PTEN及p27Kip1在子宫内膜癌中的研究进展

肿瘤抑制基因PTEN被称为子宫内膜的看家基因，许多学者提出PTEN基因在子宫内膜癌发生发展中起重要作用。另一个肿瘤抑制基因p27在子宫内膜癌的预后中具有重要的作用。现就PTEN 、p27基因在子宫内膜癌中的表达及其与子宫内膜癌发生、发展的关系以及在治疗和预后方面的研究进展进行综述。     

乙型肝炎病毒X基因在肝细胞凋亡中的作用

HBV基因组中的x基因能整合至肝细胞基因组，编码产生的HBx蛋白表现出复杂多样的生物学活性。近年来随着对HBX基因结构与功能的深入研究，发现HBx能够对肝细胞的凋亡起双向调控作用，对肝细胞肝癌（HCC）的发生发展具有重要意义。一方面，HBX能抑制肝细胞凋亡，使细胞过度增生，这对HCC的发展起着重要的作用，另一方面，HBx还具有诱导或促进肝细胞凋亡的作用，该作用在HBV相关疾病中的具体作用还不甚清楚。HBVx基因可能在肝细胞凋亡方面发挥着不同的作用，对揭示HCC发病机制有着重要意义。     

乙型肝炎病毒X基因在肝细胞凋亡中的作用

HBV基因组中的x基因能整合至肝细胞基因组,编码产生的HBx蛋白表现出复杂多样的生物学活性。近年来随着对HBX基因结构与功能的深入研究,发现HBx能够对肝细胞的凋亡起双向调控作用,对肝细胞肝癌(HCC)的发生发展具有重要意义。一方面,HBX能抑制肝细胞凋亡,使细胞过度增生,这对HCC的发展起着重要的作用,另一方面,HBx还具有诱导或促进肝细胞凋亡的作用,该作用在HBV相关疾病中的具体作用还不甚清楚。HBV x基因可能在肝细胞凋亡方面发挥着不同的作用,对揭示HCC发病机制有着重要意义。     

甲状腺肿瘤相关基因甲基化研究进展

DNA甲基化异常在肿瘤发生发展中起重要作用,可导致肿瘤细胞中基因表达异常。高甲基化引起基因表达降低,低甲基化则使基因的表达增加。探讨基因甲基化异常在甲状腺肿瘤发生发展过程中的作用,对甲状腺肿瘤的早期诊断、基因治疗和预后判断具有重要意义。     

DCC基因与妇科肿瘤的研究

结直肠癌缺失基因，即DCC基因，近年来发现的大肠癌中一个重要的肿瘤抑制基因，其在妇科肿瘤中的作用与日益受到研究的重视，但有关此方面的研究国内尚未见报道。本就DCC基因的分子生物学特性、作用机制、与妇科肿瘤关系的研究等方面作一简要综述。     

Goosecoid基因与颅颌面形态发生研究进展

Goosecoid基因是同源异型盒包含基因，组织者基因之一。其最先表达于原肠胚，之后在形态发生期表达于第一，二鳃弓处，在颅颌面，肋骨及外胚层的形态发生中起重要作用，该基因的缺失或突变可以导致颅颌面等多种畸形。本文对该基因在胚胎发育过程中的作用及导致机体发育异常机制方面的研究进展，做一简要综述。     

DCC基因与妇科肿瘤的研究

结直肠癌缺失基因 ,即 DCC基因 ,是近年来发现的大肠癌中一个重要的肿瘤抑制基因 ,其在妇科肿瘤中的作用也日益受到研究者的重视 ,但有关此方面的研究国内尚未见报道。本文就 DCC基因的分子生物学特性、作用机制、与妇科肿瘤关系的研究等方面作一简要综述     

全能性相关基因cNanog、cPouV和Sox2在鸡早期胚胎中的表达

背景：全能性相关基因cPouV、cNanog和Sox2对鸡胚胎干细胞自我更新和全能性的维持起重要调控作用,其在鸡早期胚胎中的表达情况和作用缺乏了解。 目的：通过检测cNanog、cPouV和Sox2在鸡早期胚胎中的表达情况,研究基因在早期胚胎发育过程中的作用。 方法：将180枚新鲜受精种鸡蛋分为6组,分别孵育0,8,16,22,32,42 h后取出。获取胚胎样品,以β-actin为内参基因,采用实时定量PCR检测其cNanog、cPouV和Sox2的相对表达量。 结果与结论：cNanog和cPouV的表达量模式相似,在孵育的第0,8,16,22 h表达量增加,孵育22 h达到峰值,随后逐级下降。Sox2的相对表达量呈明显上调趋势。说明,cNanog、cPouV和Sox2在鸡早期胚胎发育调控中的重要作用,且作为全能性的标志基因,作用有所相同。     

PTEN在消化道肿瘤的研究进展

PTEN是迄今发现的第一个具有双重特异性磷酸酶活性的肿瘤抑制基因,在细胞的生长发育、凋亡、迁移、信号传递等方面起着重要的调控作用,虽然已经证实PTEN基因的表达水平与多数消化系统肿瘤的发生、发展及预后存在相关性,但其精确作用点、作用机制以及它在消化系统肿瘤发生中的重要性等,均有待于进一步阐述。现对国内外PTEN基因在消化系统肿瘤中的研究进展作一综述。     

bc1－2与淋巴细胞程序性死亡

本文主要介绍了ｂｃ１－２原癌基因的基因结构、表达产物的特性及其抑制淋巴细胞程序性死亡的作用。ｂｃ１－２基因在Ｔ和Ｂ淋巴细胞发育和成熟中的作用反映了其正常的生物功能。重要的是ｂｃ１－２基因不引起淋巴细胞的分化而延长细胞的存活期。     

pERK activation in esophageal carcinomas: clinicopathological associations

MAPK (mitogen-activated protein kinase) pathway is considered a control regulator in various malignant tumors but its role in esophageal carcinomas remains elusive. In our study, we examined the possible prognostic significance of MAPK pathway in human esophageal cancer. We searched for mutations in exons 18-21 of EGFR gene, codons 12 and 13 of K-RAS gene and exon 15 of B-RAF gene by high resolution melting analysis (HRMA) and pyrosequencing in 44 esophageal carcinomas. Immunohistochemistry was performed in 29 cases in order to evaluate expression levels of pERK (extracellular-signal regulated kinase). In one laser microdissected squamous cell carcinoma, a somatic K-RAS mutation at codon 12 was detected, whereas none of the cases displayed mutations in EGFR and B-RAF genes. Elevated nuclear as well as cytoplasmic pERK expression (100% and 62% of cases respectively) was observed independently of EGFR and B-RAF mutational status. Increasing pERK nuclear and cytoplasmic expression as well as the intensity of nuclear staining was found to be significantly correlated with tumor grade in univariate and multivariate statistical analysis. Our findings depict the presence of activated ERK despite the low frequency of upstream alterations, implicating ERK activation in the acquisition of a more aggressive phenotype in esophageal cancer.     

57miRNA regulation during oncogene-induced senescence

Aberrant oncogene activation induces cellular senescence, an irreversible growth arrest which acts as a barrier against tumor formation. To identify miRNAs involved in oncogene-induced senescence we arrayed miRNA expression in primary human fibroblasts (Tig3) following over-expression of B-RAF. 18 miRNA were significantly regulated (P<0.001) 4 days after B-RAF activation; in particular, miR-34a expression increased ∼8-fold. In addition, miR-34a is up-regulated in mouse fibroblasts undergoing replicative senescence. In agreement with previous reports, we find that miR-34a reduces cellular proliferation and induces cell cycle arrest. Using microarrays, we have identified a number of putative miR-34a targets involved in oncogene-induced senescence and we are now evaluating their ability to mediate the cellular effects of miR-34a. Although members of the miR-34 family are known p53 target genes, our data indicate that miR-34a is regulated independently of p53 during oncogene-induced senescence. Hence, miR-34a responds to several independent cancer-related pathways thereby underlining the importance of miR-34a as an important tumor suppressor. We are currently investigating the regulation of miR-34a in normal and senescent cells using ChIP and promoter reporter assays.     

Identification of Aurora Kinase B and Wee1-Like Protein Kinase as Downstream Targets of V600EB-RAF in Melanoma

BRAF is the most mutated gene in melanoma, with approximately 50% of patients containing V600E mutant protein. ^V600EB-RAF can be targeted using pharmacological agents, but resistance develops in patients by activating other proteins in the signaling pathway. Identifying downstream members in this signaling cascade is important to design strategies to avoid the development of resistance. Unfortunately, downstream proteins remain to be identified and therapeutic potential requires validation. A kinase screen was undertaken to identify downstream targets in the ^V600EB-RAF signaling cascade. Involvement of aurora kinase B (AURKB) and Wee1-like protein kinase (WEE1) as downstream proteins in the ^V600EB-RAF pathway was validated in xenografted tumors, and mechanisms of action were characterized in size- and time-matched tumors. Levels of only AURKB and WEE1 decreased in melanoma cells, when ^V600EB-RAF, mitogen-activated protein kinase 1/2, or extracellular signal–regulated kinase 1/2 protein levels were reduced using siRNA compared with other identified kinases. AURKB and WEE1 were expressed in tumors of patients with melanoma at higher levels than observed in normal human melanocytes. Targeting these proteins reduced tumor development by approximately 70%, similar to that observed when inhibiting ^V600EB-RAF. Furthermore, protein or activity levels of AURKB and WEE1 decreased in melanoma cells when pharmacological agents targeting upstream ^V600EB-RAF or mitogen-activated protein kinase were used to inhibit the ^V600EB-RAF pathway. Thus, AURKB and WEE1 are targets and biomarkers of therapeutic efficacy, lying downstream of ^V600EB-RAF in melanomas.Melanoma remains the most common cause of skin cancer–related deaths worldwide.¹ The incidence of melanoma increases with age, with a 28% probability of disease for individuals <40 years and a ≥70% probability for those >60 years.² Approaches to manage advanced melanoma include surgery, radiation, immunotherapy, chemotherapy, or combinations of these approaches. Patients in the advanced stages of this disease have few treatment options for long-term management of the disease, with average 5-year survival being 10%.³ Therefore, a better understanding of the genes and processes regulating melanoma that could be used for selection of therapeutic targets as biomarkers for particular drug efficacy or prognostic indicators to assist in therapeutic agent selection and for overcoming resistance to targeted agents is needed.Kinases play a key role regulating cellular proliferation and drug resistance development.⁴ In the mitogen-activated protein (MAP) kinase pathway, 50% and 25% of sporadic melanomas harbor BRAF or NRAS mutations, respectively, which activate the MAP kinase pathway measured through the activation of extracellular signal–regulated kinase (ERK).⁵ These mutations rarely occur in the same cell, but both mutations activate pathways to regulate diverse cellular processes aiding cancer development, with the most prominent being regulation of cellular proliferation.⁶ The most frequent BRAF mutation is a valine to glutamic acid substitution at residue 600 (V600E), which increases basal kinase activity.⁷ The most common NRAS mutation is a glutamine to leucine substitution (Q61L), which impairs GTP hydrolysis and maintains a constitutively active protein.⁸Pharmacological agents have been developed to inhibit the activity of various proteins in the deregulated MAP kinase signaling pathway.^9–12 Recent FDA approval of Zelboraf (vemurafenib; formerly known as PLX4032), is a major breakthrough for individuals with mutant ^V600EB-RAF.^13–16 Vemurafenib leads to a high response rate in patients, but in most cases, more invasive resistant disease eventually recurs by circumventing ^V600EB-RAF, leading to mortality.^13,16,17 Therefore, a better understanding of downstream members of the ^V600EB-RAF pathways is needed so that these proteins could be targeted together with vemurafenib or inhibited after the development of resistance to more effectively manage this disease.To identify novel kinases regulating the proliferative potential of melanoma cells and then pinpoint those lying downstream of ^V600EB-RAF in this signaling cascade, an siRNA-based screen of a library of 636 kinases was undertaken. AURKB, Wee1-like protein kinase (WEE1), glycogen synthase kinase-3α (GSK3A), thiamin pyrophosphokinase 1 (TPK1), and B-RAF were identified as potential modulators of melanoma cell survival. The aurora kinase family consists of aurora kinase A (AURKA), aurora kinase B (AURKB), and aurora kinase C (AURKC).¹⁸ Involvement of AURKA in melanoma development has been reported, but it is not known whether AURKB and AURKC play roles in melanoma pathogenesis or development of drug resistance.¹⁹ WEE1 is a dual-specificity protein kinase involved in regulating cell cycle progression by phosphorylating and deactivating cyclin-associated CDKs.^20,21 WEE1 currently has no known role in melanoma development. Two isoforms of GSK-3, called GSK3A and GSK-3β (GSK3B), have been identified. Although GSK3B has been shown to play a role in melanoma development and drug resistance,²² GSK3A has not been identified as a melanoma therapeutic target. The TPK catalyzes phosphorylation of thiamin to thiamin pyrophosphate and also has no known role in melanoma development.²³This study shows that AURKB, WEE1, GSK3A, and TPK1 were all expressed in tumors of patients with melanoma at higher levels than observed in normal human melanocytes. However, only AURKB and WEE1 levels decreased when ^V600EB-Raf, mitogen-activated protein kinase (MEK) 1/2, or ERK1/2 were targeted using siRNA, demonstrating that these proteins were downstream of ^V600EB-RAF in the deregulated MAP kinase signaling pathway. Subsequent studies confirmed that targeting AURKB or WEE1 reduced melanoma tumor development and led to a phenotype similar to that observed when inhibiting ^V600EB-RAF in this deregulated signaling cascade. Furthermore, AURKB or WEE1 levels decreased when pharmacological agents inhibiting ^V600EB-Raf or MEK were used to target melanoma cells. Thus, AURKB and WEE1 can be used as downstream therapeutic targets and as biomarkers of efficacy of agents targeting the ^V600EB-RAF signaling cascade in melanomas.     

MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential

Recently, a new mechanism for activation of B-RAF was identified resulting from a tandem duplication, generating a fusion protein with constitutive BRAF activity and thereby activating the MAPK pathway. Different fusion variants involving BRAF and KIAA1549 were demonstrated, present in 80% of pilocytic astrocytomas in children. As the KIAA1549-BRAF fusion gene is detected at a much lower frequency in diffuse low-grade astrocytomas and survival was much longer than expected in the patients with a 'non-pilocytic' astrocytoma carrying the fusion gene, identification of this fusion gene can be of diagnostic and prognostic value. In the near future, interference with the (fusion gene causing) activation of the MAPK signalling cascade may open new therapeutic avenues for children with pilocytic astrocytomas, as a first line of defence against tumour growth or in situations where the tumour has become refractory to other therapeutic modalities.     

B-RAF mutations in the etiopathogenesis, diagnosis, and prognosis of thyroid carcinomas

The very recent discovery of B-RAF point mutations as the most prevalent genetic alteration in papillary thyroid carcinoma has revolutionized the molecular knowledge of thyroid malignancies. In this review, we address the role played by such mutations in the etiopathogenesis, diagnosis, prognosis, and therapy selection of thyroid cancer, with an emphasis on papillary carcinoma.     

Assessing the utility of a mutational assay for B-RAF as an adjunct to conventional fine needle aspiration of the thyroid gland

Thyroid carcinoma is the most common endocrine malignancy; it is typified by a number of classical genomic insults, which tend to cluster with the discrete histologic subtypes. The most common of these is a mutation in B-RAF, which is present in approximately 44% (29% to 83%) of cases. In this review we have assessed the potential utility of a molecular test for somatically acquired mutations in B-RAF using thyroid malignancy as a model system according to 3 fundamental questions: would a test enhance our ability to distinguish benign from malignant, would a test unveil a risk factor not otherwise known, and would detecting a mutation enable a therapeutic option specific to those patients who carry the mutation?     

DNA甲基化及其调控与肿瘤

表观遗传学是调控肿瘤发生的重要机制之一,其最为常见的方式是甲基化。DNA甲基化通过调节基因的表达影响胚胎发育及肿瘤发生。癌基因启动子区的低甲基化导致其转录激活,抑癌基因启动子区的高甲基化导致其转录抑制,这两者是肿瘤形成的重要途径。     

BCR/ABL融合基因与慢性粒细胞白血病的发生

BCR/ABL融合基因是一个重要的凋亡抑制基因,具有较强的PTK活性。 src激酶﹑蛋白激酶家族C﹑信号转导和转录激活因子（STAT）等在BCR/ABL融合基因介导的肿瘤恶性转化中起着重要的作用。     

p27基因和蛋白表达的调控及其在肿瘤发生机制中的作用

p27-kip1基因编码的P27蛋白作为细胞周期蛋白依赖性激酶抑制剂,在细胞周期进程中起重要的负调节作用,同时作为一个新的肿瘤抑制基因,与肿瘤的发生、发展及预后密切相关,近年来调节P27机制的新发现为肿瘤治疗开辟了新的道路。     

心血管系统中PTEN基因的研究进展

<正>PTEN基因于1997年由3个研究小组先后克隆并命名,是迄今发现的第一个具有双特异磷酸酶活性的抑癌基因,其在细胞生长、凋亡、细胞周期阻滞、细胞迁移过程起关键作用,成为新近研究的热点。