BTG1

Gene Summary

Gene:BTG1; BTG anti-proliferation factor 1
Aliases: APRO2
Location:12q21.33
Summary:This gene is a member of an anti-proliferative gene family that regulates cell growth and differentiation. Expression of this gene is highest in the G0/G1 phases of the cell cycle and downregulated when cells progressed through G1. The encoded protein interacts with several nuclear receptors, and functions as a coactivator of cell differentiation. This locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. [provided by RefSeq, Oct 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein BTG1
Source:NCBIAccessed: 10 March, 2017

Ontology:

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

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: BTG1 (cancer-related)

Yuniati L, van der Meer LT, Tijchon E, et al.
Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress.
Oncotarget. 2016; 7(3):3128-43 [PubMed] Free Access to Full Article Related Publications
Cancer cells are frequently exposed to physiological stress conditions such as hypoxia and nutrient limitation. Escape from stress-induced apoptosis is one of the mechanisms used by malignant cells to survive unfavorable conditions. B-cell Translocation Gene 1 (BTG1) is a tumor suppressor that is frequently deleted in acute lymphoblastic leukemia and recurrently mutated in diffuse large B cell lymphoma. Moreover, low BTG1 expression levels have been linked to poor outcome in several solid tumors. How loss of BTG1 function contributes to tumor progression is not well understood. Here, using Btg1 knockout mice, we demonstrate that loss of Btg1 provides a survival advantage to primary mouse embryonic fibroblasts (MEFs) under stress conditions. This pro-survival effect involves regulation of Activating Transcription Factor 4 (ATF4), a key mediator of cellular stress responses. We show that BTG1 interacts with ATF4 and positively modulates its activity by recruiting the protein arginine methyl transferase PRMT1 to methylate ATF4 on arginine residue 239. We further extend these findings to B-cell progenitors, by showing that loss of Btg1 expression enhances stress adaptation of mouse bone marrow-derived B cell progenitors. In conclusion, we have identified the BTG1/PRMT1 complex as a new modifier of ATF4 mediated stress responses.

Ceccarelli M, Micheli L, D'Andrea G, et al.
Altered cerebellum development and impaired motor coordination in mice lacking the Btg1 gene: Involvement of cyclin D1.
Dev Biol. 2015; 408(1):109-25 [PubMed] Related Publications
Cerebellar granule neurons develop postnatally from cerebellar granule precursors (GCPs), which are located in the external granule layer (EGL) where they massively proliferate. Thereafter, GCPs become postmitotic, migrate inward to form the internal granule layer (IGL), further differentiate and form synapses with Purkinje cell dendrites. We previously showed that the Btg family gene, Tis21/Btg2, is required for normal GCP migration. Here we investigated the role in cerebellar development of the related gene, Btg1, which regulates stem cell quiescence in adult neurogenic niches, and is expressed in the cerebellum. Knockout of Btg1 in mice caused a major increase of the proliferation of the GCPs in the EGL, whose thickness increased, remaining hyperplastic even after postnatal day 14, when the EGL is normally reduced to a few GCP layers. This was accompanied by a slight decrease of differentiation and migration of the GCPs and increase of apoptosis. The GCPs of double Btg1/Tis21-null mice presented combined major defects of proliferation and migration outside the EGL, indicating that each gene plays unique and crucial roles in cerebellar development. Remarkably, these developmental defects lead to a permanent increase of the adult cerebellar volume in Btg1-null and double mutant mice, and to impairment in all mutants, including Tis21-null, of the cerebellum-dependent motor coordination. Gain- and loss-of-function strategies in a GCP cell line revealed that Btg1 regulates the proliferation of GCPs selectively through cyclin D1. Thus, Btg1 plays a critical role for cerebellar maturation and function.

Zhu R, Li W, Xu Y, et al.
Upregulation of BTG1 enhances the radiation sensitivity of human breast cancer in vitro and in vivo.
Oncol Rep. 2015; 34(6):3017-24 [PubMed] Related Publications
X-ray-based radiotherapy is one of the most effective therapeutic strategies for breast cancer patients. However, radioresistance and side-effects continue to be the most challenging issues. B-cell translocation gene 1 (BTG1) is a member of the BTG/Tob family, which inhibits cancer growth and promotes apoptosis. We, therefore, hypothesized that BTG1 plays an important role in the radiosensitivity of breast cancer cells. In the present study, breast cancer cell lines that stably overexpressed BTG1 were used to investigate the effects of BTG1 on cell radiosensitivity in vitro. We found that overexpression of BTG1 enhanced the radiosensitivity both of p53-mutant breast cancer MDA-MB-231 cells and p53 wild-type breast cancer MCF-7 cells. We also found that overexpression of BTG1 along with irradiation induced cell cycle G2/M phase arrest, promoted the formation of reactive oxygen species (ROS), increased the rate of chromosomal aberrations and increased cell apoptosis. Further investigation indicated that BTG1 overexpression along with irradiation was involved in inhibition of the PI3K/Akt signaling pathway. Importantly, the finding that BTG1 promoted ionizing radiosensitivity of breast cancer cells in vitro was confirmed in an animal model. Taken together, our data suggest that BTG1 overexpression combined with radiation therapy increases the therapeutic efficacy of breast cancer treatment via regulation of the cell cycle and apoptosis-related signaling pathways.

Zhu J, Zhao C, Zhuang T, et al.
RING finger protein 31 promotes p53 degradation in breast cancer cells.
Oncogene. 2016; 35(15):1955-64 [PubMed] Free Access to Full Article Related Publications
The atypical E3 ubiquitin ligase RNF31 is highly expressed in human breast cancer, the most frequent neoplastic lethality among women. Here, RNF31 depletion in breast cancer cells in combination with global gene expression profiling revealed p53 (TP53) signaling as a potential RNF31 target. Interestingly, RNF31 decreased p53 stability, whereas depletion of RNF31 in breast cancer cells caused cell cycle arrest and cisplatin-induced apoptosis in a p53-dependent manner. Furthermore, RNF31 associated with the p53/MDM2 complex and facilitated p53 polyubiquitination and degradation by stabilizing MDM2, suggesting a molecular mechanism by which RNF31 regulates cell death. Analysis of publically available clinical data sets displayed a negative correlation between RNF31 and p53 target genes, including IGFBP3 and BTG1, consistent with RNF31 regulating p53 function in vivo as well. Together, our findings suggest RNF31 as a potential therapeutic target to restore p53 function in breast cancer.

Zheng HC, Li J, Shen DF, et al.
BTG1 expression correlates with pathogenesis, aggressive behaviors and prognosis of gastric cancer: a potential target for gene therapy.
Oncotarget. 2015; 6(23):19685-705 [PubMed] Free Access to Full Article Related Publications
Here, we found that BTG1 overexpression inhibited proliferation, migration and invasion, induced G2/M arrest, differentiation, senescence and apoptosis in BGC-823 and MKN28 cells (p < 0.05). BTG1 transfectants showed a higher mRNA expression of Cyclin D1 and Bax, but a lower mRNA expression of cdc2, p21, mTOR and MMP-9 than the control and mock (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG1 transfectants showed lower mRNA viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05) with the hypoexpression of chemoresistance-related genes (slug, CD147, GRP78, GRP94, FBXW7 TOP1, TOP2 and GST-π). BTG1 expression was restored after 5-aza-2'-deoxycytidine treatment in gastric cancer cells. BTG1 expression was statistically lower in gastric cancer than non-neoplastic mucosa and metastatic cancer in lymph node (p < 0.05). BTG1 expression was positively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, TNM staging and worse prognosis (p < 0.05). The diffuse-type carcinoma showed less BTG1 expression than intestinal- and mixed-type ones (p < 0.05). BTG1 overexpression suppressed tumor growth and lung metastasis of gastric cancer cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that down-regulated BTG1 expression might promote gastric carcinogenesis partially due to its promoter methylation. BTG1 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.

Micheli L, Ceccarelli M, Farioli-Vecchioli S, Tirone F
Control of the Normal and Pathological Development of Neural Stem and Progenitor Cells by the PC3/Tis21/Btg2 and Btg1 Genes.
J Cell Physiol. 2015; 230(12):2881-90 [PubMed] Related Publications
The PC3/Tis21/Btg2 and Btg1 genes are transcriptional cofactors belonging to the Btg/Tob family, which regulate the development of several cell types, including neural precursors. We summarize here the actions of these genes on neural precursors in the adult neurogenic niches and the cognitive defects associated when their expression is altered. We consider also recent findings implicating them in neural and non-neural tumors, since common developmental mechanisms are involved. PC3/Tis21 is required for the regulation of the maturation of stem and progenitor cells in the adult dentate gyrus and subventricular zone (SVZ), by controlling both their exit from the cell cycle and the ensuing terminal differentiation. Such actions are effected by regulating the expression of several genes, including cyclin D1, BMP4, Id3. In cerebellar precursors, however, PC3/Tis21 regulates chiefly their migration rather than proliferation or differentiation, with important implications for the onset of medulloblastoma, the cerebellar tumor. In fact PC3/Tis21 is a medulloblastoma-suppressor, as its overexpression in cerebellar precursors inhibits this tumor; PC3/Tis21 shows anti-tumor activity also in non-neural tumors. Btg1 presents a different functional profile, as it controls proliferation in adult stem/progenitor cells of dentate gyrus and SVZ, where is required to maintain their self-renewal and quiescence, but is apparently devoid of a direct control of their terminal differentiation or migration. Notably, physical exercise in Btg1-null mice rescues the loss of proliferative capability occurring in older stem cells. Both genes could be further investigated as therapeutical targets, namely, Btg1 in the process of aging and PC3/Tis21 as a tumor-suppressor.

Kawamura M, Taki T, Kaku H, et al.
Identification of SPAG9 as a novel JAK2 fusion partner gene in pediatric acute lymphoblastic leukemia with t(9;17)(p24;q21).
Genes Chromosomes Cancer. 2015; 54(7):401-8 [PubMed] Related Publications
We have identified a novel SPAG9-JAK2 fusion in a B-cell precursor acute lymphoblastic leukemia (ALL) with t(9;17)(p24;q21) and a poor outcome, using paired-end transcriptome sequencing. Homozygous and hemizygous deletions of CDKN2A/2B, and hemizygous deletions of PAX5, BTG1, CDK6, ADARB2, and IKZF1 were also identified by multiple ligation-dependent probe amplification and single nucleotide polymorphism array analyses. Having both a tyrosine kinase-activating rearrangement and genomic lesions affecting lymphoid transcription factors suggested that the leukemia was of the Philadelphia chromosome (Ph)/BCR-ABL1-like ALL subtype and that JAK2 inhibitors might be able to overcome this aggressive ALL with SPAG9-JAK2.

Lu K, Liu C, Tao T, et al.
MicroRNA-19a regulates proliferation and apoptosis of castration-resistant prostate cancer cells by targeting BTG1.
FEBS Lett. 2015; 589(13):1485-90 [PubMed] Related Publications
MicroRNAs (miRNAs) play a significant role in tumor development. Recent studies indicate that miRNAs are implicated in prostate cancer (PCa). In this study, we found that miR-19a expression was significantly increased in castration-resistant prostate cancer (CRPC) tissues compared with androgen-dependent prostate cancer (ADPC) tissues. We found that inhibiting the overexpression of miR-19a in CRPC cells suppressed proliferation and increased apoptosis. Additionally, we found that miR-19a repressed BTG1 expression by binding to its 3'-untranslated region. The overexpression of BTG1 in CRPC cells significantly suppressed proliferation and increased apoptosis. We conclude that miR-19a regulates proliferation and apoptosis of CRPC cells by directly targeting the tumor suppressor gene BTG1.

Lee AS, Kranzusch PJ, Cate JH
eIF3 targets cell-proliferation messenger RNAs for translational activation or repression.
Nature. 2015; 522(7554):111-4 [PubMed] Free Access to Full Article Related Publications
Regulation of protein synthesis is fundamental for all aspects of eukaryotic biology by controlling development, homeostasis and stress responses. The 13-subunit, 800-kilodalton eukaryotic initiation factor 3 (eIF3) organizes initiation factor and ribosome interactions required for productive translation. However, current understanding of eIF3 function does not explain genetic evidence correlating eIF3 deregulation with tissue-specific cancers and developmental defects. Here we report the genome-wide discovery of human transcripts that interact with eIF3 using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). eIF3 binds to a highly specific program of messenger RNAs involved in cell growth control processes, including cell cycling, differentiation and apoptosis, via the mRNA 5' untranslated region. Surprisingly, functional analysis of the interaction between eIF3 and two mRNAs encoding the cell proliferation regulators c-JUN and BTG1 reveals that eIF3 uses different modes of RNA stem-loop binding to exert either translational activation or repression. Our findings illuminate a new role for eIF3 in governing a specialized repertoire of gene expression and suggest that binding of eIF3 to specific mRNAs could be targeted to control carcinogenesis.

Sun G, Liu Q, Cheng Y, Hu W
B cell translocation gene 1 reduces the biological outcome of kidney cancer through induction of cell proliferation, cell cycle arrest, cell apoptosis and cell metastasis.
Int J Mol Med. 2015; 35(3):777-83 [PubMed] Related Publications
The aim of the present study was to determine the expression and function of B cell translocation gene 1 (BTG1) in kidney carcinoma. Kidney samples were obtained from cancer lesions (n=85) and the adjacent normal tissue (n=40) in kidney cancer patients immediately following endoscopic biopsy. The effect of BTG1 overexpression was examined in vitro utilizing a human kidney cancer cell line, ACHN, stably transfected with a recombinant lentivirus (LeBTG1 cells) and compared to empty vector‑transfected controls (LeEmpty). BTG1 protein expression was significantly lower in kidney cancer tissue biopsies compared to normal tissue, as measured by immunohistochemistry (34.1 vs. 77.8% of tissues; P<0.05) and western blotting (0.481±0.051 vs. 0.857±0.081; P<0.05). In vitro analyses revealed that LeBTG1 cells had a reduced survival fraction compared to control LeEmpty cells, with higher rates of apoptosis (16.6±2.5 vs. 6.1±0.7%; P<0.05). The proportion of LeBTG1 cells in G(0)/G(1) stage and S phase was also significantly different from LeEmpty cells (66.8±5.3 and 22.2±1.5% vs. 44.4±3.1 and 34.5±2.3%, respectively; P<0.05), and the migration and invasion of LeBTG1 cells was significantly impaired with respect to LeEmpty cells (74.0±9.0 and 53.0±7.0 vs. 118.0±15.0 and 103.0±13.0, respectively; P<0.05). These effects were accompanied by decreased protein expression of cyclin D1, B‑cell lymphoma 2 and matrix metalloproteinase 9 in LeBTG1 cells (0.118±0.018, 0.169±0.015 and 0.207±0.027, respectively) compared to control LeEmpty cells (0.632±0.061, 0.651±0.063 and 0.443±0.042, respectively; P<0.05). Reduced BTG1 expression is associated with increased disease severity, suggesting it is a negative regulator of kidney cancer and can serve as a prognostic indicator. The results of the present study show that BTG1 protein levels were significantly reduced in kidney cancer biopsy specimens and were associated with disease progression and prognosis.

Kanda M, Oya H, Nomoto S, et al.
Diversity of clinical implication of B-cell translocation gene 1 expression by histopathologic and anatomic subtypes of gastric cancer.
Dig Dis Sci. 2015; 60(5):1256-64 [PubMed] Related Publications
BACKGROUND: Genetic signatures may differ by histopathologic and anatomic subtypes of gastric cancer (GC). B-cell translocation gene 1 (BTG1) was identified as one of genes downregulated in GC tissues from our microarray data.
AIMS: To evaluate the clinical implications of BTG1 expression in GC and the genetic diversity among GC subtypes.
METHODS: BTG1 mRNA expression was analyzed in GC cell lines and 233 pairs of surgical specimens. The mutational and methylation status of BTG1 in GC cell lines was analyzed, and immunohistochemistry was conducted to determine the distribution of BTG1. The pattern and prognostic significance of BTG1 expression were correlated with the three proposed GC subtypes.
RESULTS: BTG1 mRNA was downregulated in 82 % of GC cell lines and in 88 % of clinical GC tissues. Promoter hypermethylation events or sequence mutations were not detected in GC cell lines. The pattern of BTG1 expression as observed by immunohistochemistry was consistent with that of its mRNA. Downregulation of BTG1 mRNA in GCs was significantly associated with shorter disease-specific and recurrence-free survival. Multivariate analysis of disease-specific survival identified downregulation of BTG1 transcription as an independent prognostic factor. BTG1 mRNA expression was more strongly suppressed in proximal nondiffuse and diffuse GC compared with distal nondiffuse GC, and subgroup analysis revealed that BTG1 downregulation led to adverse prognosis, specifically in patients with proximal nondiffuse and diffuse GC.
CONCLUSIONS: Altered expression of BTG1 is a potential biomarker for carcinogenesis and progression of GC, particularly for proximal nondiffuse and diffuse GC.

Zhang H, Tang J, Li C, et al.
MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells.
Cancer Lett. 2015; 356(2 Pt B):781-90 [PubMed] Related Publications
Autophagy has become one of the most important mechanisms of chemotherapy resistance by supporting the survival of tumor cells under metabolic and therapeutic stress. Here, we showed that miR-22 inhibited autophagy and promoted apoptosis to increase the sensitivity of colorectal cancer (CRC) cells to 5-fluorouracil (5-FU) treatment both in vitro and in vivo. B-cell translocation gene 1 (BTG1) was identified as a new target of miR-22, which could reverse the inhibition of autophagy induced by miR-22. Thus, miR-22 may function as an important switch between autophagy and apoptosis to regulate 5-FU sensitivity through post-transcriptional silencing of BTG1. Promisingly, miR-22 could be considered as both a predictor of 5-FU sensitivity for personalized treatment and a therapeutic target for colorectal cancer.

Kanda M, Sugimoto H, Nomoto S, et al.
B‑cell translocation gene 1 serves as a novel prognostic indicator of hepatocellular carcinoma.
Int J Oncol. 2015; 46(2):641-8 [PubMed] Related Publications
Although the B‑cell translocation gene 1 (BTG1) plays an important role in apoptosis and negatively regulates cell proliferation, BTG1 expression in hepatocellular carcinoma (HCC) has not been evaluated. In this study expression analysis of BTG1 was conducted to clarify the role of BTG1 in the initiation of HCC carcinogenesis and progression. BTG1 mRNA expression levels were determined for HCC cell lines and 151 surgical specimen pairs using quantitative real‑time reverse transcription polymerase chain reaction (RT‑qPCR) assay. The mutational and methylation status of HCC cell lines were analyzed via high resolution melting (HRM) analysis and direct sequencing analysis to elucidate the regulatory mechanisms of BTG1 expression. The expression and distribution of the BTG1 protein in liver tissues were evaluated using immunohistochemistry (IHC). Decreased expression of BTG1 mRNA was confirmed in the majority of HCC cell lines (89%) and clinical HCC tissues (85%) compared with non‑cancerous liver tissues. Mutations or promoter hypermethylation were not identified in HCC cell lines. BTG1 mRNA expression levels were not influenced by background liver status. The pattern of BTG1 protein expression was consistent with that of BTG1 mRNA. Downregulation of BTG1 mRNA in HCC was significantly associated with shorter disease‑specific and recurrence‑free survival rates. Multivariate analysis of disease‑specific survival rates identified BTG1 mRNA downregulation as an independent prognostic factor for HCC (hazard ratio 2.12, 95% confidence interval 1.12‑4.04, P=0.022). Our results indicate that altered BTG1 expression might affect hepatocarcinogenesis and may represent a novel biomarker for HCC carcinogenesis and progression.

Sun GG, Lu YF, Cheng YJ, et al.
Expression of BTG1 in hepatocellular carcinoma and its correlation with cell cycles, cell apoptosis, and cell metastasis.
Tumour Biol. 2014; 35(12):11771-9 [PubMed] Related Publications
This study aimed to analyze the expression, clinical significance of B cell translocation gene 1 (BTG1) in hepatocellular carcinoma, and the biological effect in its cell line by BTG1 overexpression. Immunohistochemistry and Western blot were used to analyze BTG1 protein expression in 70 cases of hepatocellular cancer and 32 cases of normal tissues to study the relationship between BTG1 expression and clinical factors. Recombinant lentiviral vector was constructed to overexpress BTG1 and then infect hepatocellular cancer HepG2 cell line. The level of BTG1 protein expression was found to be significantly lower in hepatocellular cancer tissue than normal tissues (P < 0.05). Decreased expression of BTG1 was significantly correlated with tumor invasion, lymph node metastasis, clinic stage, and histological grade of patients with hepatocellular cancer (P < 0.05). Meanwhile, loss of BTG1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function has shown that HepG2 cell-transfected BTG1 had a lower survival fraction; higher percentage of the G0/G1 phases; higher cell apoptosis; significant decrease in migration and invasion; and lower Cyclin D1 (CND1), B cell lymphoma 2 (Bcl-2), and matrix metalloproteinases (MMP)-9 protein expression compared with HepG2 cell-untransfected BTG1 (P < 0.05). BTG1 expression decreased in hepatocellular cancer and correlated significantly with lymph node metastasis, clinic stage, histological grade, poor overall survival, proliferation, and metastasis in hepatocellular cancer cell by regulating CND1, Bcl-2, and MMP-9 protein expression, suggesting that BTG1 may play important roles as a negative regulator to hepatocellular cancer cell.

Wu X, Ding N, Hu W, et al.
Down-regulation of BTG1 by miR-454-3p enhances cellular radiosensitivity in renal carcinoma cells.
Radiat Oncol. 2014; 9:179 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: B cell translocation gene 1 (BTG1) has long been recognized as a tumor suppressor gene. Recent reports demonstrated that BTG1 plays an important role in progression of cell cycle and is involved in cellular response to stressors. However, the microRNAs mediated regulatory mechanism of BTG1 expression has not been reported so far. MicroRNAs can effectively influence tumor radiosensitivity by preventing cell cycle progression, resulting in enhancement of the cytotoxicity of radiotherapy efficacy. This study aimed to demonstrating the effects of microRNAs on the BTG1 expression and cellular radiosensitivity.
METHODS: The human renal carcinoma 786-O cells were treated with 5 Gy of X-rays. Expressions of BTG1 gene and miR-454-3p, which was predicted to target BTG1 by software algorithm, were analyzed by quantitative polymerase chain reaction. Protein expressions were assessed by Western blot. Luciferase assays were used to quantify the interaction between BTG1 3'-untranslated region (3'-UTR) and miR-454-3p. The radiosensitivity was quantified by the assay of cell viability, colony formation and caspase-3 activity.
RESULTS: The expression of the BTG1 gene in 786-O cells was significantly elevated after treatments with X-ray irradiation, DMSO, or serum starvation. The up-regulation of BTG1 after irradiation reduced cellular radiosensitivity as demonstrated by the enhanced cell viability and colony formation, as well as the repressed caspase-3 activity. In comparison, knock down of BTG1 by siRNA led to significantly enhanced cellular radiosensitivity. It was found that miR-454-3p can regulate the expression of BTG1 through a direct interaction with the 3'-UTR of BTG1 mRNA. Decreasing of its expression level correlates well with BTG1 up-regulation during X-ray irradiation. Particularly, we observed that over-expression of miR-454-3p by transfection inhibited the BTG1 expression and enhanced the radiosensitivity. In addition, cell cycle analysis showed that over-expression of miR-454-3p shifted the cell cycle arrest from G2/M phase to S phase.
CONCLUSIONS: Our results indicate that BTG1 is a direct target of miR-454-3p. Down-regulation of BTG1 by miR-454-3p renders tumor cells sensitive to radiation. These results may shed light on the potential application in tumor radiotherapy.

Hanada I, Terui K, Ikeda F, et al.
Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan.
Genes Chromosomes Cancer. 2014; 53(11):902-10 [PubMed] Related Publications
In Western countries, gene alterations involving the CRLF2-JAK signaling pathway are identified in approximately 50-60% of patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS-ALL is controversial. IKZF1 deletions, found in 20-30% of DS-ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (∼2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2-JAK pathway genetic alterations and recurrent gene deletions in Japanese DS-ALL patients. We confirmed a high incidence of P2RY8-CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8-CRLF2 was slightly lower than that in Western countries (∼50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8-CRLF2-positive patients than in P2RY8-CRLF2-negative patients (44% vs. 4%, P=0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8-CRLF2-negative patients (48 and 39%, respectively) but not in P2RY8-CRLF2-positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS-ALL patients in Japan and in Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients.

Lu YF, Sun GG, Liu Q, et al.
BTG1 expression in thyroid carcinoma: diagnostic indicator and prognostic marker.
Int J Oncol. 2014; 45(4):1574-82 [PubMed] Related Publications
We determined the expression and function of B cell translocation gene 1 (BTG1) in thyroid carcinoma. Thyroid samples were obtained from cancer lesions (n=83) and adjacent normal tissue (n=35) in thyroid cancer patients immediately after endoscopic biopsy. BTG1 expression was determined by immunohistochemistry and western blotting. The effect of BTG1 overexpression was examined in vitro utilizing the human thyroid cancer cell line FTC-133, stably transfected with a recombinant lentivirus (LeBTG1 cells) and compared to empty vector transfected controls (LeEmpty). BTG1 overexpression was verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. The expression of proteins involved in cell cycle regulation (cyclin D1), apoptosis (Bcl-2) and cell migration (MMP-9) in LeBTG1 cells was analyzed by western blotting. The effect of BTG1 overexpression on cell viability and proliferation was assessed by MTT assay in LeBTG1 and LeEmpty cells. Flow cytometric analyses were used to evaluate the effect of BTG1 expression on cell cycle distribution and apoptosis. The migration and invasion potential of LeBTG1 cells was examined by plating cells in Matrigel-coated chambers. BTG1 protein expression was significantly lower in thyroid cancer tissue biopsies compared to normal tissue as measured by immunohistochemistry (36.1 vs. 80.0% of tissues; P<0.05) and western blotting (0.251±0.021 vs. 0.651±0.065; P<0.05). Decreased expression of BTG1 was significantly correlated with thyroid cancer lymph node metastasis, clinical stage and pathological differentiation (P<0.05), as well as with reduced overall 10‑year survival rates compared to patients with higher expression levels (30.2 vs. 66.7%; P<0.05). In vitro analyses revealed that LeBTG1 cells had a reduced survival fraction compared to control LeEmpty cells, with higher rates of apoptosis (11.6±2.1 vs. 2.1±0.4%; P<0.05). The proportion of LeBTG1 cells in G0/G1 stage and S phase was also significantly different from LeEmpty cells (81.8±6.3 and 10.2±1.0%, vs. 62.4±4.9 and 25.5±2.6%, respectively; P<0.05), and the migration and invasion of LeBTG1 cells was significantly impaired with respect to LeEmpty cells (72.0±8.0 and 55.0±7.0 vs. 113.0±16.0 and 89.0±9.0, respectively; P<0.05). These effects were accompanied by decreased protein expression of cyclin D1, Bcl-2 and MMP-9 in LeBTG1 cells (0.234±0.018, 0.209±0.021, 0.155±0.017, respectively) compared to control LeEmpty cells (0.551±0.065, 0.452±0.043, 0.609±0.072, respectively; P<0.05). Reduced BTG1 expression is associated with increased disease severity, suggesting it is a negative regulator of thyroid cancer and can serve as a prognostic indicator.

Xie J, Wang Q, Wang Q, et al.
High frequency of BTG1 deletions in patients with BCR-ABL1-positive acute leukemia.
Cancer Genet. 2014; 207(5):226-30 [PubMed] Related Publications
Deletions affecting the B-cell translocation gene 1 (BTG1) have recently been reported in 9% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and occur even more frequently in ETV6-RUNX1-positive and BCR-ABL1-positive subgroups. To investigate whether the BTG1 deletions occur in other BCR-ABL1-positive acute leukemias besides BCP-ALL, we analyzed 44 leukemia cases harboring the BCR-ABL1 transcript [32 BCP-ALL, six mixed-phenotype acute leukemia (MPAL), and six chronic myeloid leukemia in B-lineage blast crisis (CML-BC)] by array-based comparative genomic hybridization and reverse transcription-PCR. BTG1 deletions were present in 31.8% of BCR-ABL1-positive acute leukemia patients, including 31.3% of BCP-ALL (10/32), 33.3% of MPAL (2/6), and 33.3% of CML-BC (B-lineage) (2/6) patients. Of note, the intragenic deletion breakpoints, mapping to 5 different positions at the proximal end of the breakpoint, clustered tightly within exon 2 of BTG1, which were located within a stretch of 20 bp from nucleotide 284 to nucleotide 304 and led to truncated BTG1 transcripts. There were no significant differences in the median white blood cell count, hemoglobin concentration, platelet count, bone marrow blast count, sex, age, or overall complete remission rate between patients with and without BTG1 deletions. Taken together, our data suggest that BTG1 deletions might play a role in leukemogenesis of BCP-ALL as well as of BCR-ABL1-positive MPAL and CML-BC (B-lineage).

Sun GG, Wang YD, Cheng YJ, Hu WN
The expression of BTG1 is downregulated in nasopharyngeal carcinoma and possibly associated with tumour metastasis.
Mol Biol Rep. 2014; 41(9):5979-88 [PubMed] Related Publications
To determine the expression and function of B cell translocation gene 1 (BTG1) in nasopharyngeal carcinoma. Nasopharyngeal samples were taken from cancer lesions (n = 75) and adjacent normal tissue (n = 33) in nasopharyngeal cancer patients immediately after endoscopic biopsy. BTG1 expression was determined by immunohistochemistry and Western blotting. The effect of BTG1 overexpression was examined in vitro utilizing a human nasopharyngeal cancer cell line CNE2 stably transfected with a recombinant lentivirus (LeBTG1 cells) and compared to empty vector-transfected controls (LeEmpty). BTG1 overexpression was verified by real-time reverse transcriptase polymerase chain reaction and Western blot. The expression of proteins involved in cell cycle regulation (cyclin D1), apoptosis (Bcl-2) and cell migration (MMP-9) in LeBTG1 cells were analyzed by Western blot. The effect of BTG1 overexpression on cell viability and proliferation was assessed by an MTT assay in LeBTG1 and LeEmpty cells. Flow cytometric analyses were used to evaluate the effect of BTG1 expression on cell cycle distribution and apoptosis. The migration and invasion potential of LeBTG1 cells was examined by plating cells in Matrigel-coated chambers. BTG1 protein expression was significantly lower in nasopharyngeal cancer tissue biopsies than normal tissue as measured by immunohistochemistry (36.0 vs. 81.8 % of tissues; P < 0.05) and Western blotting (0.221 ± 0.019 vs. 0.652 ± 0.055; P < 0.05). Decreased expression of BTG1 was significantly correlated with nasopharyngeal cancer tumor stage, lymph node metastasis, clinical stage and pathologic differentiation (P < 0.05), as well as with reduced overall five-year survival rates compared to patients with higher expression levels (31.2 vs. 70.2 %; P < 0.05). In vitro analyses revealed that LeBTG1 cells had a reduced survival fraction compared to control LeEmpty cells, with higher rates of apoptosis (9.3 ± 0.7 vs. 2.3 ± 0.3 %; P < 0.05). The proportion of LeBTG1 cells in G0/G1 stage and S phase was also significantly different from LeEmpty cells (82.6 ± 3.8 and 10.1 ± 1.0 %, vs. 62.2 ± 2.4 and 28.9 ± 2.0 %, respectively; Ps < 0.05), and the migration and invasion of LeBTG1 cells was significantly impaired with respect to LeEmpty cells (96.0 ± 13.0 and 91.0 ± 11.0 vs. 158.0 ± 17.0 and 142.0 ± 15.0, respectively; Ps < 0.05). These effects were accompanied by decreased protein expression of cyclin D1, Bcl-2 and MMP-9 in LeBTG1 cells (0.231 ± 0.021, 0.413 ± 0.046, 0.131 ± 0.011, respectively) compared to control LeEmpty cells (0.636 ± 0.067, 0.821 ± 0.083, 0.451 ± 0.041, respectively; Ps < 0.05). Reduced BTG1 expression is associated with increased disease severity, suggesting it is a negative regulator of nasopharyngeal cancer and can serve as a prognostic indicator.

Sun GG, Wang YD, Cheng YJ, Hu WN
BTG1 underexpression is an independent prognostic marker in esophageal squamous cell carcinoma.
Tumour Biol. 2014; 35(10):9707-16 [PubMed] Related Publications
To determine the expression and function of B cell translocation gene 1 (BTG1) in esophageal carcinoma, esophageal samples were taken from cancer lesions (n = 74) and adjacent normal tissue (n = 34) in esophageal cancer patients immediately after endoscopic biopsy. BTG1 expression was determined by immunohistochemistry and Western blotting. The effect of BTG1 overexpression was examined in vitro utilizing a human esophageal cancer cell line ECA-109 stably transfected with a recombinant lentivirus (LeBTG1 cells) and compared to empty vector-transfected controls (LeEmpty). BTG1 overexpression was verified by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot. The expression of proteins involved in cell cycle regulation (cyclin D1) and apoptosis (Bcl-2) and cell migration (MMP-9) in LeBTG1 cells was analyzed by Western blot. The effect of BTG1 overexpression on cell viability and proliferation was assessed by an MTT assay in LeBTG1 and LeEmpty cells. Flow cytometric analyses were used to evaluate the effect of BTG1 expression on cell cycle distribution and apoptosis. The migration and invasion potential of LeBTG1 cells was examined by plating cells in Matrigel-coated chambers. The level of BTG1 protein expression was found to be significantly lower in esophageal cancer tissue than normal tissues (P < 0.05). Decreased expression of BTG1 was significantly correlated with lymph node metastasis, clinical stage, and histological grade of patients with esophageal cancer (P < 0.05). Meanwhile, loss of BTG1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function shown that Eca-109 cell-transfected BTG1 had a lower survival fraction, higher percentage of the G0/G1 phases, higher cell apoptosis, significant decrease in migration and invasion, and lower cylin D1, Bcl-2, and MMP-9 protein expression compared with Eca-109 cell-untransfected BTG1 (P < 0.05). Reduced BTG1 expression is associated with increased disease severity, suggesting it is a negative regulator of esophageal cancer and can serve as a prognostic indicator.

Moorman AV, Enshaei A, Schwab C, et al.
A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia.
Blood. 2014; 124(9):1434-44 [PubMed] Related Publications
Recent genomic studies have provided a refined genetic map of acute lymphoblastic leukemia (ALL) and increased the number of potential prognostic markers. Therefore, we integrated copy-number alteration data from the 8 most commonly deleted genes, subordinately, with established chromosomal abnormalities to derive a 2-tier genetic classification. The classification was developed using 809 ALL97/99 patients and validated using 742 United Kingdom (UK)ALL2003 patients. Good-risk (GR) genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy-number status for all 8 genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk (PR). Three-quarters of UKALL2003 patients had a GR genetic profile and a significantly improved event-free survival (EFS) (94%) compared with patients with a PR genetic profile (79%). This difference was driven by a lower relapse rate (4% vs 17%), was seen across all patient subgroups, and was independent of other risk factors. Even genetic GR patients with minimal residual disease (>0.01%) at day 29 had an EFS in excess of 90%. In conclusion, the integration of genomic and cytogenetic data defines 2 subgroups with distinct responses to treatment and identifies a large subset of children suitable for treatment deintensification.

Fouz N, Amid A, Hashim YZ
Gene expression analysis in MCF-7 breast cancer cells treated with recombinant bromelain.
Appl Biochem Biotechnol. 2014; 173(7):1618-39 [PubMed] Related Publications
The contributing molecular pathways underlying the pathogenesis of breast cancer need to be better characterized. The principle of our study was to better understand the genetic mechanism of oncogenesis for human breast cancer and to discover new possible tumor markers for use in clinical practice. We used complimentary DNA (cDNA) microarrays to compare gene expression profiles of treated Michigan Cancer Foundation-7 (MCF-7) with recombinant bromelain and untreated MCF-7. SpringGene analysis was carried out of differential expression followed by Ingenuity Pathway Analysis (IPA), to understand the underlying consequence in developing disease and disorders. We identified 1,102 known genes differentially expressed to a significant degree (p<0.001) changed between the treatment. Within this gene set, 20 genes were significantly changed between treated cells and the control cells with cutoff fold change of more than 1.5. These genes are RNA-binding motif, single-stranded interacting protein 1 (RBMS1), ribosomal protein L29 (RPL29), glutathione S-transferase mu 2 (GSTM2), C15orf32, Akt3, B cell translocation gene 1 (BTG1), C6orf62, C7orf60, kinesin-associated protein 3 (KIFAP3), FBXO11, AT-rich interactive domain 4A (ARID4A), COPS2, TBPL1|SLC2A12, TMEM59, SNORD46, glioma tumor suppressor candidate region gene 2 (GLTSCR2), and LRRFIP. Our observation on gene expression indicated that recombinant bromelain produces a unique signature affecting different pathways, specific for each congener. The microarray results give a molecular mechanistic insight and functional effects, following recombinant bromelain treatment. The extent of changes in genes is related to and involved significantly in gap junction signaling, amyloid processing, cell cycle regulation by BTG family proteins, and breast cancer regulation by stathmin1 that play major roles.

Li W, Zou ST, Zhu R, et al.
B‑cell translocation 1 gene inhibits cellular metastasis‑associated behavior in breast cancer.
Mol Med Rep. 2014; 9(6):2374-80 [PubMed] Related Publications
B-cell translocation gene 1 (BTG1) is a member of the BTG/transducer of ERBB2 family, which regulates cell cycle progression in a variety of cell types and may have a role in inhibiting proliferation, promoting apoptosis and stimulating cellular differentiation in numerous cell types. However, the role of BTG1 in cancer metastasis is yet to be elucidated. In the present study, analysis of clinical specimens revealed that BTG1 mRNA levels were lower in lymph node metastases than those in benign breast tumors and normal human breast tissue. The effect of BTG1 on the metastatic behavior of breast cancer cells following stable transfection with a BTG1 expression vector was also investigated. The overexpression of BTG1 was observed to inhibit cell adhesion, migration and invasion. Furthermore, the overexpression of BTG1 was found to be involved in the inhibition of the metastasis-related proteins matrix metalloproteinase-2 and -9, as well as the promotion of the cell-cell adhesion-associated protein E-cadherin. In syngeneic nude mice breast tumor models, hepatic metastasis and angiogenesis were observed in the mice injected with the control cells, but not in those injected with pcDNA3-BTG1 cells. Immunohistochemistry revealed that overexpression of BTG1 decreased vascular endothelial growth factor expression in tumors. To the best of our knowledge, this is the first study to show that BTG1 overexpression decreases migration and invasion of breast cancer cells and thereby inhibits distant metastasis in mice breast tumor models.

Hunter ZR, Xu L, Yang G, et al.
The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.
Blood. 2014; 123(11):1637-46 [PubMed] Related Publications
The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients included MYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM.

Sheng SH, Zhao CM, Sun GG
BTG1 expression correlates with the pathogenesis and progression of breast carcinomas.
Tumour Biol. 2014; 35(4):3317-26 [PubMed] Related Publications
This study aimed to analyze the expression, clinical significance of B cell translocation gene 1 (BTG1) in breast carcinoma and the biological effect in its cell line by BTG1 overexpression. Immunohistochemistry and western blot were used to analyze BTG1 protein expression in 72 cases of breast cancer and 36 cases of normal tissues to study the relationship between BTG1 expression and clinical factors. Recombinant lentiviral vector was constructed to over-express EMP-1 and then infect breast cancer MCF-7 cell line. Quantitative real-time RT-PCR (qRT-PCR) and western blot were used to detect the mRNA level and protein of BTG1. MTT assay, cell apoptosis, cell cycles, migration and invasion assays were also conducted as to the influence of the upregulated expression of BTG1 that might be found on MCF-7 cells biological effect. The level of BTG1 protein expression was found to be significantly lower in breast cancer tissue than normal tissues (P < 0.05). Decreased expression of BTG1 was significantly correlated with tumor invasion, lymph node metastasis, clinic stage and histological grade of patients with breast cancer (P < 0.05). Meanwhile, loss of BTG1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function shown that MCF-7 cell transfected BTG1 had a lower survival fraction, higher percentage of the G0/G1 phases, higher cell apoptosis, significant decrease in migration and invasion, and lower CyclinD1, Bcl-2, and MMP-9 protein expression compared with MCF-7 cell untransfected BTG1 (P < 0.05). BTG1 expression decreased in breast cancer and correlated significantly lymph node metastasis, clinic stage, histological grade, poor overall survival, proliferation, and metastasis in breast cancer cell by regulating CyclinD1, Bcl-2, and MMP-9 protein expression, suggesting that BTG1 may play important roles as a negative regulator to breast cancer cell.

Sun GG, Lu YF, Cheng YJ, Hu WN
The expression of BTG1 is downregulated in NSCLC and possibly associated with tumor metastasis.
Tumour Biol. 2014; 35(4):2949-57 [PubMed] Related Publications
This study aimed to analyze the expression, clinical significance of B cell translocation gene 1 (BTG1) in nonsmall cell lung cancer (NSCLC) and the biological effect in its cell line by BTG1 overexpression. Immunohistochemistry and western blot were used to analyze BTG1 protein expression in 82 cases of NSCLC and 38 cases of normal tissues to study the relationship between BTG1 expression and clinical factors. Recombinant lentiviral vector was constructed to overexpress EMP-1 and then infect NSCLC H1299 cell line. Quantitative real-time RT-PCR and western blot were used to detect the mRNA level and protein of BTG1. 3-[4,5-dimethylthiazol -2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis, cell cycles, and migration and invasion assays were also conducted as to the influence of the upregulated expression of BTG1 that might be found on H1299 cells biological effect. The level of BTG1 protein expression was found to be significantly lower in NSCLC tissue than normal tissues (P < 0.05). Decreased expression of BTG1 was significantly correlated with lymph node metastasis, clinic stage, and histological grade of patients with NSCLC (P < 0.05). Meanwhile, loss of BTG1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function show that H1299 cell transfected BTG1 had a lower survival fraction; higher percentage of the G0/G1 phases; higher cell apoptosis; significant decrease in migration and invasion; and lower CyclinD1, Bcl-2, and MMP-9 protein expression compared with H1299 cell untransfected BTG1 (P < 0.05). BTG1 expression decreased in NSCLC and correlated significantly with lymph node metastasis; clinical stage; histological grade; poor overall survival; cell proliferation; cell cycles; cell apoptosis; and migration and invasion in NSCLC cell by regulating CyclinD1, Bcl-2, and MMP-9 protein expression, suggesting that BTG1 may play important roles as a negative regulator to NSCLC cell.

Zhao Y, Gou WF, Chen S, et al.
BTG1 expression correlates with the pathogenesis and progression of ovarian carcinomas.
Int J Mol Sci. 2013; 14(10):19670-80 [PubMed] Free Access to Full Article Related Publications
BTG (B-cell translocation gene) can inhibit cell proliferation, metastasis, and angiogenesis and regulate cell cycle progression and differentiation in a variety of cell types. We aimed to clarify the role of BTG1 in ovarian carcinogenesis and progression. A BTG1-expressing plasmid was transfected into ovarian carcinoma cells and their phenotypes and related proteins were examined. BTG1 mRNA expression was detected in ovarian normal tissue (n = 17), ovarian benign tumors (n = 12), and ovarian carcinoma (n = 64) using real-time RT-PCR. Ectopic BTG1 expression resulted in lower growth rate, high cisplatin sensitivity, G1 arrest, apoptosis, and decreased migration and invasion. Phosphoinositide 3-kinase, protein kinase B, Bcl-xL, survivin, vascular endothelial growth factor, and matrix metalloproteinase-2 mRNA and protein expression was reduced in transfectants as compared to control cells. There was higher expression of BTG1 mRNA in normal tissue than in carcinoma tissue (p = 0.001) and in benign tumors than in carcinoma tissue (p = 0.027). BTG1 mRNA expression in International Federation of Gynecology and Obstetrics (FIGO) stage I/II ovarian carcinomas was higher than that in FIGO stage III/IV ovarian carcinomas (p = 0.038). Altered BTG1 expression might play a role in the pathogenesis and progression of ovarian carcinoma by modulating proliferation, migration, invasion, the cell cycle, and apoptosis.

Zhu R, Zou ST, Wan JM, et al.
BTG1 inhibits breast cancer cell growth through induction of cell cycle arrest and apoptosis.
Oncol Rep. 2013; 30(5):2137-44 [PubMed] Related Publications
BTG1, which belongs to the BTG/Tob family, regulates cell cycle progression in a variety of cell types and appears to play roles in inhibiting proliferation, promoting apoptosis and stimulating cellular differentiation in multiple cell types. However, it remains unclear whether BTG1 is a breast cancer suppressor gene, and the role of BTG1 in breast cancer cell growth has not yet been determined. In the present study, we observed that BTG1 was weakly expressed in human breast tumors and in breast cancer cells (MCF-7 and MDA-MB-231). In addition, we investigated the potential effects of BTG1 on breast cancer cell proliferation, cell cycle distribution and apoptosis after stable transfection with the BTG1 expression vector. We found that overexpression of BTG1 inhibited cell proliferation, induced G0/G1 cell cycle arrest and promoted apoptosis. Further investigation indicated that overexpression of BTG1 was involved in the inhibition of the expression of cell cycle-related proteins, cyclin B1 and cyclin D1, and pro-apoptotic factors, Bax and caspase-3, and was also involved in the promotion of anti-apoptotic factor Bcl-2. In vivo, animal experiments showed that tumors overexpressing BTG1 displayed a slower growth rate than the control xenografts. TUNEL end staining assay revealed that BTG1 induced tumor necrosis and apoptosis. Taken together, our data revealed that, in breast cancer cells, BTG1 inhibits cell growth through induction of cell cycle arrest and apoptosis. These results indicate that BTG1 may be used as a novel therapeutic target for human breast cancer treatment.

Tijchon E, Havinga J, van Leeuwen FN, Scheijen B
B-lineage transcription factors and cooperating gene lesions required for leukemia development.
Leukemia. 2013; 27(3):541-52 [PubMed] Related Publications
Differentiation of hematopoietic stem cells into B lymphocytes requires the concerted action of specific transcription factors, such as RUNX1, IKZF1, E2A, EBF1 and PAX5. As key determinants of normal B-cell development, B-lineage transcription factors are frequently deregulated in hematological malignancies, such as B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and affected by either chromosomal translocations, gene deletions or point mutations. However, genetic aberrations in this developmental pathway are generally insufficient to induce BCP-ALL, and often complemented by genetic defects in cytokine receptors and tyrosine kinases (IL-7Rα, CRLF2, JAK2 and c-ABL1), transcriptional cofactors (TBL1XR1, CBP and BTG1), as well as the regulatory pathways that mediate cell-cycle control (pRB and INK4A/B). Here we provide a detailed overview of the genetic pathways that interact with these B-lineage specification factors, and describe how mutations affecting these master regulators together with cooperating lesions drive leukemia development.

Kawahara M, Pandolfi A, Bartholdy B, et al.
H2.0-like homeobox regulates early hematopoiesis and promotes acute myeloid leukemia.
Cancer Cell. 2012; 22(2):194-208 [PubMed] Free Access to Full Article Related Publications
Homeobox domain-containing transcription factors are important regulators of hematopoiesis. Here, we report that increased levels of nonclustered H2.0-like homeobox (HLX) lead to loss of functional hematopoietic stem cells and formation of aberrant progenitors with unlimited serial clonogenicity and blocked differentiation. Inhibition of HLX reduces proliferation and clonogenicity of leukemia cells, overcomes the differentiation block, and leads to prolonged survival. HLX regulates a transcriptional program, including PAK1 and BTG1, that controls cellular differentiation and proliferation. HLX is overexpressed in 87% of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival (n = 601, p = 2.3 × 10(-6)). Our study identifies HLX as a key regulator in immature hematopoietic and leukemia cells and as a prognostic marker and therapeutic target in AML.

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