Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

1. Download high-res image (232KB)
2. Download full-size image

     

Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer

1. Download high-res image (224KB)
2. Download full-size image

     

Abnormal Methylation of Several Tumor Suppressor Genes in Sporadic Breast Cancer

Multiplex methylation-sensitive PCR was employed in studying the methylation of CpG islands in the R1, p16/CDKN2, p15/CDKN2, p14/ARF, DH1, MGMT, HIC1, and N33 promoter regions in breast cancer (105 tumors). Methylation was often observed for the two major suppressor genes involved in controlling the cell cycle through the Cdk–Rb–E2F signaling pathway, R1 (18/105, 17%) and p16 (59/105, 56%); both genes were methylated in 13 tumors. Methylation involved p15 in two (2%) tumors; CDH1, in 83 (79%) tumors; MGMT, in eight (8%) tumors, and N33, in nine (9%) tumors. The p14 promoter was not methylated in the tumors examined.     

Src Regulates the Activity of the ING1 Tumor Suppressor

The INhibitor of Growth 1 (ING1) is stoichiometric member of histone deacetylase (HDAC) complexes and functions as an epigenetic regulator and a type II tumor suppressor. It impacts cell growth, aging, apoptosis, and DNA repair, by affecting chromatin conformation and gene expression. Down regulation and mislocalization of ING1 have been reported in diverse tumor types and Ser/Thr phosphorylation has been implicated in both of these processes. Here we demonstrate that both in vitro and in vivo, the tyrosine kinase Src is able to physically associate with, and phosphorylate ING1, which results in a nuclear to cytoplasmic relocalization of ING1 in cells and a decrease of ING1 stability. Functionally, Src antagonizes the ability of ING1 to induce apoptosis, most likely through relocalization of ING1 and down regulation of ING1 levels. These effects were due to both kinase-dependent and kinase-independent properties of Src, and were most apparent at elevated levels of Src expression. These findings suggest that Src may play a major role in regulating ING1 levels during tumorigenesis in those cancers in which high levels of Src expression or activity are present. These data represent the first report of tyrosine kinase-mediated regulation of ING1 levels and suggest that kinase activation can impact chromatin structure through the ING1 epigenetic regulator.     

DLC-1基因在MCF-7人乳腺癌细胞系中低表达的机制探究

目的：探究DLC-1基因在MCF-7人乳腺癌细胞系中低表达的机制。方法：应用甲基化特异性PCR（MSP）检测人乳腺癌细胞MCF-7的DLC-1基因甲基化状态,不同浓度的5-氮杂-2＇-脱氧胞嘧啶（5-Aza-CdR）处理人乳腺癌细胞MCF-7,RT-PCR及Real-time PCR定量检测用药前后细胞中DLC-1基因mRNA表达水平变化。结果：DLC-1基因启动子区CpG岛呈甲基化状态,经过5-Aza-CdR处理后,DLC-1基因启动子区呈去甲基化状态,并且其mRNA恢复表达。结论：抑癌基因DLC-1 CpG岛甲基化是导致该基因低表达的原因之一,5-Aza-CdR能逆转DLC-1基因甲基化状态。     

肺癌肿瘤阻抑基因1:一种新的抑癌基因

新的抑癌基因TSLC1属于免疫球蛋白超家族,位于人染色体11q23.2。TSLC1编码的蛋白质参与细胞间黏附、细胞运动、信号转导及免疫调节。研究显示,TSLC1在多种肿瘤中表达异常,它对肿瘤的影响主要表现为抑制瘤细胞增殖及诱导凋亡、改变瘤细胞的生长特性及基因表达,和抑制上皮间质转化。TSLC1的缺失与启动子甲基化关系密切,但其发挥抑癌作用的分子机制及信号转导途径尚有待研究。     

Deciphering the BRCA1 Tumor Suppressor Network

The BRCA1 tumor suppressor protein is a central constituent of several distinct macromolecular protein complexes that execute homology-directed DNA damage repair and cell cycle checkpoints. Recent years have borne witness to an exciting phase of discovery at the basic molecular level for how this network of DNA repair proteins acts to maintain genome stability and suppress cancer. The clinical dividends of this investment are now being realized with the approval of first-in-class BRCA-targeted therapies for ovarian cancer and identification of molecular events that determine responsiveness to these agents. Further delineation of the basic science underlying BRCA network function holds promise to maximally exploit genome instability for hereditary and sporadic cancer therapy.     

SIRT1 Catalytic Activity Has Little Effect on Tumor Formation and Metastases in a Mouse Model of Breast Cancer

The protein deacetylase SIRT1 has been implicated in the regulation of a large number of cellular processes that are thought to be required for cancer initiation and progression. There are conflicting data that make it unclear whether Sirt1 functions as an oncogene or tumor suppressor. To assess the effect of SIRT1 on the emergence and progression of mammary tumors, we crossed mice that harbor a point mutation that abolishes SIRT1 catalytic activity with mice carrying the polyoma middle T transgene driven by the murine mammary tumor virus promoter (MMTV-PyMT). The absence of SIRT1 catalytic activity neither accelerated nor blocked the formation of tumors and metastases in this model. There was a lag in tumor latency that modestly extended survival in Sirt1 mutant mice that we attribute to a delay in mammary gland development and not to a direct effect of SIRT1 on carcinogenesis. These results are consistent with previous evidence suggesting that Sirt1 is not a tumor promoter or a tumor suppressor.     

Key Importance of Small RNA Binding for the Activity of a Glycine-Tryptophan (GW) Motif-containing Viral Suppressor of RNA Silencing

Viruses express viral suppressors of RNA silencing (VSRs) to counteract RNA silencing-based host defenses. Although virtually all stages of the antiviral silencing pathway can be inhibited by VSRs, small RNAs (sRNAs) and Argonaute (AGO) proteins seem to be the most frequent targets. Recently, GW/WG motifs of some VSRs have been proposed to dictate their suppressor function by mediating interaction with AGO(s). Here we have studied the VSR encoded by Pelargonium line pattern virus (family Tombusviridae). The results show that p37, the viral coat protein, blocks RNA silencing. Site-directed mutagenesis of some p37 sequence traits, including a conserved GW motif, allowed generation of suppressor-competent and -incompetent molecules and uncoupling of the VSR and particle assembly capacities. The engineered mutants were used to assess the importance of p37 functions for viral infection and the relative contribution of diverse molecular interactions to suppressor activity. Two main conclusions can be drawn: (i) the silencing suppression and encapsidation functions of p37 are both required for systemic Pelargonium line pattern virus infection, and (ii) the suppressor activity of p37 relies on the ability to bind sRNAs rather than on interaction with AGOs. The data also caution against potential misinterpretations of results due to overlap of sequence signals related to distinct protein properties. This is well illustrated by mutation of the GW motif in p37 that concurrently affects nucleolar localization, efficient interaction with AGO1, and sRNA binding capability. These concomitant effects could have been overlooked in other GW motif-containing suppressors, as we exemplify with the orthologous p38 of turnip crinkle virus.     

Human Umbilical Cord Matrix Mesenchymal Stem Cells Suppress the Growth of Breast Cancer by Expression of Tumor Suppressor Genes

Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species’ breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-over-expressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression.     

抑癌基因OVCA1的研究进展

随着肿瘤分子生物学技术及学科的发展,人们认识到癌症是一种基因疾病,肿瘤的发生发展是多种基因参与的复杂过程,包括癌基因的异常激活和肿瘤抑制基因失活。新近分离鉴定的重要的肿瘤抑制基因——卵巢癌基因1(OVCA1)在多种肿瘤中存在高频率的缺失和突变,对多种癌细胞增殖有明显的抑制作用,可能作用于肿瘤发生的早期阶段,在哺乳动物中高度保守,提示在细胞中具有重要作用;OVCA1可能具有调控细胞周期、翻译、DNA损伤及胚胎发育等生物功能,具体作用机制尚不明确;体外研究显示,OVCA1的缺失表达导致肿瘤发生可能与周期蛋白D1上调表达、P16下调表达相关,与p53基因突变可能存在相互作用;OVCA1的缺失表达与卵巢癌发生发展及预后密切相关,与宫颈癌及人乳头瘤病毒感染、乳腺癌等恶性肿瘤的关系尚在研究中。我们简要综述了OVCA1基因的国内外研究进展,为卵巢癌等恶性肿瘤进行基因水平的诊治提供理论依据。     

Evidence That Selenium Binding Protein 1 Is a Tumor Suppressor in Prostate Cancer

Selenium-Binding Protein 1 (SBP1, SELENBP1, hSP56) is a selenium-associated protein shown to be at lower levels in tumors, and its lower levels are frequently predictive of a poor clinical outcome. Distinguishing indolent from aggressive prostate cancer is a major challenge in disease management. Associations between SBP1 levels, tumor grade, and disease recurrence following prostatectomy were investigated by duplex immunofluorescence imaging using a tissue microarray containing tissue from 202 prostate cancer patients who experienced biochemical (PSA) recurrence after prostatectomy and 202 matched control patients whose cancer did not recur. Samples were matched by age, ethnicity, pathological stage and Gleason grade, and images were quantified using the Vectra multispectral imaging system. Fluorescent labels were targeted for SBP1 and cytokeratins 8/18 to restrict scoring to tumor cells, and cell-by-cell quantification of SBP1 in the nucleus and cytoplasm was performed. Nuclear SBP1 levels and the nuclear to cytoplasm ratio were inversely associated with tumor grade using linear regression analysis. Following classification of samples into quartiles based on the SBP1 levels among controls, tumors in the lowest quartile were more than twice as likely to recur compared to those in any other quartile. Inducible ectopic SBP1 expression reduced the ability of HCT-116 human tumor cells to grow in soft agar, a measure of transformation, without affecting proliferation. Cells expressing SBP1 also demonstrated a robust induction in the phosphorylation of the p53 tumor suppressor at serine 15. These data indicate that loss of SBP1 may play an independent contributing role in prostate cancer progression and its levels might be useful in distinguishing indolent from aggressive disease.     

Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization

Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis.     

CpG Island Hypermethylation of Tumor Suppressor microRNAs in Human Cancer

In the last few years, microRNAs have started a revolution in molecular biology and emerged as key players in the cancer process. For these reasons, it is extremely important to understand the physiological and disease-associated mechanisms underlying the regulation of these small, single-stranded RNAs. Thus, it was merely a matter of time before microRNAs and epigenetics coincided. In cancer, aberrant DNA hypermethylation of tumor suppressor genes, global genomic DNA hypomethylation, and disruption of the histone modification patterns are the main epigenetic alterations, and have consequently been widely studied. Some microRNAs are downregulated in cancer and act as bona fide tumor suppressor genes, and this knowledge led to the proposal of the hypothesis that miRNAs could be silenced by epigenetic mechanisms. It has recently been shown that miR-127 and miR-124a, two putative tumor suppressor miRNAs, are methylated in tumor cells. Epigenomic tools can be effectively used in the search for new methylated tumor suppressor microRNAs. Furthermore, this aberrant methylation can be reversed by epigenetic drugs, such as DNA demethylating agents and histone deacetylase inhibitors, restoring microRNA expression levels and reverting the tumoral phenotype. In the coming years we will come to realize more fully the relevance of this expected encounter between two forces – epigenetics and microRNAs – that are currently at the forefront of biology.     

Fastest Time to Cancer by Loss of Tumor Suppressor Genes

Genetic instability promotes cancer progression (by increasing the probability of cancerous mutations) as well as hinders it (by imposing a higher cell death rate for cells susceptible to cancerous mutation). With the loss of tumor suppressor gene function known to be responsible for a high percentage of breast and colorectal cancer (and a good fraction of lung cancer and other types as well), it is important to understand how genetic instability can be orchestrated toward carcinogenesis. In this context, this paper gives a complete characterization of the optimal (time-varying) cell mutation rate for the fastest time to a target cancerous cell population through the loss of both copies of a tumor suppressor gene. Similar to the (one-step) oncogene activation model previously analyzed, the optimal mutation rate of the present two-step model changes qualitatively with the convexity of the (mutation rate-dependent) cell death rate. However, the structure of the Hamiltonian for the new model differs significantly and intrinsically from that of the one-step model, and a completely new approach is needed for the solution of the present two-step problem. Considerable insight into the biology of optimal switching (between corner controls) is extracted from numerical results for cases with nonconvex death rates.     

肿瘤抑制因子hTid1研究进展

hTid1(human tumorous imaginal disc 1)是果蝇肿瘤抑制因子Tid56的人类同源蛋白。hTid1属于DnaJ蛋白家族成员,主要定位于线粒体基质中,作为Hsp70蛋白的辅助分子伴侣发挥作用。然而,越来越多的文献报道,hTid1可以与线粒体外的许多蛋白相互作用,进而调控细胞内许多的信号通路。该文综述了近年来hTid1蛋白的最新研究进展,并主要从hTid1蛋白的结构和功能、与肿瘤的相关性、与神经系统的联系及在细胞信号通路中的作用等方面进行系统的阐述。     

Breast Cancer Metastasis Suppressor 1 Regulates Hepatocellular Carcinoma Cell Apoptosis via Suppressing Osteopontin Expression

Breast cancer metastasis suppressor 1 (BRMS1) was originally identified as an active metastasis suppressor in human breast cancer. Loss of BRMS1 expression correlates with tumor progression, and BRMS1 suppresses several steps required for tumor metastasis. However, the role of BRMS1 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that the expression level of BRMS1 was significantly down-regulated in HCC tissues. Expression of BRMS1 in SK-Hep1 cells did not affect cell growth under normal culture conditions, but sensitized cells to apoptosis induced by serum deprivation or anoikis. Consistently, knockdown of endogenous BRMS1 expression in Hep3B cells suppressed cell apoptosis. We identified that BRMS1 suppresses osteopontin (OPN) expression in HCC cells and that there is a negative correlation between BRMS1 and OPN mRNA expression in HCC tissues. Moreover, knockdown of endogenous OPN expression reversed the anti-apoptosis effect achieved by knockdown of BRMS1. Taken together, our results show that BRMS1 sensitizes HCC cells to apoptosis through suppressing OPN expression, suggesting a potential role of BRMS1 in regulating HCC apoptosis and metastasis.     

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

1. Download high-res image (213KB)
2. Download full-size image