Recent progress in 8igenomic research of liver cancer

Along the course of occurrence and development of liver cancer, the corresponding somatic cells accumulate some important genetic variations. These variations may be divided into two categories. For the genetic changes closely related to etiology of liver cancer, the well-known cases include insertion and integration of the hepatitis B virus (HBV) DNA after infection, and mutations at site 249 of the tumor suppressor gene p53 induced by exposure to aflatoxin B1. The secondary genetic changes include amplification and deletion of certain chromosome regions, mutations in p53 at the sites other than 249, as well as the mutational activation of the Wnt/β-catenin signal pathway. The tumor cells with these genetic variations may gradually become the dominant clones under evolutionary selection. Besides, identification of genetic susceptible against risk of liver malignancy is also an important aspect of research in this field. Supported by the National Natural Science Foundation of China (Grant No. 30425019)     

Downregulation of PTEN/MMAC/TEP1 expression in human prostate cancer cell line DU145 by growth stimuli

Genetic alterations and/or deletion of the tumor suppressor gene PTEN/MMAC/TEP1 occur in many types of human cancer including prostate cancer. We describe the production of monoclonal antibody against recombinant human PTEN and the study of PTEN gene and protein expression in three commercially available human prostate cancer cell lines, PC-3, LNCaP, and DU 145. Northern blotting analyses showed that LNCaP and DU145 but not PC-3 cells expressed PTEN mRNA. However, Western blotting analyses using a monoclonal antibody against PTEN demonstrated the expression of PTEN protein in DU145 but not LNCaP cells. In DU145 cells, PTEN expression at both the mRNA and protein levels inversely correlated with serum concentrations and levels of PKB/Akt phosphorylation. In addition, the basal activity of PKB/Akt as indicated by level of phosphorylation was higher in prostate cancer cells which do not express PTEN than that in the cells expressing wild type PTEN. Thus, PTEN may play a critical role in regulating cellular signaling in prostate cancer cells.     

ING5 inhibits cancer aggressiveness by inhibiting Akt and activating p53 in prostate cancer

Prostate cancer (PCa) is one of the most common types of cancer in men. In several recent studies, chromosomal deletions in the q arm of chromosome 2, where ING5 resides within, have been identified in various cancer types including PCa. In this study, we investigate the role of ING5 as a tumor suppressor in PCa. We examined the expression level of ING5 in tissue samples and cell lines using quantitative real‐time polymerase chain reaction and western blot analysis. We tested the in vitro tumor suppressor potential of ING5 in PC3 and LNCaP cells stably overexpressing it using cell viability, colony formation, migration, invasion, and apoptosis assays. We then investigated the effects of ING5 on the Akt and p53 signaling using western blot analysis. We show that ING5 is significantly downregulated in PCa tumor tissue samples and cell lines compared with the corresponding controls. In vitro assays demonstrate that ING5 effectively suppresses proliferative, clonogenic, migratory, and invasive potential and induce apoptosis in PCa cells. ING5 may potentially exert its anti‐tumor potential by inhibiting AKT and inducing p53 signaling pathways. Our findings demonstrate that ING5 possesses tumor suppressor roles in vitro, pointing its importance during the prostatic carcinogenesis processes.     

癌基因和抑癌基因研究进展

癌基因和抑癌基因的发现和研究是肿瘤研究史上的一个里程碑,标志着肿瘤研究进入了分子时代,从而在更深层次上为阐明基因的结构、表达、调控、功能的改变与肿瘤形成的关系提供了科学依据和可能性,具有重要的理论和实际意义。本文概述了癌基因和抑癌基因的最新研究进展。     

Analysis of 41 cancer cell lines reveals excessive allelic loss and novel mutations in the SIRT1 gene

SIRT1 is an evolutionarily conserved protein deacetylase that modulates stress response, cellular metabolism and aging in model organisms. While SIRT1 exerts beneficial effects in protecting against age-related diseases, the role of SIRT1 in cancer has been controversial. SIRT1 promotes cell survival by deacetylating, and thereby negatively regulating the activity of important tumor suppressors such as p53. In this regard, SIRT1 has been considered to be a potential oncogene, and SIRT1 inhibitors have been studied for possible anticancer therapeutic effects. In contrast, it has been shown that SIRT1 deficiency leads to increased genomic instability and tumorigenesis, and that overexpression of SIRT1 attenuates cancer formation in mice, suggesting it may also act as a tumor suppressor. Based on this evidence, SIRT1-activating molecules could act as candidate chemotherapeutic drugs. In order to gain insight into the role of SIRT1 in cancer, we performed a comprehensive resequencing analysis of the SIRT1 gene in 41 tumor cell lines and found an unusually excessive homozygosity, which was confirmed to be allelic loss by microsatellite analysis. Furthermore, we found two novel SIRT1 mutations (D739Y and R65_A72del) in addition to the known, rare non-synonymous variation resulting in I731V. In vitro assays using purified SIRT1 protein showed that these mutations do not alter SIRT1 deacetylase activity or telomerase activity, which was shown to be regulated by SIRT1. We conclude that allelic loss or mutations in the SIRT1 gene occur prevalently during tumorigenesis, supporting the assertion that SIRT1 may serve as a tumor suppressor.     

Survival or death: disequilibrating the oncogenic and tumor suppressive autophagy in cancer

Autophagy (macroautophagy) is an evolutionarily conserved lysosomal degradation process, in which a cell degrades long-lived proteins and damaged organelles. Recently, accumulating evidence has revealed the core molecular machinery of autophagy in carcinogenesis; however, the intricate relationship between autophagy and cancer continue to remain an enigma. Why does autophagy have either pro-survival (oncogenic) or pro-death (tumor suppressive) role at different cancer stages, including cancer stem cell, initiation and progression, invasion and metastasis, as well as dormancy? How does autophagy modulate a series of oncogenic and/or tumor suppressive pathways, implicated in microRNA (miRNA) involvement? Whether would targeting the oncogenic and tumor suppressive autophagic network be a novel strategy for drug discovery? To address these problems, we focus on summarizing the dynamic oncogenic and tumor suppressive roles of autophagy and their relevant small-molecule drugs, which would provide a new clue to elucidate the oncosuppressive (survival or death) autophagic network as a potential therapeutic target.     

综述: 微环境调控肿瘤代谢的研究

20世纪20年代,奥托·瓦博格首次发现肿瘤细胞在正常氧的情况下优先利用糖酵解的现象．近一个世纪以来,细胞代谢在肿瘤发生发展中的作用引起了广泛的关注．其基本机制是肿瘤细胞在营养匮乏的环境中通过劫持、重塑不同的细胞代谢途径,包括合成和分解途径,从而为其生存和增殖提供生物大分子原料;而这些代谢途径改变和代谢物的变化通过转录、表观、翻译和翻译后修饰等不同机制来调控细胞的生命活动, 从而在肿瘤发生发展中起着至关重要的作用．因此,代谢异常是肿瘤的十大特征之一．近年来,随着对癌基因和抑癌基因的突变以及各类生长因子和下游信号通路的深入研究,特别是近十年对肿瘤细胞所处的微环境在肿瘤发生发展中的关键作用不断阐明,人们逐步认识到肿瘤细胞和其所处微环境的相互作用对肿瘤代谢的重塑产生重要的影响,因此揭示微环境对肿瘤细胞代谢的调控机制,将为肿瘤的诊断和治疗提供新的靶点和合理化治疗方案,从而提高肿瘤病人的生存率及其生活质量．     

MicroRNA-487a-3p functions as a new tumor suppressor in prostate cancer by targeting CCND1

Prostate cancer (PCa) is one of the major health problems of the aging male. The roles of dysregulated microRNAs in PCa remain unclear. In this study, we mined the public published data and found that miR-487a-3p was significantly downregulated in 38 pairs of clinical prostate tumor tissues compared with the normal tissues. We further verified this result by in situ hybridization on tissue chip and quantitative real-time polymerase chain reaction (qRT-PCR) in PCa/normal cells. miR-487a-3p targeting of cyclin D1 (CCND1) was identified using bioinformatics, qRT-PCR and western blot analyses. The cellular proliferation, cell cycle, migration, and invasion were assessed by cell counting kit-8, flow cytometry analysis and transwell assay. We discovered that overexpression of miR-487a-3p suppressed PCa cell growth, migration, invasion by directly targeting CCND1. Knockdown of CCND1 in PCa cells showed similar results. Meanwhile, the expression level of CCND1 was significantly upregulated in the PCa tissues and cell lines, which presented negative correlation with the expression of miR-487a-3p. More important, we demonstrated significantly reduced growth of xenograft tumors of stable miR-487a-3p-overexpressed human PCa cells in nude mice. Taken together, for the first time, our results revealed that miR-487a-3p as a tumor suppressor of PCa could target CCND1. Our finding might reveal miR-487a-3p could be potentially contributed to the pathogenesis and a clinical biomarker or the new potential therapeutic target of PCa.     

WWOX suppresses prostate cancer cell progression through cyclin D1-mediated cell cycle arrest in the G1 phase

WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and the other mechanisms of WWOX in tumor suppression have also been reported recently. In this study, we found significant down-regulation of WWOX in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. In addition, an ectopically increased WWOX expression repressed tumor progression both in vitro and in vivo. Interestingly, overexpression of WWOX in 22Rv1 cells led to cell cycle arrest in the G1 phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown to inhibit cell cycle progression into mitosis under nocodazole treatment in flow cytometry, immunoblotting and GFP fluorescence. Further, cyclin D1 but not apoptosis correlated genes were down-regulated by WWOX both in vitro and in vivo. Restoration of cyclin D1 in the WWOX-overexpressed 22Rv1 cells could abolish the WWOX-mediated tumor repression. In addition, WWOX impair c-Jun-mediated cyclin D1 promoter activity. These results suggest that WWOX inhibits prostate cancer progression through negatively regulating cyclin D1 in cell cycle lead to G1 arrest. In summary, our data reveal a novel mechanism of WWOX in tumor suppression.     

WWOX suppresses prostate cancer cell progression through cyclin D1-mediated cell cycle arrest in the G1 phase

WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and the other mechanisms of WWOX in tumor suppression have also been reported recently. In this study, we found significant down-regulation of WWOX in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. In addition, an ectopically increased WWOX expression repressed tumor progression both in vitro and in vivo. Interestingly, overexpression of WWOX in 22Rv1 cells led to cell cycle arrest in the G1 phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown to inhibit cell cycle progression into mitosis under nocodazole treatment in flow cytometry, immunoblotting and GFP fluorescence. Further, cyclin D1 but not apoptosis correlated genes were down-regulated by WWOX both in vitro and in vivo. Restoration of cyclin D1 in the WWOX-overexpressed 22Rv1 cells could abolish the WWOX-mediated tumor repression. In addition, WWOX impair c-Jun-mediated cyclin D1 promoter activity. These results suggest that WWOX inhibits prostate cancer progression through negatively regulating cyclin D1 in cell cycle lead to G1 arrest. In summary, our data reveal a novel mechanism of WWOX in tumor suppression.     

Alteration of WWOX in human cancer,a clinical view

WWOX gene is located in FRA16D, the highly affected chromosomal fragile site. Its tumor suppressor activity has been proposed on a basis of numerous genomic alterations reported in chromosome 16q23.3–24.1 locus. WWOX is affected in many cancers, showing as high as 80% loss of heterozygosity in breast tumors. Unlike most tumor suppressors impairing of both alleles of WWOX is very rare. Despite cellular and animal models information on a WWOX role in cancer tissue is limited and sometimes confusing. This review summarizes information on WWOX in human tumors.     

miR-9: From function to therapeutic potential in cancer

Malignant neoplasms are regarded as the main cause of death around the world; hence, many research studies were conducted to further perceive molecular mechanisms, treatment, and cancer prognosis. Cancer is known as a major factor for health-related problems in the world. The main challenges associated with these diseases are prompt diagnosis, disease remission classification and treatment status forecast. Therefore, progressing in such areas by developing new and optimized methods with the help of minimally invasive biological markers such as circular microRNAs (miRNAs) can be considered important. miRNA interactions with target genes have specified their role in development, apoptosis, differentiation, and proliferation and also, confirm direct miRNA function in cancer. Different miRNAs expression levels in various types of malignant neoplasms have been observed to be associated with prognosis of various carcinomas. miR-9 seems to implement opposite practices in different tissues or under various cancer incidences by influencing different genes. Aberrant miR-9 levels have been observed in many cancer types. Therefore, we intended to investigate the precise role of miR-9 in patients with malignant neoplasms. To this end, in this study, we attempted to examine different studies to clarify the overall role of miR-9 as a prognostic marker in several human tumors. The presented data in this study can help us to find the novel therapeutic avenues for treatment of human cancers.     

根据在癌突变谱中的共突变基因对识别癌基因

癌是一种涉及多基因变异的遗传异质性疾病,涉及多种生物学功能通路中不同基因的遗传变异。因此,识别癌基因是一项富有挑战性的工作。提出通过寻找在癌样本中突变显著共发生的基因筛选候选癌基因的方法。应用该方法,通过分析蛋白激酶基因在癌组织中的突变谱数据,发现了167个显著共发生突变的基因对,包含85个基因。分析这167个基因对发现:(1)发生共突变的基因富集已知的癌基因;(2)共突变基因对倾向于共扰动与癌症相关的通路对。以上结果提示,在癌样本中显著共发生突变的基因倾向于候选癌基因;在癌发生过程中起重要作用的基因倾向于协同扰动不同的癌相关细胞生物学过程。     

Thioredoxin interacting protein (TXNIP) acts as a tumor suppressor in human prostate cancer

Prostate cancer (PCa) is one of the most common malignant tumors in the world. Thioredoxin interacting protein (TXNIP) is downregulated in a variety of human tumors and plays an important role in tumor suppression. However, the expression level and biological functions of TXNIP in PCa have not been identified yet. Therefore, this study aims to investigate the expression and biological functions of TXNIP in PCa. We reported that the expression of TXNIP was significantly decreased in PCa and associated with clinicopathological features. Overexpression of TXNIP could significantly inhibited PC‐3 cells proliferation, migration, invasion, and glucose uptake. Additionally, overexpression of TXNIP could remarkably block cell cycle in the G0/G1 phase and promoted cell apoptosis. Furthermore, TXNIP expression correlated inversely with GLUT1 expression in PCa. Taken together, our results for the first time revealed that TXNIP was decreased in PCa. Moreover, TXNIP might act as a tumor suppressor of PCa and correlated with tumor occurrence and development. Our findings cast a new light on better understanding the occurrence and development of PCa and indicated that TXNIP might be favorable for PCa molecular target therapy.