Gene Summary

Gene:COL1A2; collagen type I alpha 2 chain
Summary:This gene encodes the pro-alpha2 chain 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 VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:collagen alpha-2(I) chain
Source:NCBIAccessed: 31 August, 2019


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

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Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: COL1A2 (cancer-related)

Fan X, Wang Y, Tang XQ
Extracting predictors for lung adenocarcinoma based on Granger causality test and stepwise character selection.
BMC Bioinformatics. 2019; 20(Suppl 7):197 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer, with high mortality worldwide. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, DNA methylation, and miRNA quantification. However, the hub genes, which can be served as bio-markers for discriminating cancer and healthy individuals, are not well screened.
RESULT: Here we present a new method for extracting gene predictors, aiming to obtain the least predictors without losing the efficiency. We firstly analyzed three different expression microarrays and constructed multi-interaction network, since the individual expression dataset is not enough for describing biological behaviors dynamically and systematically. Then, we transformed the undirected interaction network to directed network by employing Granger causality test, followed by the predictors screened with the use of the stepwise character selection algorithm. Six predictors, including TOP2A, GRK5, SIRT7, MCM7, EGFR, and COL1A2, were ultimately identified. All the predictors are the cancer-related, and the number is very small fascinating diagnosis. Finally, the validation of this approach was verified by robustness analyses applied to six independent datasets; the precision is up to 95.3% ∼ 100%.
CONCLUSION: Although there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new, robust, and effective method for extracting gene predictors. We identified as low as 6 genes which can be taken as predictors for diagnosing lung adenocarcinoma.

Tang X, Huang X, Wang D, et al.
Identifying gene modules of thyroid cancer associated with pathological stage by weighted gene co-expression network analysis.
Gene. 2019; 704:142-148 [PubMed] Related Publications
Thyroid cancer is the most common type of endocrine tumor. The TNM classification remains a standard for treatment determination and predicting prognosis in thyroid cancer. The genes modules associated with the progression of papillary thyroid carcinoma (PTC) were not clear. We applied a weighted gene co-expression network analysis (WGCNA) and differential expression analysis to systematically identified co-expressed gene modules and hub genes associated with PTC progression based on The Cancer Genome Atlas (TCGA) PTC transcriptome sequencing data. An independent validation cohort, GSE27155, was used to evaluate the preservation of gene modules. We identified two co-expressed genes modules associated with progression of PTC. Enrichment analysis indicated that the two modules were enriched in angiogenesis and extracellular matrix organization. DCN, COL1A1, COL1A2, COL5A2 and COL3A1 were hub genes in the co-expressed network. We systematically identified co-expressed gene modules and hub genes associated with PTC progression for the first time, which provided insights into the mechanisms underlying PTC progression and some potential targets for the treatment of PTC.

Hao S, Lv J, Yang Q, et al.
Identification of Key Genes and Circular RNAs in Human Gastric Cancer.
Med Sci Monit. 2019; 25:2488-2504 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Globally, gastric cancer (GC) is the third most common source of cancer-associated mortality. The aim of this study was to identify key genes and circular RNAs (circRNAs) in GC diagnosis, prognosis, and therapy and to further explore the potential molecular mechanisms of GC. MATERIAL AND METHODS Differentially expressed genes (DEGs) and circRNAs (DE circRNAs) between GC tissues and adjacent non-tumor tissues were identified from 3 mRNA and 3 circRNA expression profiles. Functional analyses were performed, and protein-protein interaction (PPI) networks were constructed. The significant modules and key genes in the PPI networks were identified. Kaplan-Meier analysis was performed to evaluate the prognostic value of these key genes. Potential miRNA-binding sites of the DE circRNAs and target genes of these miRNAs were predicted and used to construct DE circRNA-miRNA-mRNA networks. RESULTS A total of 196 upregulated and 311 downregulated genes were identified in GC. The results of functional analysis showed that these DEGs were significantly enriched in a variety of functions and pathways, including extracellular matrix-related pathways. Ten hub genes (COL1A1, COL3A1, COL1A2, COL5A2, FN1, THBS1, COL5A1, SPARC, COL18A1, and COL11A1) were identified via PPI network analysis. Kaplan-Meier analysis revealed that 7 of these were associated with a poor overall survival in GC patients. Furthermore, we identified 2 DE circRNAs, hsa_circ_0000332 and hsa_circ_0021087. To reveal the potential molecular mechanisms of circRNAs in GC, DE circRNA-microRNA-mRNA networks were constructed. CONCLUSIONS Key candidate genes and circRNAs were identified, and novel PPI and circRNA-microRNA-mRNA networks in GC were constructed. These may provide useful information for the exploration of potential biomarkers and targets for the diagnosis, prognosis, and therapy of GC.

Dong Z, Lin W, Kujawa SA, et al.
Predicting MicroRNA Target Genes and Identifying Hub Genes in IIA Stage Colon Cancer Patients Using Bioinformatics Analysis.
Biomed Res Int. 2019; 2019:6341967 [PubMed] Free Access to Full Article Related Publications
Background: Colon cancer is a heterogeneous disease, differing in clinical symptoms, epigenetics, and prognosis for each individual patient. Identifying the core genes is important for early diagnoses and it provides a more precise method for treating colon cancer.
Materials and Methods: In this study, we wanted to pinpoint these core genes so we obtained GSE101502 microRNA profiles from the GEO database, which resulted in 17 differential expressed microRNAs that were identified by GEO2R analysis. Then, 875 upregulated and 2920 downregulated target genes were predicted by FunRich. GO and KEGG pathway were used to do enrich analysis.
Results: GO analysis indicated that upregulated genes were significantly enriched in the regulation of cell communication and signaling and in nervous system development, while the downregulated genes were significantly enriched in nervous system development and regulation of transcription from the RNA polymerase II promoter. KEGG pathway analysis suggested that the upregulated genes were enriched in axon guidance, MAPK signaling pathway, and endocytosis, while the downregulated genes existed in pathways in cancer, focal adhesion, and PI3K-Akt signaling pathway. The top four molecules including 82 hub genes were identified from the PPI network and involved in endocytosis, spliceosome, TGF-beta signaling pathway, and lysosome. Finally, NUDT21, GNB1, CLINT1, and COL1A2 core gene were selected due to their correlation with the prognosis of IIA stage colon cancer.
Conclusion: this study suggested that NUDT21, GNB1, CLINT1, and COL1A2 might be the core genes for colon cancer that play an important role in the development and prognosis of IIA stage colon cancer.

Nissen NI, Karsdal M, Willumsen N
Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology.
J Exp Clin Cancer Res. 2019; 38(1):115 [PubMed] Free Access to Full Article Related Publications
The extracellular matrix (ECM) plays an important role in cancer progression. It can be divided into the basement membrane (BM) that supports epithelial/endothelial cell behavior and the interstitial matrix (IM) that supports the underlying stromal compartment. The major components of the ECM are the collagens. While breaching of the BM and turnover of e.g. type IV collagen, is a well described part of tumorigenesis, less is known regarding the impact on tumorigenesis from the collagens residing in the stroma. Here we give an introduction and overview to the link between tumorigenesis and stromal collagens, with focus on the fibrillar collagens type I, II, III, V, XI, XXIV and XXVII as well as type VI collagen. Moreover, we discuss the impact of the cells responsible for this altered stromal collagen remodeling, the cancer associated fibroblasts (CAFs), and how these cells are key players in orchestrating the tumor microenvironment composition and tissue microarchitecture, hence also driving tumorigenesis and affecting response to treatment. Lastly, we discuss how specific collagen-derived biomarkers reflecting the turnover of stromal collagens and CAF activity may be used as tools to non-invasively interrogate stromal reactivity in the tumor microenvironment and predict response to treatment.

Wu J, Liu J, Wei X, et al.
A feature-based analysis identifies COL1A2 as a regulator in pancreatic cancer.
J Enzyme Inhib Med Chem. 2019; 34(1):420-428 [PubMed] Free Access to Full Article Related Publications
This study aimed to identify genetic biomarkers in pancreatic cancer (PC) and explore its function in PC via a feature-base analysis of bioinformatics. OMIM and DisGeNET databases discovered 209 PC connected genes and then 516 connected genes were identified. We selected 29 genes according to optimal features and chose COL1A2, which had the highest expression, for the following experiment. The expression of COL1A2 was determined by qRT-PCR; cell proliferation was determined by MTT assay; migration and invasion after COL1A2 and miR-25-3p transfection was evaluated by Transwell assay. COL1A2 presented the highest expression in PC tissues, which was validated in functional experiments. MiR-25-3p suppressed the expression of COL1A2 in cell lines and inhibited migration, invasion and proliferation of PC cells. MiR-25-3p could suppress the expression of COL1A2 and inhibit the proliferation, migration and invasion of PC cells which provided a new idea for the detection and treatment of PC.

Di Y, Chen D, Yu W, Yan L
Bladder cancer stage-associated hub genes revealed by WGCNA co-expression network analysis.
Hereditas. 2019; 156:7 [PubMed] Free Access to Full Article Related Publications
Background: Bladder cancer was a malignant disease in patients, our research aimed at discovering the possible biomarkers for the diseases.
Results: The gene chip GSE31684, including 93samples, was downloaded from the GEO datasets and co-expression network was constructed by the data. Molecular complex detection(MCODE) was used to identify hub genes. The most significant cluster including 16 genes:

Zhang J, Li J, Saucier JB, et al.
Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA.
Nat Med. 2019; 25(3):439-447 [PubMed] Related Publications
Current non-invasive prenatal screening is targeted toward the detection of chromosomal abnormalities in the fetus

Annunziato S, de Ruiter JR, Henneman L, et al.
Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer.
Nat Commun. 2019; 10(1):397 [PubMed] Free Access to Full Article Related Publications
BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.

Lv J, Guo L, Wang JH, et al.
Biomarker identification and trans-regulatory network analyses in esophageal adenocarcinoma and Barrett's esophagus.
World J Gastroenterol. 2019; 25(2):233-244 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Esophageal adenocarcinoma (EAC) is an aggressive disease with high mortality and an overall 5-year survival rate of less than 20%. Barrett's esophagus (BE) is the only known precursor of EAC, and patients with BE have a persistent and excessive risk of EAC over time. Individuals with BE are up to 30-125 times more likely to develop EAC than the general population. Thus, early detection of EAC and BE could significantly improve the 5-year survival rate of EAC. Due to the limitations of endoscopic surveillance and the lack of clinical risk stratification strategies, molecular biomarkers should be considered and thoroughly investigated.
AIM: To explore the transcriptome changes in the progression from normal esophagus (NE) to BE and EAC.
METHODS: Two datasets from the Gene Expression Omnibus (GEO) in NCBI Database ( were retrieved and used as a training and a test dataset separately, since NE, BE, and EAC samples were included and the sample sizes were adequate. This study identified differentially expressed genes (DEGs) using the R/Bioconductor project and constructed trans-regulatory networks based on the Transcriptional Regulatory Element Database and Cytoscape software. Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) terms was identified using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. The diagnostic potential of certain DEGs was assessed in both datasets.
RESULTS: In the GSE1420 dataset, the number of up-regulated DEGs was larger than that of down-regulated DEGs when comparing EAC
CONCLUSION: After the construction and analyses of the trans-regulatory networks in EAC and BE, the results indicate that COL1A1 and MMP1 could be potential biomarkers for EAC and BE, respectively.

Ahn MY, Kim BJ, Kim HJ, et al.
Anti-cancer effect of dung beetle glycosaminoglycans on melanoma.
BMC Cancer. 2019; 19(1):9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dung beetle glycosaminoglycan is known to possess anti-aging activities. However, its anti-cancer mechanisms are not fully elucidated yet. The objective of this study was to evaluate the anti-cancer effect of insect-derived polymer dung beetle glycosaminoglycan (GAG) after intraperitoneally injecting it to melanoma mice induced by B16F10 cells.
METHODS: To determine molecular mechanism involved in the anti-cancer effect of dung beetle GAG, its origin N-glycan under 3KD Dalton was assayed for melanoma cell cytotoxicity. Quantitative comparisons of adhesive molecule on extracellular matrix and activities of tissue inhibitor of metalloprotease 2 (TIMP-2) were also investigated. In vivo anti-cancer effect of dung beetle GAG on solid tumor size, survival time and gene-expression profiles was also assayed using B10F10 melanoma mice model. Mice with induced melanoma were then treated with Catharsius molossus (dung beetle) GAG (CaG) at 5 mg/kg for 8 weeks to investigate its anti-cancer effects compared to bumblebee (Bombus ignitus) queen glycosaminoglycan (IQG) and Huechys sanguinea glycosaminoglycan (HEG).
RESULTS: These N-glycans derived from these GAG were composed of many linear heparinoid polysaccharides, polymers with hexose and N-acetylhexose. Adminstration with these GAGs increased survival time and decreased melanoma sizes in mice, in accordance with their inhibitory effects on cell growth ratio of melanoma B16F10. In addition, treatment with N-glycans derived from theses glycosaminoglycan increased activities of TIMP-2 in HMVEC cells pretreated with TNF-alpha and in melanoma cells, suggesting that they had anti-inflammatory and anticancer activities. In DNA microarray results, compared to control, CaG treated mouse group showed upregulation of 192 genes including collagen,typeI,alpha1 (Col1a1), consistent with the highly increased in vitro extracellular matrix (ECM) adhesion on collagen 1 and up-regulation of heparanase (Hpse). After treatment with CaG, a total of 152 genes were down-regulated, including nuclear RNA export factor (Nxf3) and hyaluronan proteoglycan link protein1 (Hapln1).
CONCLUSIONS: Glycosaminoglycan, CaG can strengthen ECM by increasing activity of TIMP-2 and adhesion activity on collagen known to inhibit changes of ECM, leading to tumor cell invasion and progression.

Oyama R, Kito F, Qiao Z, et al.
Establishment of novel patient-derived models of dermatofibrosarcoma protuberans: two cell lines, NCC-DFSP1-C1 and NCC-DFSP2-C1.
In Vitro Cell Dev Biol Anim. 2019; 55(1):62-73 [PubMed] Related Publications
Dermatofibrosarcoma protuberans (DFSP) is a common type of dermal sarcoma, characterized by the presence of the unique collagen type I alpha 1 chain (COL1A1)-PDGFB translocation, which causes constitutive activation of the platelet-derived growth factor β (PDGFB) signaling pathway. Patients with DFSP exhibit frequent local recurrence, and novel therapeutic approaches are required to achieve better clinical outcomes. Patient-derived cancer cell lines are essential in the preclinical research. Here, we established novel patient-derived DFSP cell lines from two patients with DFSP and designated these cell lines NCC-DFSP1-C1 and NCC-DFSP2-C1. Tumors of the two patients with DFSP had COL1A1-PDGFB translocations with distinct COL1A1 breakpoints, e.g., in exons 33 and 15, and the translocations were preserved in the established cell lines. NCC-DFSP1-C1 and NCC-DFSP2-C1 cells exhibited similar morphology and limited capability of proliferation in vitro, forming spheroids when seeded on low-attachment tissue culture plates. In contrast, NCC-DFSP1-C1 cells had considerably higher invasive capability than NCC-DFSP2-C1 cells. Overall proteome contents were similar between NCC-DFSP1-C1 and NCC-DFSP2-C1 cells. Notably, in vitro screening studies identified anticancer drugs that showed antiproliferative effects at considerably low concentrations in the DFSP cell lines. Bortezomib, mitoxantrone, ponatinib, and romidepsin were more cytotoxic to NCC-DFSP1-C1 cells than to NCC-DFSP2-C1 cells. These cell lines will be useful tools for developing novel therapeutic strategies to treat DFSP.

van Huizen NA, Coebergh van den Braak RRJ, Doukas M, et al.
Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue.
J Biol Chem. 2019; 294(1):281-289 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Changes to extracellular matrix (ECM) structures are linked to tumor cell proliferation and metastasis. We previously reported that naturally occurring peptides of collagen type I are elevated in urine of patients with colorectal liver metastasis (CRLM). In the present study, we took an MS-based proteomic approach to identify specific collagen types that are up-regulated in CRLM tissues compared with healthy, adjacent liver tissues from the same patients. We found that 19 of 22 collagen-α chains are significantly up-regulated (

Liu X, Cao M, Palomares M, et al.
Metastatic breast cancer cells overexpress and secrete miR-218 to regulate type I collagen deposition by osteoblasts.
Breast Cancer Res. 2018; 20(1):127 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
BACKGROUND: Bone is one of the most frequent metastatic sites of advanced breast cancer. Current therapeutic agents aim to inhibit osteoclast-mediated bone resorption but only have palliative effects. During normal bone remodeling, the balance between bone resorption and osteoblast-mediated bone formation is essential for bone homeostasis. One major function of osteoblast during bone formation is to secrete type I procollagen, which will then be processed before being crosslinked and deposited into the bone matrix.
METHODS: Small RNA sequencing and quantitative real-time PCR were used to detect miRNA levels in patient blood samples and in the cell lysates as well as extracellular vesicles of parental and bone-tropic MDA-MB-231 breast cancer cells. The effects of cancer cell-derived extracellular vesicles isolated by ultracentrifugation and carrying varying levels of miR-218 were examined in osteoblasts by quantitative real-time PCR, Western blot analysis, and P1NP bone formation marker analysis. Cancer cells overexpressing miR-218 were examined by transcriptome profiling through RNA sequencing to identify intrinsic genes and pathways influenced by miR-218.
RESULTS: We show that circulating miR-218 is associated with breast cancer bone metastasis. Cancer-secreted miR-218 directly downregulates type I collagen in osteoblasts, whereas intracellular miR-218 in breast cancer cells regulates the expression of inhibin β subunits. Increased cancer secretion of inhibin βA results in elevated Timp3 expression in osteoblasts and the subsequent repression of procollagen processing during osteoblast differentiation.
CONCLUSIONS: Here we identify a twofold function of cancer-derived miR-218, whose levels in the blood are associated with breast cancer metastasis to the bone, in the regulation of type I collagen deposition by osteoblasts. The adaptation of the bone niche mediated by miR-218 might further tilt the balance towards osteolysis, thereby facilitating other mechanisms to promote bone metastasis.

Wang P, Magdolen V, Seidl C, et al.
Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer.
Br J Cancer. 2018; 119(7):1-9 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Tissue kallikrein-related peptidases 4, 5, 6 and 7 (KLK4-7) strongly increase the malignancy of ovarian cancer cells. Deciphering their downstream effectors, we aimed at finding new potential prognostic biomarkers and treatment targets for ovarian cancer patients. KLK4-7-transfected (OV-KLK4-7) and vector-control OV-MZ-6 (OV-VC) ovarian cancer cells were established to select differentially regulated factors.
METHODS: With three independent approaches, PCR arrays, genome-wide microarray and proteome analyses, we identified 10 candidates (MSN, KRT19, COL5A2, COL1A2, BMP5, F10, KRT7, JUNB, BMP4, MMP1). To determine differential protein expression, we performed western blot analyses, immunofluorescence and immunohistochemistry for four candidates (MSN, KRT19, KRT7, JUNB) in cells, tumour xenograft and patient-derived tissues.
RESULTS: We demonstrated that KLK4-7 clearly regulates expression of MSN, KRT19, KRT7 and JUNB at the mRNA and protein levels in ovarian cancer cells and tissues. Protein expression of the top-upregulated effectors, MSN and KRT19, was investigated by immunohistochemistry in patients afflicted with serous ovarian cancer and related to KLK4-7 immunoexpression. Significant positive associations were found for KRT19/KLK4, KRT19/KLK5 and MSN/KLK7.
CONCLUSION: These findings imply that KLK4-7 exert key modulatory effects on other cancer-related genes and proteins in ovarian cancer. These downstream effectors of KLK4-7, MSN and KRT19 may represent important therapeutic targets in serous ovarian cancer.

Sun S, Wang Y, Wu Y, et al.
Identification of COL1A1 as an invasion‑related gene in malignant astrocytoma.
Int J Oncol. 2018; 53(6):2542-2554 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Malignant astrocytoma (MA) is the most common and severe type of brain tumor. A greater understanding of the underlying mechanisms responsible for the development of MA would be beneficial for the development of targeted molecular therapies. In the present study, the upregulated differentially expressed genes (DEGs) in MA were obtained from the Gene Expression Omnibus database using R/Bioconductor software. DEGs in different World Health Organization classifications were compared using the Venny tool and 15 genes, including collagen type I α1 chain (COL1A1) and laminin subunit γ1 (LAMC1), were revealed to be involved in the malignant progression of MA. In addition, the upregulated DEGs in MA were evaluated using functional annotations of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes with the Database for Annotation, Visualization, and Integrated Discovery tool. The results indicated that invasion‑associated enrichment was observed in 'extracellular matrix' (ECM), 'cell adhesion' and 'phosphoinositide 3‑kinase‑protein kinase B signaling pathway'. Subsequently, the analysis of the protein‑protein interactions was performed using STRING and Cytoscape software, which revealed that the ECM component was the invasion‑associated module and its corresponding genes included COL1A1, LAMC1 and fibronectin 1. Finally, survival Kaplan‑Meier estimate was conducted using cBioportal online, which demonstrated that COL1A1 expression affected the survival of and recurrence in patients with MA. Moreover, the results of in vitro Transwell assay and western blot analysis revealed that the depleted levels of COL1A1 also decreased the expression of several proteins associated with cell invasion, including phosphorylated‑signal transducer and activator of transcription 3, matrix metalloproteinase (MMP)‑2, MMP‑9 and nuclear factor‑κB. On the whole, the present study identified the invasion‑related target genes and the associated potential pathways in MA. The results indicated that COL1A1 may be a candidate biomarker for the prognosis and treatment of MA.

Erdem M, Tüfekçi Ö, Kızıldağ S, et al.
Investigation of the Relationship Between
Turk J Haematol. 2019; 36(1):12-18 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Objective: In acute lymphoblastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor (
Materials and Methods: Fifty children with ALL who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008 and were followed for at least 7 years were enrolled. The control group consisted of 96 healthy children.
Results: Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in a total of 18 patients (36%). The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged ≥10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the
Conclusion: The development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is especially higher in children aged ≥10 years and with vitamin D deficiency. The association between

Hauptman N, Boštjančič E, Žlajpah M, et al.
Bioinformatics Analysis Reveals Most Prominent Gene Candidates to Distinguish Colorectal Adenoma from Adenocarcinoma.
Biomed Res Int. 2018; 2018:9416515 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Colorectal cancer (CRC) is one of the leading causes of death by cancer worldwide. Bowel cancer screening programs enable us to detect early lesions and improve the prognosis of patients with CRC. However, they also generate a significant number of problematic polyps, e.g., adenomas with epithelial misplacement (pseudoinvasion) which can mimic early adenocarcinoma. Therefore, biomarkers that would enable us to distinguish between adenoma with epithelial misplacement (pseudoinvasion) and adenoma with early adenocarcinomas (true invasion) are needed. We hypothesized that the former are genetically similar to adenoma and the latter to adenocarcinoma and we used bioinformatics approach to search for candidate genes that might be potentially used to distinguish between the two lesions. We used publicly available data from Gene Expression Omnibus database and we analyzed gene expression profiles of 252 samples of normal mucosa, colorectal adenoma, and carcinoma. In total, we analyzed 122 colorectal adenomas, 59 colorectal carcinomas, and 62 normal mucosa samples. We have identified 16 genes with differential expression in carcinoma compared to adenoma:

Yang L, Jing J, Sun L, Yue Y
Exploring prognostic genes in ovarian cancer stage-related coexpression network modules.
Medicine (Baltimore). 2018; 97(34):e11895 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Identification of meaningful cluster modules of differential genes or representative biomarkers related to the stages of ovarian cancer (OC) is pivotal, which may help to detect mechanisms of OC progression and evaluate OC patients' prognosis.We downloaded gene expression data and the corresponding clinical information of OC patients from The Cancer Genome Atlas (TCGA) database, which included 379 ovarian cancer patients. Differentially expressed genes (DEGs) of OC patients between stages were picked out using R. There were 731 differential genes between ovarian cancer stage II and stage III (DEGs II-III) and 563 differential genes between ovarian cancer stage III and stage IV (DEGs III-IV), then we performed GO analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, CytoHubba was used to detect the top 20 hub genes in DEGs II-III and DEGs III-IV, followed Cytoscape with search tool for the retrieval of interacting genes (STRING) and MCODE plug-in was utilized to construct protein-protein interaction (PPI) modules of these genes. Three important coexpression modules of DEGs II-III and 3 more meaningful modules of DEGs III-IV were detected from PPI network using molecular complex detection (MCODE) tool. In addition, 5 hub genes in these stage-related DEGs modules with worse overall survival were selected, including COL3A1, COL1A1, COL1A2, KRAS, NRAS. This bioinformatics analysis demonstrated that stage-related prognostic DEGs, such as COL3A1, COL1A1, COL1A2, KRAS, and NRAS might play an unfavorable role in the development as well as metastasis of ovarian cancer. Furthermore, they need to be experimentally verified as a new biomarker to predict OC patient prognosis.

Zhang Z, Fang C, Wang Y, et al.
COL1A1: A potential therapeutic target for colorectal cancer expressing wild-type or mutant KRAS.
Int J Oncol. 2018; 53(5):1869-1880 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Colorectal cancer (CRC) treatment primarily relies on chemotherapy along with surgery, radiotherapy and, more recently, targeted therapy at the late stages. However, chemotherapeutic drugs have high cytotoxicity, and the similarity between the effects of these drugs on cancerous and healthy cells limits their wider use in clinical settings. Targeted monoclonal antibody treatment may compensate for this deficiency. Epidermal growth factor receptor (EGFR)‑targeted drugs have a positive effect on CRC with intact KRAS proto-oncogene GTPase (KRAS or KRASWT), but may be ineffective or harmful in patients with KRAS mutations (KRASMUT). Therefore, it is important to identify drug target genes that are uniformly effective with regards to KRASWT and KRASMUT CRC. The present study performed gene expression analysis, and identified 294 genes upregulated in KRASWT and KRASMUT CRC samples. Collagen type I α 1 (COL1A1) was identified as the hub gene through STRING and Cytoscape analyses. Consistent with results obtained from Oncomine, a cancer microarray database and web-based data-mining platform, it was demonstrated that the expression of COL1A1 was significantly upregulated in CRC tissues and cell lines regardless of KRAS status. Inhibition of COL1A1 in KRASWT and KRASMUT CRC cell lines significantly decreased cell proliferation and invasion. In addition, increased COL1A1 expression in CRC was significantly associated with serosal invasion, lymph metastases and hematogenous metastases. Taken together, the findings of the present study indicated that COL1A1 may serve as a candidate diagnostic biomarker and a promising therapeutic target for CRC.

Nanchahal J, Ball C, Davidson D, et al.
Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial.
EBioMedicine. 2018; 33:282-288 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor.
METHODS: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with (NCT03180957) and the EudraCT (2015-001780-40).
FINDINGS: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug.
INTERPRETATION: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease.
FUNDING: Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.

Khawar IA, Park JK, Jung ES, et al.
Three Dimensional Mixed-Cell Spheroids Mimic Stroma-Mediated Chemoresistance and Invasive Migration in hepatocellular carcinoma.
Neoplasia. 2018; 20(8):800-812 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Interactions between cancer cells and cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) play an important role in promoting the profibrotic microenvironment and epithelial-mesenchymal transition (EMT), resulting in tumor progression and drug resistance in hepatocellular carcinoma (HCC). In the present study, we developed a mixed-cell spheroid model using Huh-7 HCC cells and LX-2 stellate cells to simulate the in vivo tumor environment with respect to tumor-CAF interactions. Spheroids were cultured from cancer cells alone (monospheroids) or as a mixture (mixed-cell spheroids) in ultra-low-attachment plates. Compact, well-mixed, and stroma-rich mixed-cell spheroids were successfully established with heterotypic cell-cell contacts shown by the presence of gap junctions and desmosomes. Mixed-cell spheroids showed enhanced expression of collagen type-I (Col-I) and pro-fibrotic factors such as, transforming growth factor beta1 (TGF-β1), and connective tissue growth factor (CTGF) compared to the levels expressed in mono-spheroids. The EMT phenotype was evident in mixed-cell spheroids as shown by the altered expression of E-cadherin and vimentin. Differential drug sensitivity was observed in mixed-cell spheroids, and only sorafenib and oxaliplatin showed dose-dependent antiproliferative effects. Simultaneous treatment with TGF-β inhibitors further improved sorafenib efficacy in the mixed-cell spheroids, indicating the involvement of TGF-β in the mechanism of sorafenib resistance. In 3D matrix invasion assay, mixed-cell spheroids exhibited fibroblast-led collective cell movement. Overall, our results provide evidence that mixed-cell spheroids formed with Huh-7 and LX-2 cells well represent HCC tumors and their TME in vivo and hence are useful in studying tumor-stroma interactions as mechanisms associated with drug resistance and increased cell motility.

Dadone-Montaudié B, Alberti L, Duc A, et al.
Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions.
Mod Pathol. 2018; 31(11):1683-1693 [PubMed] Related Publications
Dermatofibrosarcoma protuberans is underlined by recurrent collagen type I alpha 1 chain-platelet-derived growth factor B chain (COL1A1-PDGFB) fusions but ~ 4% of typical dermatofibrosarcoma protuberans remain negative for this translocation in routine molecular screening. We investigated a series of 21 cases not associated with the pathognomonic COL1A1-PDGFB fusion on routine fluorescence in situ hybridization (FISH) testing. All cases displayed morphological and clinical features consistent with the diagnosis of dermatofibrosarcoma protuberans. RNA-sequencing analysis was successful in 20 cases. The classical COL1A1-PDGFB fusion was present in 40% of cases (n = 8/20), and subsequently confirmed with a COL1A1 break-apart FISH probe in all but one case (n = 7/8). 55% of cases (n = 11/20) displayed novel PDGFD rearrangements; PDGFD being fused either to the 5' part of COL6A3 (2q37.3) (n = 9/11) or EMILIN2 (18p11) (n = 2/11). All rearrangements led to in-frame fusion transcripts and were confirmed at genomic level by FISH and/or array-comparative genomic hybridization. PDGFD-rearranged dermatofibrosarcoma protuberans presented clinical outcomes similar to typical dermatofibrosarcoma protuberans. Notably, the two EMILIN2-PDGFD cases displayed fibrosarcomatous transformation and homozygous deletions of CDKN2A at genomic level. We report the first recurrent molecular variant of dermatofibrosarcoma protuberans involving PDGFD, which functionally mimic bona fide COL1A1-PDGFB fusions, leading presumably to a similar autocrine loop-stimulating PDGFRB. This study also emphasizes that COL1A1-PDGFB fusions can be cytogenetically cryptic on FISH testing in a subset of cases, thereby representing a diagnostic pitfall that pathologists should be aware of.

Shea MP, O'Leary KA, Wegner KA, et al.
High collagen density augments mTOR-dependent cancer stem cells in ERα+ mammary carcinomas, and increases mTOR-independent lung metastases.
Cancer Lett. 2018; 433:1-9 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Metastatic estrogen receptor alpha positive (ERα+) cancers account for most breast cancer mortality. Cancer stem cells (CSCs) and dense/stiff extracellular matrices are implicated in aggression and therapy resistance. We examined this interplay and response to mTOR inhibition using ERα+ adenocarcinomas from NRL-PRL females in combination with Col1a1

Li T, Gao X, Han L, et al.
Identification of hub genes with prognostic values in gastric cancer by bioinformatics analysis.
World J Surg Oncol. 2018; 16(1):114 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Gastric cancer (GC) is a prevalent malignant cancer of digestive system. To identify key genes in GC, mRNA microarray GSE27342, GSE29272, and GSE33335 were downloaded from GEO database.
METHODS: Differentially expressed genes (DEGs) were obtained using GEO2R. DAVID database was used to analyze function and pathways enrichment of DEGs. Protein-protein interaction (PPI) network was established by STRING and visualized by Cytoscape software. Then, the influence of hub genes on overall survival (OS) was performed by the Kaplan-Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Additionally, potential stem loop miRNAs of hub genes were predicted by miRecords and screened by TCGA dataset. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst.
RESULTS: In total, 67 DEGs were identified; upregulated DEGs were mainly enriched in biological process (BP) related to angiogenesis and extracellular matrix organization and the downregulated DEGs were mainly enriched in BP related to ion transport and response to bacterium. KEGG pathways analysis showed that the upregulated DEGs were enriched in ECM-receptor interaction and the downregulated DEGs were enriched in gastric acid secretion. A PPI network of DEGs was constructed, consisting of 43 nodes and 87 edges. Twelve genes were considered as hub genes owing to high degrees in the network. Hsa-miR-29c, hsa-miR-30c, hsa-miR-335, hsa-miR-33b, and hsa-miR-101 might play a crucial role in hub genes regulation. In addition, the transcription factors-hub genes pairs were displayed with 182 edges and 102 nodes. The high expression of 7 out of 12 hub genes was associated with worse OS, including COL4A1, VCAN, THBS2, TIMP1, COL1A2, SERPINH1, and COL6A3.
CONCLUSIONS: The miRNA and TFs regulation network of hub genes in GC may promote understanding of the molecular mechanisms underlying the development of gastric cancer and provide potential targets for GC diagnosis and treatment.

Mikami T, Bologna-Molina R, Mosqueda-Taylor A, et al.
Pathogenesis of primordial odontogenic tumour based on tumourigenesis and odontogenesis.
Oral Dis. 2018; 24(7):1226-1234 [PubMed] Related Publications
OBJECTIVE: Primordial odontogenic tumour (POT) is a rare benign mixed epithelial and mesenchymal odontogenic tumour. POT is composed of dental papilla-like tissue covered with cuboidal to columnar epithelium that resembles to inner and outer enamel epithelium of the enamel organ without dental hard tissue formation. The aim of this study was to examine pathogenesis of POT based on tumourigenesis and odontogenesis.
SUBJECTS AND METHODS: Six cases of POT were submitted for study. DNA analysis and transcriptome analysis were performed by next-generation sequencing. Expression of amelogenin, ameloblastin and dentin sialophosphoprotein (DSPP) was examined by immunohistochemistry.
RESULTS: There were no gene mutations detected in any of analysed 151 cancer- and 42 odontogenesis-associated genes. Enamel protein-coding genes of Amelx, Ambn and Enam, and dentin protein-coding genes of Col1a1, Dspp, Nes and Dmp1 were expressed, whereas expression of dentinogenesis-associated genes of Bglap, Ibsp and Nfic was negative or very weak suggesting inhibition of dentin formation in POT after odontoblast differentiation. Immunoreactivity of amelogenin, ameloblastin and DSPP was detected in POT.
CONCLUSIONS: Pathogenesis of POT is considered to be genetically different from other odontogenic tumours. It is suggested that inhibition of enamel and dentin formation in POT is due to defects in dentin formation process.

Liu J, Shen JX, Wu HT, et al.
Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target.
Discov Med. 2018; 25(139):211-223 [PubMed] Related Publications
PURPOSE: Extracellular matrix (ECM) is an important component of tumor microenvironment and plays critical roles in cancer development and metastasis, in which collagen is the major structural protein. Collagen type I alpha 1 (COL1A1) is reportedly associated with the development of several human diseases. However, the functions and mechanisms of cellular expression of COL1A1 in breast cancer remain unknown. The purpose of this study is to investigate the cellular expression of COL1A1 in breast cancer cells and patients, and its role in the development and metastasis of breast cancer.
METHODS: The immunofluorescence staining was used to identify the cellular location of COL1A1 in breast cancer cell lines. Real-time PCR was applied to measuring the mRNA levels of COL1A1 and genes of interest. Wound healing and transwell assay were performed to evaluate the effect of COL1A1 on metastasis of breast cancer cells. 97 patients with breast cancer were recruited in this study for evaluating the correlation of COL1A1 with survival and clinicopathological parameters.
RESULTS: COL1A1 was expressed in all examined breast cancer cells. Knockdown of COL1A1 inhibited metastasis of breast cancer cells, with a low-level of CXCR4, independent of the epithelial-mesenchymal transition (EMT) process. In patients with breast cancer, cellular expression of COL1A1 was associated with ER/PR expression and metastasis status. The increased COL1A1 level was associated with poor survival, especially in patients with ER+ breast cancer. Patients with a high-level of COL1A1 showed better cisplatin-based chemotherapy response.
CONCLUSION: Cellular expression of COL1A1 could promote breast cancer metastasis. COL1A1 is a new prognostic biomarker and a potential therapeutic target for breast cancer, especially in ER+ patients.

Hutchenreuther J, Vincent K, Norley C, et al.
Activation of cancer-associated fibroblasts is required for tumor neovascularization in a murine model of melanoma.
Matrix Biol. 2018; 74:52-61 [PubMed] Related Publications
Metastatic melanoma is highly fatal. Within the tumor microenvironment, the role of cancer-associated fibroblasts (CAFs) in melanoma metastasis and progression is relatively understudied. The matricellular protein CCN2 (formerly termed connective tissue growth factor, CTGF) is overexpressed, in a fashion independent of BRAF mutational status, by CAFs in melanoma. Herein, we find, in human melanoma patients, that CCN2 expression negatively correlates with survival and positively correlates with expression of neovascularization markers. To assess the role of CAFs in melanoma progression, we used C57BL/6 mice expressing a tamoxifen-dependent cre recombinase expressed under the control of a fibroblast-specific promoter/enhancer (COL1A2) to delete CCN2 postnatally in fibroblasts. Mice deleted or not for CCN2 in fibroblasts were injected subcutaneously with B16-F10 melanoma cells. Loss of CCN2 in CAFs resulted in reduced CAF activation, as detected by staining with anti-α-smooth muscle actin antibodies, and reduced tumor-induced neovascularization, as detected by micro-computed tomography (micro-CT) and staining with anti-CD31 antibodies. CCN2-deficient B16(F10) cells were defective in a tubule formation/vasculogenic mimicry assay in vitro. Mice deleted for CCN2 in CAFs also showed impaired vasculogenic mimicry of subcutaneously-injected B16-F10 cells in vivo. Our results provide new insights into the cross-talk among different cell types in the tumor microenvironment and suggest CAFs play a heretofore unappreciated role by being essential for tumor neovascularization via the production of CCN2. Our data are consistent with the hypothesis that activated CAFs are essential for melanoma metastasis and that, due to its role in this process, CCN2 is a therapeutic target for melanoma.

Meng C, He Y, Wei Z, et al.
MRTF-A mediates the activation of COL1A1 expression stimulated by multiple signaling pathways in human breast cancer cells.
Biomed Pharmacother. 2018; 104:718-728 [PubMed] Related Publications
Deposition of type I collage in ECM is an important property of various fibrotic diseases including breast cancer. The excessive expression of type I collagen contributes to the rigidity of cancer tissue and increases the mechanical stresses which facilitate metastasis and proliferation of cancer cells via the activation of TGF-β signaling pathway. The increased mechanical stresses also cause the compression of blood vessels and result in hypoperfusion and impaired drug delivery in cancer tissue. Additionally, type I collage functions as the ligand of α2β1-integrin and DDR1/2 receptors on the membrane of cancer cells to initiate signal transduction leading to metastasis. The expression of type I collage in cancer cells is previously shown to be inducible by TGF-β however the detailed mechanism by which the synthesis of type I collagen is regulated in breast cancer cells remains unclear. Herein, we report that MRTF-A, a co-activator of SRF, is important for the regulation of type I collagen gene COL1A1 in breast cancer cells. MRTF-A physically interacted with the promoter of COL1A1 to facilitate histone acetylation and RNA polymerase II recruitment. The RhoC-ROCK signaling pathway which controls the nuclear localization of MRTF-A regulated the transcription of COL1A1 in human breast cancer cells. TGF-β and Wnt signaling increased the expression of both MRTF-A and COL1A1. Furthermore, depletion of MRTF-A abolished the upregulation of COL1A1 in response to the TGF-β or Wnt signaling, indicating the importance of MRTF-A in the synthesis of type I collagen in breast cancer. Given the crucial roles of type I collagen in the formation of metastasis-prone and hypoperfusion microenvironment, MRTF-A would be a potential target for the development of anti-breast cancer activities.

Vera-Ramirez L, Vodnala SK, Nini R, et al.
Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence.
Nat Commun. 2018; 9(1):1944 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Cancer recurrence after initial diagnosis and treatment is a major cause of breast cancer (BC) mortality, which results from the metastatic outbreak of dormant tumour cells. Alterations in the tumour microenvironment can trigger signalling pathways in dormant cells leading to their proliferation. However, processes involved in the initial and the long-term survival of disseminated dormant BC cells remain largely unknown. Here we show that autophagy is a critical mechanism for the survival of disseminated dormant BC cells. Pharmacologic or genetic inhibition of autophagy in dormant BC cells results in significantly decreased cell survival and metastatic burden in mouse and human 3D in vitro and in vivo preclinical models of dormancy. In vivo experiments identify autophagy gene autophagy-related 7 (ATG7) to be essential for autophagy activation. Mechanistically, inhibition of the autophagic flux in dormant BC cells leads to the accumulation of damaged mitochondria and reactive oxygen species (ROS), resulting in cell apoptosis.

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