Gene Summary

Gene:TRIM27; tripartite motif containing 27
Aliases: RFP, RNF76
Summary:This gene encodes a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This protein localizes to the nuclear matrix. It interacts with the enhancer of polycomb protein and represses gene transcription. It is also thought to be involved in the differentiation of male germ cells. Fusion of the N-terminus of this protein with the truncated C-terminus of the RET gene product has been shown to result in production of the ret transforming protein. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:zinc finger protein RFP
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (27)

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.

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

Specific Cancers (6)

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

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

Latest Publications: TRIM27 (cancer-related)

Zang W, Bian H, Huang X, et al.
Traditional Chinese Medicine (TCM)
Anticancer Res. 2019; 39(6):2739-2747 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs).
MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a.
RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-β. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control.
CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.

von Muhlinen N
Methods to Measure Autophagy in Cancer Metabolism.
Methods Mol Biol. 2019; 1928:149-173 [PubMed] Related Publications
Autophagy, a dynamic pathway in which intracellular membrane structures sequester portions of the cytosol for degradation, plays multiple roles in physiological and pathological processes. Autophagy may have suppressive and promotive roles in the formation and progression of cancer. A growing number of methods to identify, quantify, and manipulate autophagy have been developed. Because most of these methods are semiquantitative and have significant limitations, it is important to emphasize that a combination of these assays is recommended for the analysis of autophagy. Here, I briefly discuss the autophagic process, its role in disease, and I summarize some of the best-known and most widely used methods to study autophagy in vitro in the context of cancer, including transmission electron microscopy (TEM), detection and quantification of the autophagy protein LC3 by western blot, and the use of GFP-LC3 to quantify puncta by fluorescence microscopy and tandem labeled RFP/mCherry-GFP-LC3 fluorescence microscopy to measure autophagic flux.

Phelan JJ, MacCarthy F, O'Toole D, et al.
The Mitochondrial Genes
Int J Mol Sci. 2018; 19(11) [PubMed] Free Access to Full Article Related Publications
Barrett's esophagus and esophageal cancer lack prognostic markers that allow the tailoring of personalized medicine and biomarkers with potential to provide insight into treatment response. This study aims to characterize mitochondrial function across the metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett's esophagus and examines the functional effect of manipulating mitochondrial genes. Mitochondrial genes of interest were validated in in vitro cell lines across the metaplasia (QH), dysplasia (GO) and adenocarcinoma (OE33) sequence and in in vivo patient tissue samples. These genes were subsequently knocked down in QH and OE33 cells and the functional effect of siRNA-induced knockdown on reactive oxygen species production, mitochondrial mass, mitochondrial membrane potential and cellular metabolism was investigated. Three global mitochondrial genes (

Jiang J, Xie C, Liu Y, et al.
Up-regulation of miR-383-5p suppresses proliferation and enhances chemosensitivity in ovarian cancer cells by targeting TRIM27.
Biomed Pharmacother. 2019; 109:595-601 [PubMed] Related Publications
MicroRNAs are small non-coding RNAs which play important roles in tumor progression. MiR-383-5p has been characterized as a cancer suppressor in several cancers. The aim of theses present study was to explore the role of miR-383-5p in the proliferation and chemosensitivity of ovarian cancer cells. MiR-383-5p expression was down-regulated while the expression of TRIM27 was up-regulated in ovarian cancer tissues and cell lines. We came up with the hypothesis that miR-383-5p might be involved in the tumor progression and chemoresistance of ovarian cancer through targeting TRIM27. Bioinformatics study and Luciferase reporter assay indicated that TRIM27 was a target of miR-383-5p and negatively regulated by miR-383-5p in ovarian cancer cells. Up-regulation of miR-383-5p was found to suppress cell proliferation and decrease Ki67 and PCNA expression in ovarian cancer cells (OVCAR3, A2780), suggesting that overexpressed miR-383-5p inhibited cell proliferation of ovarian cancer cells. In addition, up-regulation of miR-383-5p decreased the IC

Zhang HX, Xu ZS, Lin H, et al.
TRIM27 mediates STAT3 activation at retromer-positive structures to promote colitis and colitis-associated carcinogenesis.
Nat Commun. 2018; 9(1):3441 [PubMed] Free Access to Full Article Related Publications
STAT3 is a transcription factor that plays central roles in various physiological processes and its deregulation results in serious diseases including cancer. The mechanisms on how STAT3 activity is regulated remains enigmatic. Here we identify TRIM27 as a positive regulator of II-6-induced STAT3 activation and downstream gene expression. TRIM27 localizes to retromer-positive punctate structures and serves as a critical link for recruiting gp130, JAK1, and STAT3 to and subsequent phosphorylation of STAT3 at the retromer-positive structures. Overexpression of TRIM27 promotes cancer cell growth in vitro and tumor growth in nude mice, whereas knockdown of TRIM27 has opposite effects. Deficiency of TRIM27 significantly impairs dextran sulfate sodium (DSS)-induced STAT3 activation, inflammatory cytokine expression and colitis as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. These findings reveal a retromer-dependent mechanism for regulation of STAT3 activation, inflammation, and inflammation-associated cancer development.

Kim HS, Jung M, Choi SK, et al.
IL-6-mediated cross-talk between human preadipocytes and ductal carcinoma in situ in breast cancer progression.
J Exp Clin Cancer Res. 2018; 37(1):200 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The function of preadipocytes in the progression of early stage breast cancer has not been fully elucidated at the molecular level. To delineate the role of preadipocytes in breast cancer progression, we investigated the cross-talk between human breast ductal carcinoma in situ (DCIS) cells and preadipocytes with both an in vitro culture and xenograft tumor model.
METHODS: GFP or RFP was transduced into human DCIS cell line cells or preadipocytes using lentivirus. Cell sorter was used to separate pure, viable populations of GFP- or RFP-transduced cells. Cell viability and proliferation was assessed by crystal violet assays and cell migration and invasion capability was assayed by the transwell strategy. Gene and protein levels were measured by western blot, RT-PCR and immunostaining. Adipokines and cytokines were quantified using ELISA. Human tumor xenografts in a nude mice model were used. Ultrasound imaging of tumors was performed to evaluate the therapeutic potential of a IL-6 neutralizing antibody.
RESULTS: In the co-culture system with the and preadipocytes, proliferation, migration and invasion were enhanced by preadipocytes. Preadipocytes exhibited in an increased IL-6 secretion and cancer-associated fibroblast markers expression, FSP1 and α-SMC in co-culture with or in conditioned media, whereas the adipocyte differentiation capacity was suppressed by co-culture with A neutralizing antibody of IL-6 or IL-6R suppressed the promotion of proliferation and migration by co-culture with preadipocytes. In the xenograft tumor model, the tumor growth of was enhanced by the co-injection of preadipocytes, and the administration of IL-6 neutralizing antibodies resulted in potent effects on tumor inhibition.
CONCLUSIONS: Our findings suggest that IL-6-mediated cross-talk between preadipocytes and breast DCIS cells can promote the progression of early stage breast cancer. Therefore, blocking IL-6 signaling might be a potential therapeutic strategy for breast DCIS characterized by pathological IL-6 overproduction.

Cheng YX, Chen GT, Yang X, et al.
Effects of HPV Pseudotype Virus in Cutting E6 Gene Selectively in SiHa Cells.
Curr Med Sci. 2018; 38(2):212-221 [PubMed] Related Publications
The objectives of this study were to investigate the effects of the CRISPR/Cas9 system mediated by the HPV pseudotype virus on SiHa cytobiology behavior by cutting the HPV16 E6 gene selectively and to explore the role of this system in the treatment of cervical cancer. After designing specific gRNA sequences targeting HPV16 E6, generating hCas9-EGFP and E6-gRNA-RFP plasmids, and preparing the pseudovirus of HPV16 carrying E6-gRNA and Cas9 plasmids, we determined the titer of the pseudotype virus using the TCID50 method. We obtained the pseudotype virus of HPV16 carrying E6-gRNA and Cas9 plasmids to transfect cervical cancer SiHa cells. Experimental subjects were divided into control group, empty virus group, E6-gRNA transfected group, Cas9 transfected group and Cas9+E6-gRNA transfected group. The molecular size of the cutting sequence was detected using the T7E1 enzyme digestion method and agarose gel electrophoresis, and the cleavage function of CRISPR/Cas9 on the E6 gene was determined at the same time. RT-PCR and Western blotting were performed to detect the mRNA and protein expression levels of E6 in all the groups; the Transwell cell migration assay was performed to detect the cell migration ability and metastasis in all groups. Heterotopic transplantation tumors were incorporated into mice and were used to investigate the effects of the CRISPR/Cas9 system mediated by the HPV pseudovirus on the tumorigenic ability of SiHa cells by selectively cutting HPV16 E6. The HPV16 pseudotype virus carrying E6-gRNA and Cas9 plasmids could successfully infect SiHa cells, and there were two cutting zones in the Cas9+E6-gRNA transfected group. However, the empty virus group, E6-gRNA transfected group and Cas9 transfected group had no corresponding zone. Compared with those in the control group, the empty virus group, E6-gRNA transfected group and Cas9 transfected group, the mRNA and protein expression levels of E6 in SiHa cells were downregulated in the Cas9+E6-gRNA transfected group (P<0.01). In addition, the proliferation and migration abilities of SiHa cells were significantly inhibited (P<0.01). There were no significant differences among the other groups. In contrast to the control group, the HPV pseudotype virus carrying E6-gRNA and Cas9 plasmids could significantly delay the growth of tumor cells of the ectopic tumor transplantation model (P<0.01). The CRISPR/Cas9 system mediated by the HPV pseudotype virus to knockout E6 gene expression exhibited a clear inhibitory effect on the biological function of SiHa cells, which indicated that knocking out the E6 gene using the CRISPR/Cas9 system mediated by the HPV pseudotype virus had a potential effect of eliminating HPV infection and inhibiting the growth of HPV-related tumors. Taken together, these findings provide insight into a new treatment strategy for the prevention and treatment of hr-HPV infected disease, particularly in HPV-related tumors.

Zhang Y, Feng Y, Ji D, et al.
TRIM27 functions as an oncogene by activating epithelial-mesenchymal transition and p-AKT in colorectal cancer.
Int J Oncol. 2018; 53(2):620-632 [PubMed] Free Access to Full Article Related Publications
Tripartite motif‑containing 27 (TRIM27) belongs to the tripartite motif (TRIM) protein family and is involved in various malignant tumor processes. However, the function and mechanism of TRIM27 in colorectal cancer (CRC) remains to be elucidated. In the present study, the expression of TRIM27 was analyzed in CRC tissues and adjacent normal tissues by reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. LoVo and HCT116 cell lines were then selected to further investigate the function of TRIM27 in the proliferation, invasion and metastasis of CRC in vitro and in vivo. Finally, the potential mechanism underlying the effects of TRIM27 in CRC was examined by western blotting. The results showed that TRIM27 was upregulated in CRC tissues, and the expression level of TRIM27 was significantly associated with tumor invasion, metastasis and prognosis. Following TRIM27 inhibition and overexpression in CRC cells, it was found that TRIM27 promoted cell proliferation, possibly via the inhibition of apoptosis and cell cycle regulation. TRIM27 also facilitated invasion and metastasis. Finally, it was observed that TRIM27 promoted epithelial‑mesenchymal transition and activated phosphorylated AKT serine/threonine kinase in CRC cells. These results suggested that TRIM27 is an oncogenic protein in the progression of CRC, and may represent a novel target for CRC detection and therapy.

Dong F, Li C, Wang P, et al.
The RNA binding protein tristetraprolin down-regulates autophagy in lung adenocarcinoma cells.
Exp Cell Res. 2018; 367(1):89-96 [PubMed] Related Publications
Tristetraprolin (TTP) is the most well-known member of RNA-binding zinc-finger protein that play a significant role in accelerating mRNA decay. Increasingly studies have reported that TTP was functioned as a tumor suppressor gene in several types of carcinomas, while its underlying mechanism is not clear yet. In the current study, we found that TTP overexpression decreased cell proliferation and increased cell death in lung adenocarcinoma cells, with the cell cycle arrest at the S phase. Remarkably, instead of inducing cell apoptosis directly, TTP overexpression alters cell autophagy. Our studies demonstrate that TTP overexpression has no effect on apoptosis related genes, but decreases the expression of autophagy-related genes, including Beclin 1 and LC3II. The level of autophagy flux assessed by infection with the mGFP-RFP-LC3 adenovirus construction has been blocked by TTP overexpression. Moreover, the autophagic vacuoles number detected by transmission electron microscopy decreased with TTP expression up-regulation. Our results indicate, for the first time, that TTP suppresses cell proliferation and increases cell death through cell autophagy pathway in lung cancer cells. Our study provides a new angle of view for TTP function as a tumor suppressor which could be targeted in tumor treatment.

Yang B, Li M, Tang W, et al.
Dynamic network biomarker indicates pulmonary metastasis at the tipping point of hepatocellular carcinoma.
Nat Commun. 2018; 9(1):678 [PubMed] Free Access to Full Article Related Publications
Developing predictive biomarkers that can detect the tipping point before metastasis of hepatocellular carcinoma (HCC), is critical to prevent further irreversible deterioration. To discover such early-warning signals or biomarkers of pulmonary metastasis in HCC, we analyse time-series gene expression data in spontaneous pulmonary metastasis mice HCCLM3-RFP model with our dynamic network biomarker (DNB) method, and identify CALML3 as a core DNB member. All experimental results of gain-of-function and loss-of-function studies show that CALML3 could indicate metastasis initiation and act as a suppressor of metastasis. We also reveal the biological role of CALML3 in metastasis initiation at a network level, including proximal regulation and cascading influences in dysfunctional pathways. Our further experiments and clinical samples show that DNB with CALML3 reduced pulmonary metastasis in liver cancer. Actually, loss of CALML3 predicts shorter overall and relapse-free survival in postoperative HCC patients, thus providing a prognostic biomarker and therapy target in HCC.

Vangangelt KMH, van Pelt GW, Engels CC, et al.
Prognostic value of tumor-stroma ratio combined with the immune status of tumors in invasive breast carcinoma.
Breast Cancer Res Treat. 2018; 168(3):601-612 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor-stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated.
METHODS: A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs).
RESULTS: TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles.
CONCLUSIONS: Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients.

Kobuke K, Oki K, Gomez-Sanchez CE, et al.
Calneuron 1 Increased Ca
Hypertension. 2018; 71(1):125-133 [PubMed] Free Access to Full Article Related Publications
Aldosterone production is initiated by angiotensin II stimulation and activation of intracellular Ca

Kou B, Liu W, Xu X, et al.
Autophagy induction enhances tetrandrine-induced apoptosis via the AMPK/mTOR pathway in human bladder cancer cells.
Oncol Rep. 2017; 38(5):3137-3143 [PubMed] Related Publications
Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra is a traditional Chinese medicine and exerts anticancer capacity in various types of cancers. Previous studies have shown that tetrandrine induces apoptosis in bladder cancer cells via activation of the caspase cascade. However, the underlying mechanism has not yet been reported. Autophagy is a cellular process involved in the degradation of broken proteins and aging organelles to maintain homeostasis. Recent studies indicate that autophagy is implicated in cancer therapy. Thus, we focused on the correlation between autophagy and apoptosis upon tetrandrine treatment in human bladder cancer cells. Firstly, our results observed a marked increase in autophagic double-membrane vacuoles and fluorescent puncta of red fluorescence protein-green fluorescence protein-LC3 (GRP-RFP-LC3) upon tetrandrine treatment, as evidenced by transmission electron microscopy and confocal fluorescence microscopy. Secondly, the expression of LC3-II was increased in tetrandrine-treated T24 and 5637 cells in a time- and concentration-dependent manner. Subsequently, downregulation of p62 and LC3 turnover assay further confirmed that tetrandrine induced autophagic flux in bladder cancer T24 and 5637 cells. Thirdly, the protein levels of phosphorylated-AMP-activated protein kinase (AMPK) and phosphorylated-acetyl-coenzyme A carboxylase (ACC) were upregulated in the tetrandrine-treated cells, while the mammalian target of rapamycin (mTOR)-related proteins were downregulated. Moreover, AICAR, a common AMPK activator, further increased the expression the LC3-II, while AMPK inhibitor compound C partially reversed the LC3-II protein levels in bladder cancer T24 cells. Finally, AICAR significantly reinforced the growth inhibition and apoptosis induction of tetrandrine in T24 and 5637 cells, while compound C had an opposite effect, suggesting that AMPK-mediated autophagy enhanced the cytotoxic and pro-apoptosis effect of tetrandrine in human bladder cancer cells. Taken together, the present study showed that tetrandrine induced autophagy in human bladder cancer cells by regulating the AMPK/mTOR signaling pathway, which contributed to the apoptosis induction by tetrandrine, indicating that tetrandrine may be a potential anticancer candidate for the treatment of bladder cancer, and autophagy may be a possible mechanism for cancer therapy.

Wang R, Zhang K, Tao H, et al.
Molecular Imaging of Tumor Angiogenesis and Therapeutic Effects with Dual Bioluminescence.
Curr Pharm Biotechnol. 2017; 18(5):422-428 [PubMed] Related Publications
BACKGROUND: Angiogenesis is critical for the growth of tumor by supplying nutrients and oxygen that exacerbates the metastasis and progression of cancer. Noninvasive imaging of angiogenesis during the tumor therapeutic processes may provide novel opportunities for image-guided tumor management.
OBJECTIVE: Here, we want to develop a mouse animal model for assessing cancer progression and angiogenesis in the same individuals by molecular imaging.
METHODS: Breast cancer model was developed with mouse breast cancer cell line 4T1 carrying a reporter system encoding a triple fusion (TF) reporter gene consisting of renilla luciferase (Rluc), red fluorescent protein (RFP) and herpes simplex virus truncated thymidine kinase (HSV-ttk) in transgenic mice, which expressed firefly luciferase (Fluc) under the promoter of vascular endothelial growth factor receptor 2 (Vegfr2-luc). The mice were subsequently treated with ganciclovir (GCV) and the tumor angiogenesis was tracked by Fluc imaging and the growth status of tumor was monitored by imaging of Rluc simultaneously.
CONCLUSION: Overall, this traceable breast cancer model can simultaneously image the tumor growth and angiogenesis in single individual, which may facilitate a better understanding the mechanisms of angiogenesis in the progression and regression of tumor.

Khan GN, Kim EJ, Shin TS, Lee SH
Heterogeneous Cell Types in Single-cell-derived Clones of MCF7 and MDA-MB-231 Cells.
Anticancer Res. 2017; 37(5):2343-2354 [PubMed] Related Publications
BACKGROUND/AIM: Variations in cell phenotype in a single-cell-derived clone may result from asymmetric cell divisions that lead to different cell fate in a homogenous microenvironment. The aim of this study was to demonstrate the extent of cell variety in single-cell-derived clones and propose a different strategy in treating cancer by observed phenotypic heterogeneity in cellular types. Additionally, the role of metabolic enzyme and housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in cellular phenotype was evaluated in two breast cancer cell lines.
MATERIALS AND METHODS: Two GAPDH-overexpressing breast cancer cell lines, MCF7-GAPDH-RFP (MCF7-RFP) and MDA-MB-231-GAPDH-RFP (MDA-RFP), were established. Microscopic recordings were made at 12-h intervals in single-cell-derived clones of both cell lines up to 8-10 days. Crystal violet and Hoechst 33342 (Hoechst), as well as specific cell-type (epithelial and mesenchymal) antibodies, were used for cytochemical and immunohistochemical staining analyses, respectively, at 3, 6 and 9 days during cell growth.
RESULTS: Three types of clones with distinct morphologies were identified as holo-, mero- and paraclones. The rates of colony survival during cell growth were 8.3 and 41.7% in MCF7-RFP and MDA-RFP, respectively. Although no significant difference was found in the colony forming efficiency (CFE) of both MCF7 and MDA-MD-231 wild-type cells, a markedly significant difference was seen in the CFE of MCF7-RFP and MDA-RFP cells (p=0.001). Wild-type cell-derived holoclones of both cell lines showed drug resistance to doxorubicin (Dox). However, levels of proliferating cell nuclear antigen (PCNA) and vimentin (VIM) marginally decreased in Dox-treated clones. Furthermore, high level of intraclonal heterogeneity was found for CD44, CD140a, VIM, fibronectin (FN), focal adhesion kinase (FAK), paxillin (PXN) and vinculin (VCL) in MCF7 and MDA clones during different stages of clonal development. Expressions of CD140a, FN, VIM and FAK were induced in GAPDH-red fluorescent protein (RFP)-tagged clones of both cell lines.
CONCLUSION: The GAPDH-RFP recombinant protein played an important role in morphological heterogeneity detection in early stages of clonal development. Moreover, phenotypic heterogeneity in clones, caused by the cells expressing specific antigens, such as CD44, CD140a, FN, VIM, FAK and VCL, can be the right target for therapeutic drugs.

Dai X, Liu L, Ouyang J, et al.
Coaxial 3D bioprinting of self-assembled multicellular heterogeneous tumor fibers.
Sci Rep. 2017; 7(1):1457 [PubMed] Free Access to Full Article Related Publications
Three-dimensional (3D) bioprinting of living structures with cell-laden biomaterials has been achieved in vitro, however, some cell-cell interactions are limited by the existing hydrogel. To better mimic tumor microenvironment, self-assembled multicellular heterogeneous brain tumor fibers have been fabricated by a custom-made coaxial extrusion 3D bioprinting system, with high viability, proliferative activity and efficient tumor-stromal interactions. Therein, in order to further verify the sufficient interactions between tumor cells and stroma MSCs, CRE-LOXP switch gene system which contained GSCs transfected with "LOXP-STOP-LOXP-RFP" genes and MSCs transfected with "CRE recombinase" gene was used. Results showed that tumor-stroma cells interacted with each other and fused, the transcription of RFP was higher than that of 2D culture model and control group with cells mixed directly into alginate, respectively. RFP expression was observed only in the cell fibers but not in the control group under confocal microscope. In conclusion, coaxial 3D bioprinted multicellular self-assembled heterogeneous tumor tissue-like fibers provided preferable 3D models for studying tumor microenvironment in vitro, especially for tumor-stromal interactions.

Murakami T, Hiroshima Y, Miyake K, et al.
Color-coded intravital imaging demonstrates a transforming growth factor-β (TGF-β) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model.
Cell Cycle. 2017; 16(10):1008-1014 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer is a recalcitrant malignancy, partly due to desmoplastic stroma which stimulates tumor growth, invasion, and metastasis, and inhibits chemotherapeutic drug delivery. Transforming growth factor-β (TGF-β) has an important role in the formation of stromal desmoplasia. The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF-β inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The BxPC-3 human pancreatic adenocarcinoma cell line expressing green fluorescent protein (GFP), which also has a high TGF-β expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3 weeks) and a treated group (n = 7, SB431542 [TGF-β receptor type I inhibitor] 0.3 mg, i.p., weekly, for 3 weeks). Stromal cells expressing RFP and cancer cells expressing GFP were observed weekly for 3 weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells, relative to the GFP fluorescence area of the cancer cells, was significantly decreased in the TGF-β-inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in an orthotopic pancreatic-cancer cell-line mouse model can readily detect the selective anti-stromal-cell targeting of a TGF-β inhibitor.

Chen L, Zhang S, Wu J, et al.
circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family.
Oncogene. 2017; 36(32):4551-4561 [PubMed] Free Access to Full Article Related Publications
Circular RNAs (circRNAs) represent a class of non-coding RNAs that are widely expressed in mammals. However, it is largely unknown about the function of human circRNAs and the roles of circRNAs in human oral squamous cell carcinomas (OSCC). Here we performed a comprehensive study of circRNAs in human OSCC using circRNA and mRNA microarrays, and identified many circRNAs that are differentially expressed between OSCC tissue and paired non-cancerous matched tissue. We further found a circRNA termed circRNA_100290 that served as a critical regulator in OSCC development. We discovered that circRNA_100290 was upregulated and co-expressed with CDK6 in OSCC tissue. Knockdown of circRNA_100290 decreased expression of CDK6 and inhibited proliferation of OSCC cell lines in vitro and in vivo. Via luciferase reporter assays, circRNA_100290 was observed to directly bind to miR-29 family members. Further EGFP/RFP reporter assays showed that CDK6 was the direct target of miR-29b. Taken together, we conclude that circRNA_100290 may function as a competing endogenous RNA to regulate CDK6 expression through sponging up miR-29b family members. Taken together, it indicates that circRNAs may exert regulatory functions in OSCC and may be a potential target for OSCC therapy.

Chen Z, Feng X, Herting CJ, et al.
Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma.
Cancer Res. 2017; 77(9):2266-2278 [PubMed] Free Access to Full Article Related Publications
In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1

Gendelman R, Xing H, Mirzoeva OK, et al.
Bayesian Network Inference Modeling Identifies TRIB1 as a Novel Regulator of Cell-Cycle Progression and Survival in Cancer Cells.
Cancer Res. 2017; 77(7):1575-1585 [PubMed] Free Access to Full Article Related Publications
Molecular networks governing responses to targeted therapies in cancer cells are complex dynamic systems that demonstrate nonintuitive behaviors. We applied a novel computational strategy to infer probabilistic causal relationships between network components based on gene expression. We constructed a model comprised of an ensemble of networks using multidimensional data from cell line models of cell-cycle arrest caused by inhibition of MEK1/2. Through simulation of a reverse-engineered Bayesian network model, we generated predictions of G

Yano S, Takehara K, Kishimoto H, et al.
Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models.
Anticancer Res. 2017; 37(1):57-60 [PubMed] Related Publications
BACKGROUND: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice.
MATERIALS AND METHODS: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room.
RESULTS: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDA-MB-231 tumors were resected.
CONCLUSION: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC.

Chen JC, Chuang HY, Hsu FT, et al.
Sorafenib pretreatment enhances radiotherapy through targeting MEK/ERK/NF-κB pathway in human hepatocellular carcinoma-bearing mouse model.
Oncotarget. 2016; 7(51):85450-85463 [PubMed] Free Access to Full Article Related Publications
Patients with unresectable hepatocellular carcinoma (HCC) usually have poor prognosis because current monotherapy including surgery, chemotherapy and radiotherapy (RT) are not effective. Combination therapy may be effective to overcome this clinical problem. Here, we proposed the combination of sorafenib and RT, which have been applied in HCC treatment, could improve the treatment outcome of HCC. Our previous study showed that sorafenib could suppress the expression of NF-κB which is related to the chemo- and radio-resistance. Nevertheless, the expression of NF-κB is oscillatory and is affected by the treatments. Thus, understanding the oscillation of NF-κB expression would be beneficial for determining the optimal treatment schedule in combination therapy. Here established Huh7/NF-κB-tk-luc2/rfp cell line, in which NF-κB indicates a NF-κB promoter, was utilized to noninvasively monitor the expression of NF-κB overtime in vitro and in vivo. The results show that pretreatment of sorafenib with RT suppresses the expressions of NF-κB and its downstream proteins induced by radiation through downregulation of phosphorylated extracellular signal-regulated kinase (pERK) most significantly compared with other treatment schedules. The results were further verified with Western blotting, EMSA, and NF-κB molecular imaging. These findings suggest that pretreatment of sorafenib with RT may be the ideal treatment schedule for the treatment of HCC.

Yano S, Takehara K, Miwa S, et al.
Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence.
Oncotarget. 2016; 7(46):75635-75647 [PubMed] Free Access to Full Article Related Publications
We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative high-invasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)-light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model.

Kato S, Subbiah V, Marchlik E, et al.
Clin Cancer Res. 2017; 23(8):1988-1997 [PubMed] Related Publications

He K, Qu H, Xu LN, et al.
Epigenetics changes caused by the fusion of human embryonic stem cell and ovarian cancer cells.
Biosci Rep. 2016; 36(5) [PubMed] Free Access to Full Article Related Publications
To observe the effect of gene expression and tumorigenicity in hybrid cells of human embryonic stem cells (hESCs) and ovarian cancer cells in vitro and in vivo using a mouse model, and to determine its feasibility in reprogramming tumour cells growth and apoptosis, for a potential exploration of the role of hESCs and tumour cells fusion in the management of ovarian cancer. Stable transgenic hESCs (H1) and ovarian cancer cell line OVCAR-3 were established before fusion, and cell fusion system was established to analyse the related indicators. PTEN expression in HO-H1 cells was higher than those in the parental stem cells and lower than those in parental tumour cells; the growth of OV-H1 (RFP+GFP) hybrid cells with double fluorescence expressions were obviously slower than that of human embryonic stem cells and OVCAR-3 ovarian cancer cells. The apoptosis signal of the OV-H1 hybrid cells was significantly higher than that of the hESCs and OVCAR-3 ovarian cancer cells. In vivo results showed that compared with 7 days, 28 days and 35 days after inoculation of OV-H1 hybrid cells; also, apoptotic cell detection indicated that much stronger apoptotic signal was found in OV-H1 hybrid cells inoculated mouse. The hESCs can inhibit the growth of OVCAR-3 cells in vitro by suppressing p53 and PTEN expression to suppress the growth of tumour that may be achieved by inducing apoptosis of OVCAR-3 cells. The change of epigenetics after fusion of ovarian cancer cells and hESCs may become a novel direction for treatment of ovarian cancer.

Wang Z, Yu B, Wang B, et al.
A novel capsid-modified oncolytic recombinant adenovirus type 5 for tumor-targeting gene therapy by intravenous route.
Oncotarget. 2016; 7(30):47287-47301 [PubMed] Free Access to Full Article Related Publications
Oncolytic adenovirus (Ad)-vectored gene therapy is a promising strategy for cancer treatment. However, the lack of cancer cell selectivity or tumor tissue specificity of Ads limits their clinical application by intravenous (IV) injection. In this paper, a novel recombinant Ad5 vector was constructed carrying the capsid protein IX modified by the tumor necrosis factor related apoptosis-inducing ligand (TRAIL), which targets tumor cells bearing high levels of its receptor far above those of normal cells. Specific association of the Ad virion with TRAIL was achieved using synthetic leucine zipper-like dimerization domains (zippers). Analysis of the chemical properties of the modified recombinant Ad (rAd5pz-zTRAIL-RFP) showed that the TRAIL protein was present on the surface of purified virus particles, and it could induce apoptosis of infected cancer cells prior to expression of foreign genes. We also constructed a novel modified recombinant oncolytic Ad (rAd5pz-zTRAIL-RFP-SΔ24E1a) which showed significantly enhanced anti-tumor effects both in vitro and in vivo by linkage of TRAIL to the viral capsid. Moreover, rAd5pz-zTRAIL-RFP-SΔ24E1a showed significantly improved tumor tissue targeting and reduced liver tropism when IV injected in vivo. Thus, we successfully obtained new oncolytic Ad5 gene therapy vectors with enhanced targeting and efficacy, providing a platform for further clinical application of Ad vectors for cancer treatment.

Zhang F, Dong W, Zeng W, et al.
Naringenin prevents TGF-β1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation.
Breast Cancer Res. 2016; 18(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Targeting the TGF-β1 pathway for breast cancer metastasis therapy has become an attractive strategy. We have previously demonstrated that naringenin significantly reduced TGF-β1 levels in bleomycin-induced lung fibrosis and effectively prevented pulmonary metastases of tumors. This raised the question of whether naringenin can block TGF-β1 secretion from breast cancer cells and inhibit their pulmonary metastasis.
METHODS: We transduced a lentiviral vector encoding the mouse Tgf-β1 gene into mouse breast carcinoma (4T1-Luc2) cells and inoculated the transformant cells (4T1/TGF-β1) into the fourth primary fat pat of Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored using bioluminescent imaging. Spleens, lungs and serum (n = 18-20 per treatment group) were analyzed for immune cell activity and TGF-β1 level. The mechanism whereby naringenin decreases TGF-β1 secretion from breast cancer cells was investigated at different levels, including Tgf-β1 transcription, mRNA stability, translation, and extracellular release.
RESULTS: In contrast to the null-vector control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-β1 tumors were observed. Administration of the TGF-β1 blocking antibody 1D11 or naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-β1 tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-β1 bearing mice was observed, represented by a higher proportion of regulatory T cells and myeloid-derived suppressor cells and a lower proportion of activated T cells and INFγ expression in CD8(+) T cells. These metrics were improved by administration of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted TGF-β1 but did not affect intracellular TGF-β1 levels, naringenin reduced the secretion of TGF-β1 from the cells, leading to an accumulation of intracellular TGF-β1. Further experiments revealed that naringenin had no effect on Tgf-β1 transcription, mRNA decay or protein translation, but prevented TGF-β1 transport from the trans-Golgi network by inhibiting PKC activity.
CONCLUSIONS: Naringenin blocks TGF-β1 trafficking from the trans-Golgi network by suppressing PKC activity, resulting in a reduction of TGF-β1 secretion from breast cancer cells. This finding suggests that naringenin may be an attractive therapeutic candidate for TGF-β1 related diseases.

Wang X, Enomoto A, Asai N, et al.
Collective invasion of cancer: Perspectives from pathology and development.
Pathol Int. 2016; 66(4):183-92 [PubMed] Related Publications
Clinical pathologists have long been aware that in many types of human malignant tumors, the cells are often connected and form groups of various sizes or "nests". In this way, they achieve "collective invasion" into the surrounding stroma, rather than spreading out individually. Such collective behavior is also a common feature of migration during embryonic and postnatal developmental stages, suggesting there are advantages gained by collective cell migration in the organisms. Recent studies have revealed the mechanisms underlying the collective invasion of cancer cells. These mechanisms differ from those observed in the migration of single cells in culture, including reliance on the epithelial-mesenchymal transition program. Whereas intercellular adhesion appears to be coordinated, cancer cell groups can be heterogenous, including cells that are leaders and those that are followers. There is also interaction with the tumor microenvironment that is a prerequisite for collective invasion of cancer. In this review, we describe recently emerging mechanisms underlying the collective migration of cells, with a particular focus in our studies on the actin-binding protein Girdin/GIV and the transcriptional regulator tripartite motif containing 27. These studies provide new perspectives on the mechanistic analogy between cancer and development.

Hoffman RM, Yano S
Salmonella typhimurium A1-R and Cell-Cycle Decoy Therapy of Cancer.
Methods Mol Biol. 2016; 1409:165-75 [PubMed] Related Publications
Cancer cells in G0/G1 are resistant to cytotoxic chemotherapy agents which kill only cycling cancer cells. Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed cancer cells in monolayer culture and in tumor spheres to cycle from G0/G1 to S/G2/M, as demonstrated by fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging. S. typhimurium A1-R targeted FUCCI-expressing subcutaneous tumors, and tumors growing on the liver, growing in nude mice and also decoyed quiescent cancer cells, which were the majority of the cells in the tumors, to cycle from G0/G1 to S/G2/M. The S. typhimurium A1-R-decoyed cancer cells became sensitive to cytotoxic agents.

Hoffman RM, Zhao M
Methods for Tumor Targeting with Salmonella typhimurium A1-R.
Methods Mol Biol. 2016; 1409:143-64 [PubMed] Related Publications
Salmonella typhimurium A1-R (S. typhimurium A1-R) has shown great preclinical promise as a broad-based anti-cancer therapeutic (please see Chapter 1 ). The present chapter describes materials and methods for the preclinical study of S. typhimurium A1-R in clinically-relevant mouse models. Establishment of orthotopic metastatic mouse models of the major cancer types is described, as well as other useful models, for efficacy studies of S. typhimurium A1-R or other tumor-targeting bacteria, as well. Imaging methods are described to visualize GFP-labeled S. typhimurium A1-R, as well as GFP- and/or RFP-labeled cancer cells in vitro and in vivo, which S. typhimurium A1-R targets. The mouse models include metastasis to major organs that are life-threatening to cancer patients including the liver, lung, bone, and brain and how to target these metastases with S. typhimurium A1-R. Various routes of administration of S. typhimurium A1-R are described with the advantages and disadvantages of each. Basic experiments to determine toxic effects of S. typhimurium A1-R are also described. Also described are methodologies for combining S. typhimurium A1-R and chemotherapy. The testing of S. typhimurium A1-R on patient tumors in patient-derived orthotopic xenograft (PDOX) mouse models is also described. The major methodologies described in this chapter should be translatable for clinical studies.

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