Gene Summary

Gene:RUNX2; RUNX family transcription factor 2
Aliases: CCD, AML3, CCD1, CLCD, OSF2, CBFA1, OSF-2, PEA2aA, PEBP2aA, CBF-alpha-1
Summary:This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:runt-related transcription factor 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (37)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA-Binding Proteins
  • Osteolysis
  • Epithelial-Mesenchymal Transition
  • Neoplasm Proteins
  • Neoplasm Invasiveness
  • Core Binding Factor Alpha 1 Subunit
  • Cell Differentiation
  • Mutation
  • DNA Methylation
  • Chromosome 6
  • RNA-Binding Proteins
  • Stem Cells
  • Apoptosis
  • Gene Knockdown Techniques
  • Prostate Cancer
  • beta Karyopherins
  • Proteomics
  • Gene Expression Regulation
  • Cell Movement
  • MicroRNAs
  • Core Binding Factor Alpha 2 Subunit
  • Disease Progression
  • Ovarian Cancer
  • Cell Proliferation
  • Biomarkers, Tumor
  • Bone Cancer
  • Western Blotting
  • Breast Cancer
  • Transcriptional Activation
  • Gene Expression Profiling
  • Adolescents
  • siRNA
  • Cell Survival
  • Messenger RNA
  • RUNX3
  • Osteoblasts
  • Down-Regulation
  • Cancer Gene Expression Regulation
  • Base Sequence
  • Immunohistochemistry
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: RUNX2 (cancer-related)

Yoshii S, Hayashi Y, Iijima H, et al.
Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression.
Cancer Sci. 2019; 110(8):2396-2407 [PubMed] Free Access to Full Article Related Publications
The tumor microenvironment offers favorable conditions for tumor progression, and activated fibroblasts, known as cancer-associated fibroblasts, play a pivotal role. TP53-deficient cancer cells are known to induce strong fibroblast activation. We aimed to elucidate the oncogenic role of exosomes derived from TP53-deficient colon cancer cells in fibroblast proliferation and tumor growth. Cancer cell-derived exosomes (CDEs) were isolated from the conditioned media of cancer cells using a sequential ultracentrifugation method. The effects of exosomes on tumor growth were evaluated using human cell lines (TP53-WT colon cancer, HCT116; TP53-mutant colon cancer, HT29; and fibroblasts, CCD-18Co and WI-38) and an immune-deficient nude mouse xenograft model. HCT116 (HCT116

Herreño AM, Ramírez AC, Chaparro VP, et al.
Role of RUNX2 transcription factor in epithelial mesenchymal transition in non-small cell lung cancer lung cancer: Epigenetic control of the RUNX2 P1 promoter.
Tumour Biol. 2019; 41(5):1010428319851014 [PubMed] Related Publications
Lung cancer has a high mortality rate in men and women worldwide. Approximately 15% of diagnosed patients with this type of cancer do not exceed the 5-year survival rate. Unfortunately, diagnosis is established in advanced stages, where other tissues or organs can be affected. In recent years, lineage-specific transcription factors have been associated with a variety of cancers. One such transcription factor possibly regulating cancer is RUNX2, the master gene of early and late osteogenesis. In thyroid and prostate cancer, it has been reported that RUNX2 regulates expression of genes important in tumor cell migration and invasion. In this study, we report on RUNX2/ p57 overexpression in 16 patients with primary non-small cell lung cancer and/or metastatic lung cancer associated with H3K27Ac at P1 gene promoter region. In some patients, H3K4Me3 enrichment was also detected, in addition to WDR5, MLL2, MLL4, and UTX enzyme recruitment, members of the COMPASS-LIKE complex. Moreover, transforming growth factor-β induced RUNX2/ p57 overexpression and specific RUNX2 knockdown supported a role for RUNX2 in epithelial mesenchymal transition, which was demonstrated through loss of function assays in adenocarcinoma A549 lung cancer cell line. Furthermore, RUNX2 increased expression of epithelial mesenchymal transition genes VIMENTIN, TWIST1, and SNAIL1, which reflected increased migratory capacity in lung adenocarcinoma cells.

Li G, Zhang Y, Mao J, et al.
LncRNA TUC338 is overexpressed in prostate carcinoma and downregulates miR-466.
Gene. 2019; 707:224-230 [PubMed] Related Publications
LncRNA TUC338 has recently been characterized as an oncogene in several types of cancer. Our study aimed to characterize the functionality of TUC338 in prostate carcinoma. It was observed that TUC338 was upregulated in tumor tissues comparing to adjacent healthy tissues of prostate carcinoma patients. Plasma levels of TUC338 were also higher in prostate carcinoma patients than in healthy controls. A 5-year follow-up study showed that high plasma level of TUC338 was correlated with poor survival. miR-466 was downregulated in tumor tissues compared with adjacent healthy tissues of prostate carcinoma patients. TUC338 and miR-466 were inversely correlated in tumor tissues. miR-466 overexpression failed to affect TUC338 expression, while TUC338 overexpression led to downregulated miR-466 expression. TUC338 overexpression failed to significantly affect cancer cell proliferation, but promoted cancer cell migration and invasion. MiR-466 overexpression resulted in reduced rates of cancer cell migration and invasion, and also attenuated the effect of TUC338 overexpression. Therefore, TUC338 may serve as an oncogenic lncRNA in prostate carcinoma by downregulating miR-466.

Kubota S, Tokunaga K, Umezu T, et al.
Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm.
Nat Commun. 2019; 10(1):1653 [PubMed] Free Access to Full Article Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.

Ye ZN, Yuan F, Liu JQ, et al.
Molecules. 2019; 24(6) [PubMed] Free Access to Full Article Related Publications
Deregulation of the Wnt signaling pathway leads to colorectal cancer progression. Natural dietary compounds serve as promising candidates for development as chemopreventive agents by suppressing the Wnt/β-catenin signaling pathway.

Lingling J, Xiangao J, Guiqing H, et al.
SNHG20 knockdown suppresses proliferation, migration and invasion, and promotes apoptosis in non-small cell lung cancer through acting as a miR-154 sponge.
Biomed Pharmacother. 2019; 112:108648 [PubMed] Related Publications
Long noncoding RNAs (LncRNAs) play critical roles in the development and progression of cancers. However, little is known about the function and mechanism of lncRNAs in non-small cell lung cancer (NSCLC). In this study, we investigated the expression and functional role of lncRNA small nucleolar RNA host gene 20 (SNHG20) as well as its underlying mechanism in NSCLC. Our results showed that SNHG20 was significantly up-regulated in NSCLC tissues and cells. High SNHG20 expression was implicated with poor prognosis in NSCLC patients. Moreover, SNHG20 knockdown suppressed proliferation, migration and invasion, and induced apoptosis in NSCLC cells. Furthermore, SNHG20 could function as a competing endogenous RNA (ceRNA) to elevate ZEB2 and RUNX2 expression by sponging miR-154. Rescue assays revealed that miR-154 inhibition could reverse the inhibitory effect of SNHG20 silence on proliferation, migration and invasion in NSCLC cells. More importantly, SNHG20 knockdown suppressed tumor growth in NSCLC in vivo through suppressing miR-154 and elevating ZEB2 and RUNX2 expression. In summary, knockdown of lncRNA SNHG20 suppressed proliferation, migration and invasion, and promotes apoptosis through up-regulating ZEB2 and RUNX2 expression by sponging miR-154 in NSCLC, providing a promising therapeutic target for NSCLC patients.

Šekoranja D, Boštjančič E, Salapura V, et al.
Primary aneurysmal bone cyst with a novel SPARC-USP6 translocation identified by next-generation sequencing.
Cancer Genet. 2018; 228-229:12-16 [PubMed] Related Publications
Aneurysmal bone cyst (ABC) is a benign but locally aggressive, mostly pediatric neoplasm, with characteristic USP6 gene rearrangement that distinguishes it from a secondary ABC and other primary bone tumors. With the advent of next-generation sequencing (NGS) technology, several hitherto unknown USP6 fusion partners have been identified in ABC. Accordingly, we present a case of an 18-year-old male with a solid sub-periosteal primary ABC in the diaphysis of the left femur. Using an NGS-based assay, we identified SPARC-USP6 fusion, which has not previously been described in ABC. Including our case, the list of currently known USP6 fusion partners in primary ABC include: CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3 and THRAP3.

Qi D, Wang M, Yu F
Knockdown of lncRNA-H19 inhibits cell viability, migration and invasion while promotes apoptosis via microRNA-143/RUNX2 axis in retinoblastoma.
Biomed Pharmacother. 2019; 109:798-805 [PubMed] Related Publications
BACKGROUND: Even though the role of long non-coding RNA H19 (lncRNA-H19) in diverse cancer types has been studied, exact effect of lncRNA-H19 as well as the underlying mechanism in retinoblastoma (RB) is poorly reported. We aimed to explore the possible functions of lncRNA-H19 in human RB Y79 cells.
METHODS: LncRNA-H19 in Y79 cells was silenced, and effects of lncRNA-H19 silence on cell viability, migration and invasion, and apoptosis were analyzed by using trypan blue exclusion, Transwell assay, and flow cytometry assay/Western blot analysis, respectively. Then, miR-143 expression in cells with lncRNA-H19 silence was determined by RT-qPCR, and effects of miR-143 inhibition on lncRNA-H19-suppressing cells were assessed. Whether RUNX2 was a target of miR-143 and the involved signaling pathways in the modulation of miR-143 were also studied.
RESULTS: LncRNA-H19 knockdown repressed cell viability, migration and invasion while promoted apoptosis in Y79 cells. miR-143 was a downstream factor of lncRNA-H19, and its inhibition reversed the effects of lncRNA-H19 silence on Y79 cells. RUNX2 was a target gene of miR-143, and miR-143 was found to affect Y79 cells via down-regulation of RUNX2. Phosphorylation of key kinases related in the PI3K/AKT/mTOR pathways was reduced by miR-143 via regulation of RUNX2.
CONCLUSION: Knockdown of lncRNA-H19 acted a tumor suppressive role in Y79 cells through up-regulating miR-143. Moreover, miR-143 exerted tumor suppressive effects on Y79 cells by targeting RUNX2, along with inhibition of the PI3K/AKT/mTOR pathways.

Jiang ZY, Jiang JJ, Ma YS, et al.
Downregulation of miR-223 and miR-19a induces differentiation and promotes recruitment of osteoclast cells in giant-cell tumor of the bone via the Runx2/TWIST-RANK/RANKL pathway.
Biochem Biophys Res Commun. 2018; 505(4):1003-1009 [PubMed] Related Publications
Giant-cell tumor (GCT) of the bone is an invasiveness and high recurrent bone tumor that is considered borderline or potentially malignant. To explore the molecular mechanism leading to bone destruction and identify novel targets for treatment, we conducted silencing of miR-223 and miR-19a in stromal giant cells and identified TWIST and Runx2 as their target genes. We investigated the impact of these microRNAs and their target genes on stromal giant cells that promote the differentiation of monocyte/macrophages into osteoclast cells and recruitment to the bone microenvironment, which in turn enhances the bone destruction capacity of GCT. MiR-223 and miR-19a were found to regulate the expression of TWIST and Runx2, influence the RANKL-RANK pathway and the expression of MCP-1, and finally regulate the pathophysiological process of osteolytic bone destruction. Our results indicate that re-expression of miR-223 and miR-19a induces an inhibitory effect on the bone destruction capacity of GCT, suggesting that re-expression of miR-223 and miR-19a can be a novel strategy for the treatment of GCT.

Yamada D, Fujikawa K, Kawabe K, et al.
RUNX2 Promotes Malignant Progression in Glioma.
Neurochem Res. 2018; 43(11):2047-2054 [PubMed] Related Publications
Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor. However, therapeutic strategies against malignant gliomas have not been completely established. Runt-related transcription factor 2 (Runx2) is an essential gene for skeletal development but its regulatory role in the malignant progression of glioma remains unclear. Here we investigated expression levels of RUNX2 in glioma tissues and its regulatory effects on aberrant growth of glioma cells. RUNX2 mRNA levels were higher in GBM tissues than that of normal brains or low-grade gliomas. RUNX2 protein was detected in five out of seven human GBM cell lines and its level was positively correlated with proliferative capacity. Stable transduction of dominant-negative Runx2 in rat-derived C6 glioma cells not only inhibited the promoter activity containing Runx2 response element, but also decreased mRNA expression levels of Runx2 target genes, such as Mmp13 and Spp1, as well as the proliferative capacity. Furthermore, transient introduction of Runx2-targeted siRNAs into C6 glioma cells significantly decreased mRNA expression levels of Mmp13 and Spp1 and the proliferative capacity. Furthermore, Runx2 knockdown suppressed both Ccnd1 mRNA expression and activation of the Ccnd1 promoter by forskolin, a PKA-activating reagent, in C6 glioma cells. Our results demonstrate that cross-talk between cAMP/PKA signaling and RUNX2 promotes a malignant phenotype of glioma cells.

Rohini M, Haritha Menon A, Selvamurugan N
Role of activating transcription factor 3 and its interacting proteins under physiological and pathological conditions.
Int J Biol Macromol. 2018; 120(Pt A):310-317 [PubMed] Related Publications
Activating transcription factor 3 (ATF3) is a stress-responsive factor that belongs to the activator protein 1 (AP-1) family of transcription factors. ATF3 expression is stimulated by various factors such as hypoxia, cytokines, and chemotherapeutic and DNA damaging agents. Upon stimulation, ATF3 can form homodimers or heterodimers with other members of the AP-1 family to repress or activate transcription. Under physiological conditions, ATF3 expression is transient and plays a pivotal role in controlling the expression of cell-cycle regulators and tumor suppressor, DNA repair, and apoptosis genes. However, under pathological conditions such as those during breast cancer, a sustained and prolonged expression of ATF3 has been observed. In this review, the structure and function of ATF3, its posttranslational modifications (PTM), and its interacting proteins are discussed with a special emphasis on breast cancer metastasis.

Valdez BC, Tang X, Li Y, et al.
Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells.
Exp Hematol. 2018; 67:49-59.e1 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The combination of the DNA-alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pretransplantation conditioning therapy for myeloid leukemias. However, it is associated with significant nonrelapse mortality, which prohibits dose escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase antileukemic efficacy without jeopardizing patient safety. A preclinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC), and the hypomethylating agent decitabine (DAC) in human acute myeloid leukemia (AML) cell lines. Exposure of KBM3/Bu250

Huang W, Lu Y, Wang F, et al.
Downregulation of circular RNA hsa_circ_0000144 inhibits bladder cancer progression via stimulating miR-217 and suppressing RUNX2 expression.
Gene. 2018; 678:337-342 [PubMed] Related Publications
Although increasing aberrantly expressed circular RNAs (circRNAs) have been identified among many human cancer tissues, their roles in tumor progression still remain largely unknown. In bladder cancer, the function of hsa_circ_0000144 has not been reported. In our study, we found hsa_circ_0000144 as a novel oncogene in bladder cancer by bioinformatics analysis. We found that hsa_circ_0000144 expression was significantly upregulated in bladder cancer tissues compared with adjacent normal tissues, and its high expression was related with poor prognosis. Additionally, knockdown of hsa_circ_0000144 remarkably suppressed the proliferation and invasion of bladder cancer cells in vitro. Hsa_circ_0000144 silence also led to reduced tumor volumes in vivo. In mechanism, we found that hsa_circ_0000144 was a sponge of miR-217 while miR-217 targeted RUNX2. Our results indicated that the expression of miR-217 was inversely correlated with that of both hsa_circ_0000144 and RUNX2 in bladder cancer tissues. Rescue assays showed that either inhibition of miR-217 or restoration of RUNX2 reversed the suppressive effects of hsa_circ_0000144 knockdown on bladder cancer cell proliferation and invasion. Taken together, these findings demonstrated that hsa_circ_0000144 exerts oncogenic roles in bladder cancer via repressing miR-217 to facilitate RUNX2 expression.

Rohini M, Gokulnath M, Miranda PJ, Selvamurugan N
miR-590-3p inhibits proliferation and promotes apoptosis by targeting activating transcription factor 3 in human breast cancer cells.
Biochimie. 2018; 154:10-18 [PubMed] Related Publications
We previously reported that ATF3 and Runx2 are involved in breast cancer progression and bone metastasis. The expression of these genes can be controlled by post-transcriptional regulators such as microRNAs (miRNAs). In this study, we identified and validated the functional role of miR-590-3p in human breast cancer cells (MDA-MB231). There was an inverse correlation between the expression of miR-590-3p and its putative target genes, ATF3 and Runx2 in these cells. Overexpression of miR-590-3p decreased the expression of ATF3 and Runx2 at the mRNA and protein levels in MDA-MB231 cells. Luciferase reporter assay identified a direct interaction of 3' UTRs of ATF3 and Runx2 with miR-590-3p in these cells. Overexpression of miR-590-3p also decreased proliferation and increased apoptosis of breast cancer cells. Based on our results, we suggest that miR-590-3p might have potential clinical applications towards controlling breast cancer progression and bone metastasis.

Wang W, Luo P, Guo W, et al.
LncRNA SNHG20 knockdown suppresses the osteosarcoma tumorigenesis through the mitochondrial apoptosis pathway by miR-139/RUNX2 axis.
Biochem Biophys Res Commun. 2018; 503(3):1927-1933 [PubMed] Related Publications
Increasing evidence has indicated the important roles of long noncoding RNAs (lncRNAs) in human osteosarcoma tumorigenesis. In present study, we aim to investigate the roles of lncRNA SNHG20 (small nucleolar RNA host gene 20) in osteosarcoma tumorigenesis and explore the in-depth molecular mechanism. Results showed that lncRNA SNHG20 expression was up-regulated in osteosarcoma samples and its high-expression indicated the poor prognosis. Loss-of-functional experiments indicated that SNHG20 knockdown inhibited the proliferation, invasion and induced the apoptosis of osteosarcoma cells in vitro. Specifically, SNHG20 knockdown up-regulated the expression levels of caspase-9, caspase-3 and Bax, indicating that SNHG20 knockdown accelerated the apoptosis of osteosarcoma cells via mitochondrial apoptosis pathway. Bioinformatics analysis revealed that miR-139 both targeted with the 3'-UTR of runt-related transcription factor 2 (RUNX2) and SNHG20, which was verified by luciferase reporter assay and RNA immunoprecipitation (RIP). In conclusion, our data reveals that lncRNA SNHG20/miR-139/RUNX2 axis modulates the osteosarcoma tumorigenesis and apoptosis via mitochondrial apoptosis pathway, providing a novel insight for the pathophysiological process.

Carriere PP, Kapur N, Mir H, et al.
Cinnamtannin B-1 inhibits cell survival molecules and induces apoptosis in colon cancer.
Int J Oncol. 2018; 53(4):1442-1454 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Colon cancer patients receiving chemotherapy continue to be burdened with therapeutic failure and adverse side effects, yielding a need to develop more effective treatments. The present study investigates Cinnamtannin B-1 (CTB-1) as a potential low-toxicity therapeutic alternative for colon cancer. CTB-1-treated DLD-1, COLO 201 and HCT-116 (WT p53 and p53 null) colon cancer cells and CCD 841 CoN normal colon epithelial cells were assessed for changes in survival using MTT assay. The effects of CTB-1 on cell cycle progression and the apoptosis of colon cancer cells were measured using flow cytometry and/or immunofluorescence. The expression profiles of cell survival molecules, particularly apoptotic proteins, in the colon cancer cells were evaluated following CTB-1 treatment via antibody array, then validated by western blot analysis. Additionally, the potential synergy between CTB-1 and 5-fluorouracil (5-FU), a conventional chemotherapeutic agent used in the treatment of colon cancer, against colon cancer cells was assessed using MTT assay and Calcusyn software. The results revealed that CTB-1 significantly decreased the survival of the DLD-1, COLO 201 and HCT-116 cells in a time and/or dose-dependent manner, with minimal cytotoxicity to normal colon cells. CTB-1 treatment was shown to induce cell cycle arrest and apoptosis of DLD-1 and COLO 201 cells. Of note, CTB-1 modulated the expression of several cell survival molecules, which tend to be deregulated in colon cancer, including p53, a key transcription factor involved in apoptosis. The downstream regulation of Bcl-2 and Bak expression, as well as cytochrome c release into the cytosol, was also observed following CTB-1 treatment. Furthermore, CTB-1 was shown to significantly enhance the potency of 5-FU via a synergistic drug interaction. This study reveals for the first time, to the best of our knowledge, the ability of CTB-1 to decrease the survival of colon cancer cells through pro-apoptotic mechanisms and display synergy with conventional chemotherapy, demonstrating the potential therapeutic benefit of CTB-1 in colon cancer.

Kong X, Li Y, Zhang X
Increased Expression of the YPEL3 Gene in Human Colonic Adenocarcinoma Tissue and the Effects on Proliferation, Migration, and Invasion of Colonic Adenocarcinoma Cells In Vitro via the Wnt/b-Catenin Signaling Pathway.
Med Sci Monit. 2018; 24:4767-4775 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND The aim of this study was to investigate the effects of the expression of the YPEL3 gene in colonic adenocarcinoma cells grown in vitro and in colonic adenocarcinoma tissue from patients treated by surgical resection. MATERIAL AND METHODS The study included 108 patients diagnosed with primary colon cancer (Stages I to IV). The expression of the YPEL3 gene in colonic adenocarcinoma tissue and adjacent normal colonic tissue was detected by real-time quantitative PCR (qRT-PCR). The normal human colonic cell line CCD-1Co and colorectal adenocarcinoma cell lines HT-29 and HCT-8 were induced to overexpress the YPEL3 gene, and the effects on cell proliferation, migration, and invasion of colonic adenocarcinoma cells were investigated by the Cell Counting Kit-8 (CCK-8) assay, a transwell migration assay, and a transwell invasion assay, respectively. The effects of YPEL3 gene overexpression on the Wnt/β-catenin signaling pathway were detected by Western blot. RESULTS Increased expression levels of the YPEL3 gene were present in colon adenocarcinoma tissue compared with adjacent normal colonic tissue in 98 of 108 patients. Overexpression of the YPEL3 gene inhibited the proliferation, migration, and invasion of the HT-29 and HCT-8 colonic adenocarcinoma cells, and inactivated the Wnt/β-catenin signaling pathway; treatment with the Wnt agonist, CAS 853220-52-7, reduced the inhibitory effects of YPEL3 overexpression on proliferation, migration, and invasion in vitro. CONCLUSIONS Expression of the YPEL3 gene was upregulated in human colonic adenocarcinoma tissue, and also inhibited the proliferation, migration, and invasion of colonic adenocarcinoma cells in vitro by inactivating the Wnt/β-catenin signaling pathway.

de Smith AJ, Walsh KM, Francis SS, et al.
BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.
Int J Cancer. 2018; 143(11):2647-2658 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (p

Banskota S, Dahal S, Kwon E, et al.
β-Catenin gene promoter hypermethylation by reactive oxygen species correlates with the migratory and invasive potentials of colon cancer cells.
Cell Oncol (Dordr). 2018; 41(5):569-580 [PubMed] Related Publications
PURPOSE: Over half of the colon cancer patients suffer from cancer-related events, mainly metastasis. Loss of β-catenin activity has previously been found to facilitate cancer cell dissociation and migration. Here, we aimed to investigate whether epigenetic silencing of β-catenin induces human colon cancer cell migration and/or invasion.
METHODS: HCT-116, Caco-2, HT-29 and SW620 cell migration and invasion capacities were assessed using scratch wound healing and Matrigel invasion assays, respectively. Confocal microscopy, qRT-PCR and Western blotting were performed to determine gene expression levels, whereas methylation-specific quantitative real-time PCR was used to assess the extent of β-catenin gene (CTNNB1) promoter methylation after treatment of the cells with TPA, hydrogen peroxide, 5-aza-2'-deoxycytidine and/or VAS2870.
RESULTS: We found that treatment of HT-29 and Caco-2 cells (differentiated and low metastatic) with 12-O-tetradecanoyl phorbol-13-acetate (TPA; a tumor promoter) suppressed E-cadherin and β-catenin expression at both the mRNA and protein levels and, in addition, enhanced cell migration. Furthermore, we found that the CTNNB1 gene promoter methylation levels were higher in the more invasive HCT-116 and SW620 colon cancer cells than in HT-29 and CCD-841 (normal colon epithelial) cells. We also found that TPA or hydrogen peroxide induced CTNNB1 gene promoter methylation to a higher extent in HT-29 and CCD-841 cells than in HCT-116 and SW620 cells, and that the degree of CTNNB1 gene promoter methylation positively correlated with cell dissociation and migration. In addition, we found that co-treatment with 5-aza-2'-deoxycytidine (decitabine, a DNA methyl transferase inhibitor) and VAS2870 (a NADPH oxidase inhibitor) almost completely blocked the invasion of TPA-treated HT-29 and TPA-untreated HCT-116 and SW620 cells, and that these inhibitions surpassed those of the cells treated with decitabine or VAS2870 alone.
CONCLUSIONS: From our data we conclude that the extent of CTNNB1 gene promoter methylation by reactive oxygen species correlates with the migratory and invasive abilities of colon cancer cells. Our results suggest that epigenetic regulation of CTNNB1 may serve as a novel avenue to block colon cancer cell migration and invasion.

Kanwal R, Shukla S, Walker E, Gupta S
Acquisition of tumorigenic potential and therapeutic resistance in CD133+ subpopulation of prostate cancer cells exhibiting stem-cell like characteristics.
Cancer Lett. 2018; 430:25-33 [PubMed] Related Publications
The role of CD133 (Prominin-1) as a cancer stem cell marker may be useful for therapeutic approaches and prognostication in prostate cancer patients. We investigated the stem-cell-related function and biological features of a subpopulation of CD133+ cells isolated from established primary human prostate cancer cell lines. The CD133+ cells sorted from human prostate cancer 22Rv1 exhibited high clonogenic and tumorigenic capabilities, sphere forming capacity and serially reinitiated transplantable tumors in NOD-SCID mice. Gene profiling analysis of CD133+ cells showed upregulation of markers of stem cell differentiation (CD44, Oct4, SOX9 and Nanog), epithelial-to-mesenchymal transition (c-myc and BMI1), osteoblastic differentiation (Runx2), and skeletal morphogenesis (BMP2), compared to side population of CD133- cells. These cells are highly malignant and resistant to γ-radiation and chemotherapeutic drug, docetaxel. Importantly, a docetaxel-resistant subclone was more enriched in CD133+ cells with significant increase in Runx2 expression, compared to CD133- cells. Furthermore, knockdown of Runx2 in these cells resulted in differential response to chemotherapy, sensitizing them to increased cell death. These results demonstrate therapy-resistant population with stem-like features are distinct subpopulation of malignant cells that resides within parental cell lines. The molecular signature of CD133+ cells may lead to identification of novel therapeutic targets and prognostic markers in the treatment of prostate cancer.

Pan BL, Wu L, Pan L, et al.
Up-regulation of microRNA-340 promotes osteosarcoma cell apoptosis while suppressing proliferation, migration, and invasion by inactivating the CTNNB1-mediated Notch signaling pathway.
Biosci Rep. 2018; 38(4) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Osteosarcoma (OS) is the most common histological form of primary bone cancer. It is most prevalent in teenagers and young adults. The present study aims at exploring the regulatory effect of microRNA-340 (miR-340) on OS cell proliferation, invasion, migration, and apoptosis via regulating the Notch signaling pathway by targeting β-catenin (cadherin-associated protein) 1 (CTNNB1). OS tissues belonging to 45 patients and normal femoral head tissues of 45 amputees were selected. Cells were allocated to different groups.

Gillis NE, Taber TH, Bolf EL, et al.
Thyroid Hormone Receptor β Suppression of RUNX2 Is Mediated by Brahma-Related Gene 1-Dependent Chromatin Remodeling.
Endocrinology. 2018; 159(6):2484-2494 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Thyroid hormone receptor β (TRβ) suppresses tumor growth through regulation of gene expression, yet the associated TRβ-mediated changes in chromatin assembly are not known. The chromatin ATPase brahma-related gene 1 (BRG1; SMARCA4), a key component of chromatin-remodeling complexes, is altered in many cancers, but its role in thyroid tumorigenesis and TRβ-mediated gene expression is unknown. We previously identified the oncogene runt-related transcription factor 2 (RUNX2) as a repressive target of TRβ. Here, we report differential expression of BRG1 in nonmalignant and malignant thyroid cells concordant with TRβ. BRG1 and TRβ have similar nuclear distribution patterns and significant colocalization. BRG1 interacts with TRβ, and together, they are part of the regulatory complex at the RUNX2 promoter. Loss of BRG1 increases RUNX2 levels, whereas reintroduction of TRβ and BRG1 synergistically decreases RUNX2 expression. RUNX2 promoter accessibility corresponded to RUNX2 expression levels. Inhibition of BRG1 activity increased accessibility of the RUNX2 promoter and corresponding expression. Our results reveal a mechanism of TRβ repression of oncogenic gene expression: TRβ recruitment of BRG1 induces chromatin compaction and diminishes RUNX2 expression. Therefore, BRG1-mediated chromatin remodeling may be obligatory for TRβ transcriptional repression and tumor suppressor function in thyroid tumorigenesis.

Tan J, Qian X, Song B, et al.
Integrated bioinformatics analysis reveals that the expression of cathepsin S is associated with lymph node metastasis and poor prognosis in papillary thyroid cancer.
Oncol Rep. 2018; 40(1):111-122 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The prognosis of the majority of patients with papillary thyroid cancer (PTC) is excellent, although there are patients who experience disease recurrence and progression. The aim of the present study was to identify potential prognostic risk markers in PTC. Differentially expressed genes (DEGs), identified from four Genome Expression Omnibus cohorts were subjected to functional enrichment analyses with Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genome pathways. Hub genes, filtered from cytoHubba, were validated using the The Cancer Genome Atlas (TCGA) cohort, and their associations with clinicopathological features and prognosis were analyzed. A total of 277 DEGs were identified following data preprocessing. DEGs were primarily enriched in 'small cell lung cancer', 'ECM-receptor interaction', 'pathways in cancer'and 'tyrosine metabolism'. Hub genes [APOE, cathepsin S (CTSS), insulin receptor substrate 1 (IRS1), KIT, LGALS3, RUNX2 and TGFBR1] were extracted from cytoHubba. Their expression in the TCGA cohort was consistent with that in the GEO cohorts. CTSS (P=0.006) and IRS1 (P=0.005) were associated with disease‑free survival, as determined using the Kaplan-Meier analysis. CTSS was an independent risk factor for poor disease‑free survival (HR, 2.649; 95% CI, 1.095-6.409; P=0.031). Patients with high expression of CTSS exhibited different histological types (increased tall-cell subtype and reduced follicular subtype; P<0.001), more frequent lymph node metastasis (P<0.001) and advanced tumor-node-metastasis stages (P=0.049) compared with the low-expression group. High expression of CTSS was independently associated with lymph node metastasis (OR, 2.015; 95% CI, 1.225-3.315; P=0.006). Therefore, CTSS may serve as a predictive risk marker for the progression and prognosis of PTC.

Oh JH, Rhyu MG, Kim SI, et al.
Gastric Mucosal Atrophy Impedes Housekeeping Gene Methylation in Gastric Cancer Patients.
Cancer Res Treat. 2019; 51(1):267-279 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
PURPOSE: Helicobacter pylori infection induces phenotype-stabilizing methylation and promotes gastric mucosal atrophy that can inhibit CpG-island methylation. Relationship between the progression of gastric mucosal atrophy and the initiation of CpG-island methylation was analyzed to delineate epigenetic period for neoplastic transformation.
Materials and Methods: Normal-appearing gastric mucosa was biopsied from 110 H. pylori-positive controls, 95 H. pylori-negative controls, 99 gastric cancer patients, and 118 gastric dysplasia patients. Gastric atrophy was assessed using endoscopic-atrophic-border score. Methylation-variable sites of eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR (MMP2, CDKN2A, RUNX2, and RUNX3) retroelements and stomach-specific TFF3 gene were analyzed using radioisotope-labeled methylation-specific polymerase chain reaction.
RESULTS: Mean ages of H. pylori-positive controls with mild, moderate, and severe atrophy were 51, 54, and 65 years and those of H. pylori-associated TFF3 overmethylation at the three atrophic levels (51, 58, and 63 years) tended to be periodic. Alu-adjacent overmethylation (50 years) was earlier than TFF3 overmethylation (58 years) in H. pylori-positive controls with moderate atrophy. Cancer patients with moderate atrophy showed late Alu-adjacent (58 years) overmethylation and frequent LTR-adjacent overmethylation. LTR-adjacent overmethylation was frequent in cancer (66 years) and dysplasia (68 years) patients with severe atrophy.
CONCLUSION: Atrophic progression is associated with gastric cancer at moderate level by impeding the initiation of Alu-adjacent methylation. LTR-adjacent methylation is increased in cancer patients and subsequently in dysplasia patients.

Shen H, Yin L, Deng G, et al.
Knockdown of Beclin-1 impairs epithelial-mesenchymal transition of colon cancer cells.
J Cell Biochem. 2018; 119(8):7022-7031 [PubMed] Related Publications
Activation of autophagy significantly affects cancer cell behaviors, such as proliferation, differentiation, and invasiveness. Epithelial-to-mesenchymal transition (EMT) as an initial step of malignant transformation of cancer cells was linked to the activation of autophagy, but the detailed molecular mechanisms are still unknown. The present study investigates the effects of Beclin-1, a key molecule involved in activation of autophagy, on EMT of colon cancer cells. The normal colon epithelia cell line of CCD-18Co and six colon cancer cell lines with different expression levels of Beclin-1 were used in this study. The activation of autophagy and EMT markers of cancer cells were monitored by Western blotting and quantitative real-time PCR assay in the presence or absence of rapamycin (autophagy activator) and 3-MA (autophagy inhibitor). The expression of Beclin-1 in selected cell lines was modulated using small interfering RNA, and consequentially EMT markers, and cancer cell behaviors including migration and invasion, were also explored. Activation or inhibition of autophagy in colon cancer cells had positive or negative impacts on the expression of EMT markers and malignant behaviors such as cell migration and invasion. Knockdown of beclin-1 by siRNA apparently inhibited the activation of autophagy induced by rapamycin, consequentially resulted in suppression of EMT and attenuation of invasiveness of colon cancer cells. The results in this study demonstrated an association between activation of autophagy and EMT in colon cancer cells. The results showed suppression of Beclin-1 expression significantly reduced EMT and invasive behaviors in colon cancer cells.

Nordstrand A, Bovinder Ylitalo E, Thysell E, et al.
Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity.
Int J Mol Sci. 2018; 19(4) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (

Sang M, Nakamura M, Ogata T, et al.
Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres.
Oncol Rep. 2018; 39(6):2749-2758 [PubMed] Related Publications
Recently, it has been well‑recognized that the response toward anticancer drugs differs between two‑ and three‑dimensional (2D and 3D) in vitro cancer cell growth models. In the present study, we have demonstrated that, similar to the conventional 2D monolayer culture systems which often lack in vivo physiological insights, RUNX2 gene silencing increases the gemcitabine (GEM) sensitivity of the 3D spheres generated from p53‑mutated pancreatic cancer MiaPaCa‑2 cells. According to our results, MiaPaCa‑2 cells, but not p53‑wild‑type pancreatic cancer SW1990 cells efficiently formed sphere structures in serum‑free sphere‑forming medium. Although GEM treatment caused a marked induction of TAp73/TAp63 in MiaPaCa‑2 spheres accompanied by the transcriptional activation of p53 family‑target genes such as p21WAF1 and NOXA, only 20% of cells underwent cell death. Under these experimental conditions, mutant p53 expression level was increased in response to GEM and RUNX2 remained unchanged at the protein level regardless of GEM exposure, which may suppress the pro‑apoptotic activity of TAp73/TAp63. Notably, RUNX2 gene silencing markedly augmented GEM‑mediated cell death of MiaPaCa‑2 spheres compared to that of non‑depleted ones. Expression analyses revealed that forced depletion of RUNX2 further stimulated GEM‑induced upregulation of TAp63 as well as its downstream target genes such as p21WAF1 and NOXA. In summary, our observations strongly indicated that, similarly to 2D monolayer culture, RUNX2 gene silencing increased GEM sensitivity of MiaPaCa‑2 spheres and highlighted the therapeutic potential of RUNX2 in pancreatic cancer with p53 mutation.

Gowda PS, Wildman BJ, Trotter TN, et al.
Runx2 Suppression by miR-342 and miR-363 Inhibits Multiple Myeloma Progression.
Mol Cancer Res. 2018; 16(7):1138-1148 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
In multiple myeloma, abnormal plasma cells accumulate and proliferate in the bone marrow. Recently, we observed that Runx2, a bone-specific transcription factor, is highly expressed in multiple myeloma cells and is a major driver of multiple myeloma progression in bone. The primary goal of the present study was to identify Runx2-targeting miRNAs that can reduce tumor growth. Expression analysis of a panel of miRNAs in multiple myeloma patient specimens, compared with healthy control specimens, revealed that metastatic multiple myeloma cells express low levels of miR-342 and miR-363 but high levels of Runx2. Reconstituting multiple myeloma cells (CAG) with miR-342 and miR-363 reduced the abundance of Runx2 and the expression of metastasis-promoting Runx2 target genes RANKL and DKK1, and suppressed Runx2 downstream signaling pathways Akt/β-catenin/survivin, which are required for multiple myeloma tumor progression. Intravenous injection of multiple myeloma cells (5TGM1), stably overexpressing miR-342 and miR-363 alone or together, into syngeneic C57Bl/KaLwRij mice resulted in a significant suppression of 5TGM1 cell growth, decreased osteoclasts and increased osteoblasts, and increased antitumor immunity in the bone marrow, compared with mice injected with 5TGM1 cells expressing a miR-Scramble control. In summary, these results demonstrate that enhanced expression of miR-342 and miR-363 in multiple myeloma cells inhibits Runx2 expression and multiple myeloma growth, decreases osteolysis, and enhances antitumor immunity. Thus, restoring the function of Runx2-targeting by miR-342 and miR-363 in multiple myeloma cells may afford a therapeutic benefit by preventing multiple myeloma progression.

Yu X, Zhao J, He Y
Long non-coding RNA PVT1 functions as an oncogene in human colon cancer through miR-30d-5p/RUNX2 axis.
J BUON. 2018 Jan-Feb; 23(1):48-54 [PubMed] Related Publications
PURPOSE: Recently, long noncoding RNAs (lncRNAs) have caught more attention for their role in tumor progression. Colon cancer is one of these ordinary malignant tumors. This study aimed to identify how lnc RNA PVT1 affects the progression of colon cancer.
METHODS: PVT1 expression of both colon cancer cell tissue and 60 paired cancer and peri-tumoral tissue samples was detected by real-time quantitative polymerase chain reaction (RT-qPCR). The associations between lnc RNA PVT1 expression level and clinicopathological characteristics and patients' disease-free survival rate were evaluated. Furthermore, function assays containing cell proliferation assay, colony formation and transwell assay were conducted. Mechanism-associated experiments included western blot assay, luciferase assay and RNA immunoprecipitation assay.
RESULTS: PVT1 expression was significantly higher in tumor tissues than in peritumoral tissues, and was associated with lymph node metastasis, tumor stage and survival time of these patients. Moreover, knockdown of PVT1 promoted tumor growth and invasion in vitro. In addition, further experiments revealed that miR-30d-5p was a direct target of PVT1 and its expression in tumor tissues negatively correlated to PVT1 expression. Moreover, RUNX2 was identified as the direct target spot of miR-30d-5p according to the mechanism experiments. Besides, RUNX2 expression was positively correlated with PVT1 in cancer tissues and cells.
CONCLUSIONS: These results indicate that PVT1 could promote metastasis and proliferation of colon cancer via suppressing miR-30d-5p/RUNX2 axis, which may offer a new way for interpreting the mechanism of colon cancer development.

Shi H, Chen W, Dong Y, et al.
BAG3 promotes chondrosarcoma progression by upregulating the expression of β-catenin.
Mol Med Rep. 2018; 17(4):5754-5763 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
To investigate the roles of B‑cell lymphoma‑2 associated athanogene 3 (BAG3) in human chondrosarcoma and the potential mechanisms, the expression levels of BAG3 were detected in the present study, and the associations between BAG3 and clinical pathological parameters, clinical stage as well as the survival of patients were analyzed. The present study detected BAG3 mRNA and protein expression in the normal cartilage cell line HC‑a and in SW1353 chondrosarcoma cells by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The BAG3 protein expression in 59 cases of chondrosarcoma, 30 patients with endogenous chondroma and 8 cases of normal cartilage was semi-quantitatively analyzed using the immunohistochemical method. In addition, the BAG3 protein expression level, the clinical pathological parameters, clinical stage and the survival time of patients with chondrosarcoma were analyzed. The plasmid transfection method was employed to upregulate the expression BAG3 and small RNA interference to downregulate the expression of BAG3 in SW1353 cells. The expression levels of BAG3 protein and mRNA were significantly increased in the chondrosarcoma cell line when compared with the normal cartilage cell line. The immunohistochemistry results indicated that BAG3 protein was overexpressed in the tissue of human chondrosarcoma. Statistical analysis showed that the expression level of BAG3 was significantly increased in the different Enneking staging of patients with chondrosarcoma and Tumor staging, and there were no statistical differences in age, gender, histological classification and tumor size. In the in vitro experiments, the data revealed that BAG3 significantly promoted chondrosarcoma cell proliferation, colony‑formation, migration and invasion; however, it inhibited chondrosarcoma cell apoptosis. It was observed that BAG3 upregulated β‑catenin expression at the mRNA and protein levels. In addition, BAG3 induced the expression of runt‑related transcription factor 2 (RUNX2) in chondrosarcoma cells by upregulating β‑catenin. These clinical analyses revealed a positive association between β‑catenin and BAG3 in chondrosarcoma tumors. BAG3 was significantly increased in chondrosarcoma cells and tissues compared with the normal cartilage cells, tissue and cartilage benign tumors. Thus, BAG3 may serve as an oncogene in the development of chondrosarcoma via the induction of RUNX2 expression. The results of the present study contribute to further research on the biological development of chondrosarcoma.

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