sporadic DFSP. To our knowledge, this is the first report of DFSP in a patient with CS. Although the association is likely to be coincidental, the authors revisited the PTEN and the PDGF pathways to speculate any possible interplay of the 2 conditions on a molecular level.

Piersma B, de Rond S, Werker PM, et al.
YAP1 Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts.
Am J Pathol. 2015; 185(12):3326-37 [PubMed] Related Publications
Dupuytren disease is a fibrotic disorder characterized by contraction of myofibroblast-rich cords and nodules in the hands. The Hippo member Yes-associated protein 1 (YAP1) is activated by tissue stiffness and the profibrotic transforming growth factor-β1, but its role in cell fibrogenesis is yet unclear. We hypothesized that YAP1 regulates the differentiation of dermal fibroblasts into highly contractile myofibroblasts and that YAP1 governs the maintenance of a myofibroblast phenotype in primary Dupuytren cells. Knockdown of YAP1 in transforming growth factor-β1-stimulated dermal fibroblasts decreased the formation of contractile smooth muscle α-actin stress fibers and the deposition of collagen type I, which are hallmark features of myofibroblasts. Translating our findings to a clinically relevant model, we found that YAP1 deficiency in Dupuytren disease myofibroblasts resulted in decreased expression of ACTA2, COL1A1, and CCN2 mRNA, but this did not result in decreased protein levels. YAP1-deficient Dupuytren myofibroblasts showed decreased contraction of a collagen hydrogel. Finally, we showed that YAP1 levels and nuclear localization were elevated in affected Dupuytren disease tissue compared with matched control tissue and partly co-localized with smooth muscle α-actin-positive cells. In conclusion, our data show that YAP1 is a regulator of myofibroblast differentiation and contributes to the maintenance of a synthetic and contractile phenotype, in both transforming growth factor-β1-induced myofibroblast differentiation and primary Dupuytren myofibroblasts.

Grigoroiu M, Tagett R, Draghici S, et al.
Gene-expression Profiling in Non-small Cell Lung Cancer with Invasion of Mediastinal Lymph Nodes for Prognosis Evaluation.
Cancer Genomics Proteomics. 2015 Sep-Oct; 12(5):231-42 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the study was to determine the pathways and expression profile of the genes that might predict response to neoadjuvant chemotherapy in patients with stage IIIA non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: We evaluated, by microarray, the gene-expression profile of tumoral mediastinal lymph node samples surgically removed from 27 patients with stage IIIA NSCLC before neoadjuvant chemotherapy treatment. Depending on the response to the induction treatment, the patients were divided in two groups: group A: patients whose disease evolved, stabilized or who had minor response to chemotherapy, and group B: patients whose disease stabilized or had major response to chemotherapy.
RESULTS: The microarray experiments identified 1,127 genes with a modified expression in the tumoral tissue compared to normal tissue with p≤0.05 and 44 genes with p≤0.01. The identified up-regulated genes between tumoral versus normal tissue included collagen, type I, alpha 1 (COL1A1), inhibin beta A (INHBA) and thioredoxin interacting protein (TXNIP). Pathways identified with a false-discovery rate of <0.005 included: cytokine pathways, focal adhesion or extracellular matrix receptor interaction.
CONCLUSION: Our approach identified important characteristics of NSCLC and pointed-out molecular differences between sub-groups of patients based on their response to therapy.

Chai F, Liang Y, Zhang F, et al.
Systematically identify key genes in inflammatory and non-inflammatory breast cancer.
Gene. 2016; 575(2 Pt 3):600-14 [PubMed] Related Publications
Although the gene expression in breast tumor stroma, playing a critical role in determining inflammatory breast cancer (IBC) phenotype, has been proved to be significantly different between IBC and non-inflammatory breast cancer (non-IBC), more effort needs to systematically investigate the gene expression profiles between tumor epithelium and stroma and to efficiently uncover the potential molecular networks and critical genes for IBC and non-IBC. Here, we comprehensively analyzed and compared the transcriptional profiles from IBC and non-IBC patients using hierarchical clustering, protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analyses, and identified PDGFRβ, SUMO1, COL1A1, FYN, CAV1, COL5A1 and MMP2 to be the key genes for breast cancer. Interestingly, PDGFRβ was found to be the hub gene in both IBC and non-IBC; SUMO1 and COL1A1 were respectively the key genes for IBC and non-IBC. These analysis results indicated that those key genes might play important role in IBC and non-IBC and provided some clues for future studies.

Noguchi S, Eitoku M, Moriya S, et al.
Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition.
Lung. 2015; 193(5):691-700 [PubMed] Related Publications
PURPOSE: Epithelial-to-mesenchymal transition (EMT) is an important mechanism in cancer metastasis and pulmonary fibrosis. Previous studies demonstrated effect of histone H3 and H4 acetylation in cancer and pulmonary fibrosis, so we hypothesized that histone modification might play a crucial role in gene regulation during EMT. In this study, we investigated the mechanism behind EMT by analyzing comprehensive gene expression and the effect of sodium valproate (VPA), a class I histone deacetylase inhibitory drug, on histone modification.
METHODS: EMT was induced in human alveolar epithelial cells (A549) using 5 ng/mL of transforming growth factor (TGF)-β1. Various concentrations of VPA were then administered, and Western blotting was used to analyze histone acetylation or methylation. Comprehensive gene expression analysis was carried out by RNA sequencing, and chromatin immunoprecipitation was performed with an anti-acetyl histone H3 lysine 27 antibody.
RESULTS: TGF-β1 stimulation led to a decrease in histone acetylation, especially that of histone H3K27, and H3K27ac localization was decreased at particular gene loci. This decrease was recovered by VPA treatment, which also up-regulated the mRNA expression of genes down-regulated by TGF-β1, and correlated with the localization of H3K27ac. However, genes up-regulated by TGF-β1 stimulation were not suppressed by VPA, with the exception of COL1A1.
CONCLUSIONS: Histone acetylation was down-regulated by TGF-β1 stimulation in A549 cells. VPA partially inhibited EMT and the decrease of histone acetylation, which plays an important role in the progression of EMT.

Ilhan-Mutlu A, Siehs C, Berghoff AS, et al.
Expression profiling of angiogenesis-related genes in brain metastases of lung cancer and melanoma.
Tumour Biol. 2016; 37(1):1173-82 [PubMed] Related Publications
Brain metastases (BM) are the most common brain tumors of adults and are associated with fatal prognosis. Formation of new blood vessels, named angiogenesis, was proposed to be the main hallmark of the growth of BM. Previous preclinical evidence revealed that angiogenic blockage might be considered for treatment; however, there were varying responses. In this study, we aimed to characterize the expression pattern of angiogenesis-related genes in BM of lung cancer and melanoma, which might be of importance for the different responses against anti-angiogenic treatment. Fifteen snap-frozen tissues obtained from BM of non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and melanoma patients were analyzed for angiogenesis-related genes using a commercially available gene expression kit. Epilepsy tissue was used as control. Expression values were analyzed using hierarchical clustering investigating relative fold changes and mapping to Omicsnet protein interaction network. CXCL10, CEACAM1, PECAM1, KIT, COL4A2, COL1A1, and HSPG2 genes were more than 50-fold up-regulated in all diagnosis groups when compared to control, whereas genes such as ANGPT4, PDGFRB, and SERPINF1 were down-regulated only in SCLC and melanoma groups, respectively. Using hierarchical clustering, 12 out of 15 cases were allocated to the correct histological primary tumor type. We identified genes with consistent up-regulation in BM of lung cancer and melanoma and other genes with differential expression across BM of these tumor types. Our data may be of relevance for targeted therapy or prophylaxis of BM using anti-angiogenic agents.

Xu WJ, Wang JS
Atrophic dermatofibrosarcoma protuberans with the fusion gene COL1A1-PDGFB detected by RT-PCR using only a single primer pair.
Int J Clin Exp Pathol. 2015; 8(6):7457-63 [PubMed] Free Access to Full Article Related Publications
Dermatofibrosarcoma protuberans (DFSPs) is an uncommon dermal tumor of intermediate to low-grade malignancy. A few patients have clinically persistent plaques that might be atrophic, and they are difficult to be diagnosed clinically. With the development of cytogenetic and molecular biology techniques, the detection of fusion transcripts of the collagen type 1a1 (COL1A1) and platelet-derived growth factor-BB (PDGFB) genes has been recognized as a reliable and valuable molecular tool for the diagnosis of DFSPs. We reported a 24-year-old woman who had a 2 years history of atrophic DFSPs, and detected the gene fusion between COL1A1 to PDGFB by one-step method of RT-PCR using only a single primer pair. The gene fusion detected by this rapid and efficient one-step method in our patient appears to be the first report of atrophic DFSPs, and we detected a novel COL1A1 breakpoint between exon 2 and exon 3.

Stacchiotti S, Pantaleo MA, Negri T, et al.
Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP).
Clin Cancer Res. 2016; 22(4):837-46 [PubMed] Related Publications
PURPOSE: To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology.
EXPERIMENTAL DESIGN: Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFB was performed. Two IM-treated and 4 naïve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis.
RESULTS: All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 partial response, 1 stable disease, and 1 progressive disease. Median progression-free survival was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most upregulated genes included those encoding for immunoglobulins and those affecting functions and differentiation of endothelial cells. Pathway enrichment analysis revealed upregulation in genes involved in antigen processing and presentation, natural killer-mediated cytotoxicity, and drug and xenobiotics metabolism. Conversely, a significant down-regulation of kinase signaling pathways was detected.
CONCLUSIONS: All metastatic cases were fibrosarcomatous. Most patients responded to IM, but PFS was shorter than reported in published series which included both DFSP and FS-DFSP. All patients operated after IM had a relapse, suggesting that IM cannot eradicate metastatic cases and that the role of surgery is limited. Transcriptional profile of naïve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.

Lin J, Goldstein L, Nesbit A, Chen MY
Influence of Hormone Receptor Status on Spinal Metastatic Lesions in Patients with Breast Cancer.
World Neurosurg. 2016; 85:42-8 [PubMed] Related Publications
OBJECTIVE: Bony metastasis predominantly affects the spinal column and has been commonly associated in patients with breast cancer. There are two types of lesions that can occur with spine cancer-osteolytic or osteoblastic. Some patients may have mixed lesions, which include lytic and blastic in one vertebra or lytic and blastic in different vertebrae. Previous studies have shown that patients with breast cancer have an increased likelihood for development of lytic spinal metastases.
METHODS: A retrospective chart review was conducted to more closely examine the association between hormone receptor status and spinal lesion type. A total of 195 patients were initially identified through the City of Hope Cancer Registry. Of the 195, only 153 patients had hormone receptor marker status available. Associations between spinal lesion and hormone receptor status were evaluated using χ(2) tests with alpha = 0.05 significance level. In a secondary analysis, the Oncomine Platform was used, which integrated The Cancer Genome Atlas (TCGA) datasets, to identify osteogenic genes that may be relevant to invasive breast cancers.
RESULTS: Contrary to previous studies, our findings revealed progesterone receptor positive (PR+) patients were significantly more likely to present with blastic than lytic or mixed lesions. Furthermore, using TCGA analysis, COL1A1 and COL1A2 were found to be up-regulated, which could provide a molecular explanation for the development of blastic metastases.
CONCLUSIONS: By integrating clinical and bioinformatic techniques, this study provides a novel discovery of the relationship between blastic and PR + breast cancers, which may have important implications for diagnostic strategies concerning vertebral metastases.

Zhu LH, Miao XT, Wang NY
Integrated miRNA-mRNA analysis of Epstein-Barr virus-positive nasopharyngeal carcinoma.
Genet Mol Res. 2015; 14(2):6028-36 [PubMed] Related Publications
This study aims to identify the crucial miRNAs in Epstein-Barr virus-positive nasopharyngeal carcinoma (NPC) and their target genes. Gene expression profile data (GSE12452) that included 31 NPC and 10 normal nasopharyngeal tissue specimens were downloaded. Differentially expressed genes (DEGs) were identified using significance analysis of microarrays. The underlying function of DEGs was predicted via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The miRNA sequencing dataset GSE14738 was also downloaded, and expression levels of miRNA were calculated by the number of reads mapped to each miRNA. The selected miRNAs were integrated into the miRecords database to obtain their target genes. Target genes associated with DEGs were used to construct the interaction network via Cytoscape. A total of 1437 DEGs between NPC and control were identified, most of which were enriched in cell cycle and extracellular matrix-receptor interaction signaling pathways. Furthermore, 112 miRNAs were considered upregulated in NPC samples. A total of 2228 relationships between 39 miRNAs and 1247 target genes were obtained, of which 182 relationships between 32 miRNAs and 97 target genes were chosen to construct an interaction network. The interactions between DEGs and the let-7 or miR-29 families appeared strongest in this network, where CDC25A, COL3A1, and COL1A1 were regulated by several let-7 family members, while COL4A1 and COL5A2 were regulated by several miR-29 family members. The let-7 and miR-29 families may be related to the development of NPC by regulating the genes involved in cell cycle and ECM-receptor interaction.

Bai C, Yang M, Fan Z, et al.
Associations of chemo- and radio-resistant phenotypes with the gap junction, adhesion and extracellular matrix in a three-dimensional culture model of soft sarcoma.
J Exp Clin Cancer Res. 2015; 34:58 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Three-dimensional (3D) culture models are considered to recapitulate the cell microenvironment in solid tumors, including the extracellular matrix (ECM), cell-cell interactions, and signal transduction. These functions are highly correlated with cellular behaviors and contribute to resistances against chemo- and radio-therapies. However, the biochemical effects and mechanisms remain unknown in soft sarcoma. Therefore, we developed an in vitro 3D model of sarcoma to analyze the reasons of the chemo- and radio-resistance in therapies.
METHODS: Four soft sarcoma cell lines, HT1080, RD, SW872, and human osteosarcoma cell line 1 (HOSS1), a cell line established from a patient-derived xenograft, were applied to 3D culture and treated with growth factors in methylcellulose-containing medium. Spheroids were examined morphologically and by western blotting, RT-qPCR, and immunofluorescence staining to analyze cell adhesion, gap junctions, ECM genes, and related factors. Proliferation and colony formation assays were performed to assess chemo- and radio-resistances between 3D and two-dimensional (2D) cell cultures. Annexin V and Propidium Iodide staining was used to detect early apoptotic sarcoma cells treated with Doxorubicin, Gemcitabine, and Docetaxel in the 3D model.
RESULTS: The four soft sarcoma cell lines formed spheres in vitro by culture in modified condition medium. Compared with 2D cell culture, expression of ECM genes and proteins, including COL1A1, LOX, SED1, FN1, and LAMA4, was significantly increased in 3D culture. Analysis of cadherin and gap junction molecules showed significant changes in the gene and protein expression profiles under 3D conditions. These changes affected cell-cell communication and were mainly associated with biological processes such as cell proliferation and apoptosis related to chemo- and radio-resistances.
CONCLUSIONS: Our findings revealed significant differences between 3D and 2D cell culture systems, and indicated that cellular responsiveness to external stress such as radiation and chemotherapeutics is influenced by differential expression of genes and proteins involved in regulation of the ECM, cell adhesion, and gap junction signaling.

Moreira D, Zhang Q, Hossain DM, et al.
TLR9 signaling through NF-κB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells.
Oncotarget. 2015; 6(19):17302-13 [PubMed] Free Access to Full Article Related Publications
Prostate cancer progression was associated with tumorigenic signaling activated by proinflammatory mediators. However, the etiology of these events remains elusive. Here, we demonstrate that triggering of the innate immune receptor, Toll-like Receptor 9 (TLR9), in androgen-independent prostate cancer cells initiates signaling cascade leading to increased tumor growth and progression. Using limited dilution/serial transplantation experiments, we show that TLR9 is essential for prostate cancer cells' potential to propagate and self-renew in vivo. Furthermore, low expression or silencing of TLR9 limits the clonogenic potential and mesenchymal stem cell-like properties of LNCaP- and PC3-derived prostate cancer cell variants. Genome-wide transcriptional analysis of prostate cancer cells isolated from xenotransplanted TLR9-positive and -negative tumors revealed a unique gene expression signature, with prominent upregulation of inflammation- and stem cell-related markers. TLR9 signaling orchestrated expression of critical stem cell-related genes such as NKX3.1, KLF-4, BMI-1 and COL1A1, at both mRNA and protein levels. Our further analysis identified that TLR9-induced NF-κB/RELA and STAT3 transcription factors co-regulated NKX3.1 and KLF4 gene expression by directly binding to both promoters. Finally, we demonstrated the feasibility of using TLR9-targeted siRNA delivery to block RELA- and STAT3-dependent prostate cancer cell self-renewal in vivo. The intratumoral administration of CpG-RELAsiRNA or CpG-STAT3siRNA but not control conjugates inhibited growth of established prostate tumors and reduced clonogenic potential of cancer cells. Overcoming cancer cell self-renewal and tumor-propagating potential by targeted inhibition of TLR9 signaling can provide therapeutic strategy for late-stage prostate cancer patients.

Lichner Z, Ding Q, Samaan S, et al.
miRNAs dysregulated in association with Gleason grade regulate extracellular matrix, cytoskeleton and androgen receptor pathways.
J Pathol. 2015; 237(2):226-37 [PubMed] Related Publications
The Gleason grading system is an important determinant of treatment decisions and prognosis in prostate cancer. It has a number of limitations, including significant inter-observer variability, creating a need for biological parameters to accurately assess the Gleason grade. The objective of this study was to determine the molecular correlates of the different Gleason grades. Global miRNA expression was analysed in pure regions of each Gleason grade. Bioinformatics analysis was performed to predict miRNA-mediated signalling. We experimentally validated the effect of miRNAs on target gene expression and cellular functions using cell line models. We also examined the correlation of miRNAs with biochemical failure, metastasis and prognosis. We identified miRNAs that are differentially expressed between grades 3 and 5, and the top biological processes associated with Gleason grade transition were extracellular matrix (ECM)-mediated signalling, focal adhesion kinase- and mitogen-activated kinase pathways. Transfection with miR-29c, miR-34a and miR-141 repressed genes involved in ECM-mediated pathways, such as SRC, PRKCA, COL1A1, ITGB1 and MAPK13, and decreased cell proliferation and migration. Furthermore, miR-29c and miR-34a influenced downstream pathways that affect actin cytoskeleton organization and androgen receptor localization. Finally, miR-29c, miR-34a, miR-141 and miR-148a showed inverse correlations with biochemical recurrence, but were independent of other clinical parameters. Our results demonstrate the potential role of miRNAs as independent prognostic markers and pave the road for a biological-based reclassification of the Gleason grading system.

Wang C, Luo Z, Chen J, et al.
Target therapy of unresectable or metastatic dermatofibrosarcoma protuberans with imatinib mesylate: an analysis on 22 Chinese patients.
Medicine (Baltimore). 2015; 94(17):e773 [PubMed] Free Access to Full Article Related Publications
Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors.

Bashir S, Tariq M, Aslam HM, et al.
Orbital dermatofibrosarcoma protuberans with intracranial extension preceded by recurrent leiomyoma of the orbit: a case report.
J Med Case Rep. 2015; 9:96 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Dermatofibrosarcoma protuberans is a rare, locally aggressive cutaneous tumor of intermediate to low-grade malignancy. COL1A1-PDGFβ translocation is specific to dermatofibrosarcoma protuberans, where the abnormally fused COL1A1-PDGFβ gene directs formation of an abnormal combined (fusion) protein that researchers believe to ultimately function like the platelet-derived growth factor-beta protein.
CASE PRESENTATION: In this report, we present a case of a 63-year-old Asian man with dermatofibrosarcoma protuberans of the right orbit with intracranial extension. He had a prior history of recurrent leiomyomas at the identical site. He underwent near-total en bloc resection of the tumor through a wide craniectomy with a 6 cm rim of the frontal scalp, allowing the tumor to be resected en bloc, leaving negative margins. Microscopically, the tumor comprised spindle cells with mild nuclear atypia and a low mitotic index embedded in a spiraling pattern of decussating fascicles consistent with dermatofibrosarcoma protuberans. The lesion was positive for CD34 and BCL2. Following resection, the patient was started on imatinib mesylate therapy (800 mg/day).
CONCLUSIONS: We propose that platelet-derived growth factor, which has been implicated in the progression of leiomyomas by augmenting mitogenesis, may have acted in an autocrine manner to cause cell division, which may have led to the development of dermatofibrosarcoma protuberans in our patient. Further research is imperative to find certain molecular associations between the discussed soft tissue tumors. Also important is the effective utilization of platelet-derived growth factor receptor kinase inhibitors to prevent transformation to any platelet-derived growth factor-driven tumor, which in our patient was a dermatofibrosarcoma protuberans.

Zhang H, Teng X, Liu Z, et al.
Gene expression profile analyze the molecular mechanism of CXCR7 regulating papillary thyroid carcinoma growth and metastasis.
J Exp Clin Cancer Res. 2015; 34:16 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To detect genetic expression profile alterations after papillary thyroid carcinoma (PTC) cells transfected with chemokine receptor CXCR7 gene by gene microarray, and gain insights into molecular mechanisms of how CXCR7 regulating PTC growth and metastasis.
METHODS: The Human OneArray microarray was used for a complete genome-wide transcript profiling of CXCR7 transfected PTCs (K1-CXCR7 cells), defined as experimental group. Non CXCR7 transfected PTCs (K1 cells) were used as control group. Differential analysis for per gene was performed with a random variance model and t test, p values were adjusted to control the false discovery rate. Gene ontology (GO) on differentially expressed genes to identify the biological processes in modulating the progression of papillary thyroid carcinoma. Pathway analysis was used to evaluate the signaling pathway that differentially expressed genes were involved in. In addition, quantitative real-time polymerase chain reaction (q-PCR) and Western blot were used to verify the top differentially expression genes.
RESULTS: Comparative analysis revealed that the expression level of 1149 genes was changed in response to CXCR7 transfection. After unsupervised hierarchical clustering analysis, 270 differentially expressed genes were filtered, of them 156 genes were up-regulated whereas 114 genes were down-regulated in K1-CXCR7 cells. GO enrichment analysis revealed the differentially expressed genes were mainly involved in biopolymer metabolic process, signal transduction and protein metabolism. Pathway enrichment analysis revealed differentially expressed genes were mainly involved in ECM-receptor interaction, Focal adhesion, MAPK signaling pathway and Cytokine-cytokine receptor interaction pathway. More importantly, the expression level of genes closely associated with tumor growth and metastasis was altered significantly in K1-CXCR7 cells, including up-regulated genes FN1, COL1A1, COL4A1, PDGFRB, LTB, CXCL12, MMP-11, MT1-MMP and down-regulated genes ITGA7, and Notch-1.
CONCLUSIONS: Gene expression profiling analysis of papillary thyroid carcinoma can further delineate the mechanistic insights on how CXCR7 regulating papillary thyroid carcinoma growth and metastasis. CXCR7 may regulate growth and metastasis of papillary thyroid carcinoma via the activation of PI3K/AKT pathway and its downstream NF-κB signaling, as well as the down-regulation of Notch signaling.

Shi Y, Wang J, Xin Z, et al.
Transcription factors and microRNA-co-regulated genes in gastric cancer invasion in ex vivo.
PLoS One. 2015; 10(4):e0122882 [PubMed] Free Access to Full Article Related Publications
Aberrant miRNA expression abnormally modulates gene expression in cells and can contribute to tumorigenesis in humans. This study identified functionally relevant differentially expressed genes using the transcription factors and miRNA-co-regulated network analysis for gastric cancer. The TF-miRNA co-regulatory network was constructed based on data obtained from cDNA microarray and miRNA expression profiling of gastric cancer tissues. The network along with their co-regulated genes was analyzed using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Transcriptional Regulatory Element Database (TRED). We found eighteen (17 up-regulated and 1 down-regulated) differentially expressed genes that were co-regulated by transcription factors and miRNAs. KEGG pathway analysis revealed that these genes were part of the extracellular matrix-receptor interaction and focal adhesion signaling pathways. In addition, qRT- PCR and Western blot data showed an increase in COL1A1 and decrease in NCAM1 mRNA and protein levels in gastric cancer tissues. Thus, these data provided the first evidence to illustrate that altered gene network was associated with gastric cancer invasion. Further study with a large sample size and more functional experiments is needed to confirm these data and contribute to diagnostic and treatment strategies for gastric cancer.

Sakai Y, Yamamori T, Yasui H, Inanami O
Downregulation of the DNA repair enzyme apurinic/apyrimidinic endonuclease 1 stimulates transforming growth factor-β1 production and promotes actin rearrangement.
Biochem Biophys Res Commun. 2015; 461(1):35-41 [PubMed] Related Publications
The DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in base excision repair and functions as a reductive activator of various transcription factors. Multiple other functionalities have been ascribed to APE1 in addition to these major functions. A recent study showed that APE1 knockdown upregulated the expression of a set of genes related to extracellular matrix (ECM) production, indicating an additional novel biological role for this enzyme. Based on this finding, we have investigated the effect of APE1 downregulation on ECM-related gene expression and its biological consequences. Endogenous APE1 expression was downregulated in human cervical carcinoma HeLa cells and human lung carcinoma A549 cells using siRNA. When the expression of six ECM-related genes (TGFB1, LAMC1, FN1, COL1A1, COL3A1, and COL4A1) was evaluated, we found that APE1 knockdown upregulated the expression of TGFB1 in both cell lines. APE1 downregulation promoted actin rearrangement, inducing F-actin accumulation in HeLa cells and the dissipation of stress fibers in A549 cells. We also discovered that APE1 knockdown enhanced cellular motility in A549 cells, which was suppressed by the inhibition of transforming growth factor (TGF)-β1 signaling. These results suggested that APE1 controls the organization of actin cytoskeleton through the regulation of TGF-β1 expression, providing novel insights into the biological significance of APE1.

Tian ZQ, Li ZH, Wen SW, et al.
Identification of Commonly Dysregulated Genes in Non-small-cell Lung Cancer by Integrated Analysis of Microarray Data and qRT-PCR Validation.
Lung. 2015; 193(4):583-92 [PubMed] Related Publications
BACKGROUND: Non-small-cell lung cancer (NSCLC), the most common lung cancer, leads to the largest number of cancer-related deaths worldwide. There are many studies to identify the differentially expressed genes (DEGs) between NSCLC and normal control (NC) tissues by means of microarray technology. Because of the inconsistency of the microarray data sets, we performed an integrated analysis to identify DEGs and analyzed their biological function.
METHODS AND RESULTS: We combined 15 microarray data sets and identified 1063 DEGs between NSCLC and NC tissues; in addition, we found that the DEGs were enriched in regulation of cell proliferation process and focal adhesion signaling pathway. The protein-protein interaction network analysis for the top 20 significantly DEGs revealed that CAV1, COL1A1, and ADRB2 were the significant hub proteins. Finally, we employed qRT-PCR to validate the meta-analysis approach by determining the expression of the top 10 most significantly DEGs and found that the expression of these genes were significantly different between tumor and NC tissues, in accordance with the results of meta-analysis.
CONCLUSION: qRT-PCR results indicated that the meta-analysis approach in our study was acceptable. Our data suggested that some of the DEGs, including MMP12, COL11A1, THBS2, FAP, and CAV1, may participate in the pathology of NSCLC and could be applied as potential markers or therapeutic targets for NSCLC.

Kološa K, Motaln H, Herold-Mende C, et al.
Paracrine effects of mesenchymal stem cells induce senescence and differentiation of glioblastoma stem-like cells.
Cell Transplant. 2015; 24(4):631-44 [PubMed] Related Publications
Glioblastoma multiforme (GBM) displays high resistance to radiation and chemotherapy, due to the presence of a fraction of GBM stem-like cells (GSLCs), which are thus representing the target for GBM elimination. Since mesenchymal stem cells (MSCs) display high tumor tropism, we examined possible antitumor effects of the secreted factors from human MSCs on four GSLC lines (NCH421k, NCH644, NIB26, and NIB50). We found that conditioned media from bone marrow and umbilical cord-derived MSCs (MSC-CM) mediated cell cycle arrest of GSLCs by downregulating cyclin D1. PCR arrays revealed significantly deregulated expression of 13 genes associated with senescence in NCH421k cells exposed to MSC-CM. Among these, ATM, CD44, COL1A1, MORC3, NOX4, CDKN1A, IGFBP5, and SERPINE1 genes were upregulated, whereas IGFBP3, CDKN2A, CITED2, FN1, and PRKCD genes were found to be downregulated. Pathway analyses in GO and KEGG revealed their association with p53 signaling, which can trigger senescence via cell cycle inhibitors p21 or p16. For both, upregulated expression was proven in all four GSLC lines exhibiting senescence after MSC-CM exposure. Moreover, MSC paracrine signals were shown to increase the sensitivity of NCH421k and NCH644 cells toward temozolomide, possibly by altering them toward more differentiated cell types, as evidenced by vimentin and GFAP upregulation, and Sox-2 and Notch-1 downregulation. Our findings support the notion that MSCs posses an intrinsic ability to inhibit cell cycle and induce senescence and differentiation of GSLCs.

Garcia-Carracedo D, Yu CC, Akhavan N, et al.
Smad4 loss synergizes with TGFα overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis.
PLoS One. 2015; 10(3):e0120851 [PubMed] Free Access to Full Article Related Publications
AIMS: While overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation.
METHODS: The MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR.
RESULTS: Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFα mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC.
CONCLUSION: We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer.

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