Pygopus 研究进展

Pygopus（Pygo）是 Wnt 信号通路中新发现的成员,位于该信号通路核心蛋白β-连接蛋白（β-catenin）下游,可介导β-catenin 入核,激活下游靶基因转录。Pygo 对哺乳动物的胚胎发育及肿瘤的形成起着重要的作用。研究表明,Pygo 通过组蛋白解读、组蛋白修饰等表观遗传学机制调控干细胞、肿瘤细胞、肿瘤干细胞。阐述 Pygo 蛋白在其中的作用及机制,将会加深对与该蛋白相关肿瘤的认识。     

肿瘤抑制基因PTEN研究新进展

PTEN是具有磷酸酶活性的抑癌基因,其低表达或缺失与肿瘤的进展及不良预后密切相关,其抑制肿瘤作用机制系通过抑制P13K／AKT信号通路,FAK／P130C和MAPK信号通路,FRAP／mTOR信号通路及影响核转录因子-kB／IB信号通路;另外,NEDIM-1通过泛素化蛋白体降解途径调节PTEN,BMP通过RAS／ERK信号通路抑制PTEN表达,IGF-1通过IGF-1／P13K／Akt信号通路调节PTEN。     

蛋白质精氨酸甲基转移酶在前列腺癌中的研究进展

蛋白质精氨酸甲基转移酶(PRMT)是在真核生物细胞中广泛分布的甲基转移酶,可通过甲基化组蛋白和非组蛋白的精氨酸残基发挥生物学功能。PRMT参与肿瘤的发生、发展,是近年来肿瘤研究领域的新发现,特别是其在前列腺癌中异常表达。PRMT高表达促进前列腺癌细胞的生长和迁移。PRMT能与雄激素受体(AR)相互作用,参与AR信号通路,AR信号通路异常被认为是前列腺癌发生的主要原因之一。此外,PRMT通过甲基化组蛋白激活或抑制基因的表达,通过甲基化非组蛋白参与Wnt信号通路等。     

乳腺癌转移抑制基因1抑制肿瘤转移的作用机制

乳腺癌转移抑制基因1 (BRMS1)在多种恶性肿瘤细胞中表达降低或缺失,具有明显降低癌细胞侵袭和转移的作用.BRMS1基因通过磷酸肌醇信号及核转录因子-κB(NF-κB)信号通路等调节基因转录和蛋白翻译,还可与mSin3-组蛋白去乙酰化酶(HDAC)复合体、雌激素受体等蛋白相互作用、修复细胞间隙通讯等途径抑制肿瘤细胞的侵袭及转移.BRMS1基因将可能成为有效抑制肿瘤转移基因治疗的新靶点.     

HMGB1与肿瘤的相关性

高迁移率族蛋白B1(HMGB1)是存在于真核细胞核内的非组蛋白染色体结合蛋白,参与多种生理和病理过程。近年研究表明,HMGB1在多种肿瘤中高表达,通过与其受体结合,激活一系列相关的信号通路,从而促进肿瘤的发生、增殖、浸润和转移。了解HMGB1与肿瘤的相关性,将会为肿瘤的防治提供新的理论依据及有效的措施。     

组蛋白去乙酰化酶抑制剂在HR阳性HER-2阴性晚期乳腺癌的研究进展

组蛋白去乙酰化酶（histone deacetylase,HDAC）是可调节表观遗传学改变的组蛋白修饰酶，在一些肿瘤中HDACs被异常激活，与肿瘤进展和耐药密切相关。HDAC抑制剂（HDAC inhibitor,HDACi）通过调节肿瘤细胞的表观遗传属性，靶向性控制肿瘤细胞增殖、调节肿瘤细胞周期及修复DNA损伤。HDACi可抑制多个乳腺癌致癌信号通路，从而有可能逆转激素受体（hormone receptor,HR）阳性HER-2阴性乳腺癌的治疗耐药。本文将对HDACi在HR阳性HER-2阴性晚期乳腺癌治疗方面进行综述，探讨其在乳腺癌治疗领域中的应用前景。     

核转录因子E2相关因子2在肿瘤血管生成调控中的研究进展

摘 要：研究发现核转录因子E2相关因子2(Nrf2)在多种肿瘤中异常表达，并通过氧化应激、HO-1通路、缺氧及炎症介质等多种途径参与调控肿瘤血管生成过程。对Nrf2与肿瘤血管生成的相关性进行探究，有助于发现抗肿瘤血管生成治疗的新靶点。全文就近年来肿瘤血管生成与Nrf2信号通路相关研究进展作一综述。     

低氧诱导因子-1促进肿瘤血管生成的研究

低氧诱导因子-1（HIF-1）是调节血管内皮生长因子转录最重要的核转录因子之一,在肿瘤血管生长、转移中起重要的作用。HIF-1对肿瘤血管生成的转录调控作用与其本身的分子结构、生物学特性、分子机制及信号通路密切相关。     

RbAP48与恶性肿瘤的研究进展

视网膜母细胞瘤结合蛋白48(Retinoblastoma associated protein 48,RbAP48)是一种新型肿瘤特异性蛋白,属于WD-40蛋白家族成员,作为一种Rb结合蛋白,是从不同染色质组装、装配及核小体修饰复合物(包括组蛋白乙酰化酶HDACs)分离出来的第一个被鉴定的高峰度蛋白,在Rb/E2F信号传导通路中起转录抑制作用。研究证实,RbAP48通过HDAC1靶向作用于视网膜母细胞瘤蛋白Rb,从而结合形成Rb·HDAC1·RbAP48三聚复合体,该复合物在G₁期定位于E2F上,抑制该调节因子转录。RbAP48在肺癌、宫颈癌、甲状腺癌、急性髓系白血病、乳腺癌、胃癌和原发性肝癌等恶性肿瘤中均表达异常,并且与肿瘤的发生发展关系密切,因此,进一步了解RbAP48的作用及在不同种类肿瘤中的表达情况对了解肿瘤的发生发展有重要意义。     

肿瘤抑制基因PTEN研究新进展

PTEN是具有磷酸酶活性的抑癌基因,其低表达或缺失与肿瘤的进展及不良预后密切相关,其抑制肿瘤作用机制系通过抑制PI3K/AKT信号通路,FAK/PI30C和MAPK信号通路,FRAP/Mtor信号通路及影响核转录因子-Kb/IB信号通路;另外,NEDD4-1通过泛素化蛋白体降解途径调节PTEN,BMP通过RAS/ERK信号通路抑制PTEN表达,IGF-1通过IGF-1/PI3K/Akt信号通路调节PTEN.     

Prognostication of prostate cancer based on NUCB2 protein assessment: NUCB2 in prostate cancer

Background

Nucleobindin 2 (NUCB2) protein, a novel oncoprotein, is overexpressed in breast cancer. To date, there have been no published data regarding the role of NUCB2 protein expression in prostate cancer (PCa). Therefore, this study was performed to investigate the correlations between NUCB2 protein expression and prognosis in patients with PCa.

Methods

Through immunohistochemistry, NUCB2 protein expression was evaluated in 60 benign prostatic hyperplasia (BPH) specimens and 180 PCa specimens. The correlation of NUCB2 protein expression with clinicopathological parameters was assessed using χ² analysis. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between NUCB2 protein expression and prognosis of PCa patients.

Results

The immunohistochemistry results showed that the expression level of NUCB2 in PCa cases was significantly higher than that in BPH tissues (P < 0.001). Moreover, statistical analysis also showed that high NUCB2 protein expression was positively related to seminal vesicle invasion, lymph node metastasis, angiolymphatic invasion, higher Gleason score, biochemical recurrence (BCR), and higher preoperative prostate-specific antigen (PSA). Furthermore, it was also shown that patients with high NUCB2 protein expression had significantly poorer overall survival and BCR- free survival compared with patients with low expression of NUCB2 protein. Multivariate Cox regression analysis revealed that high NUCB2 protein expression level was an independent prognostic factor for overall survival and BCR-free survival of patients with PCa.

Conclusions

NUCB2 protein expression showed a strong association with the potencies of BCR and progression of PCa, and that may be applied as a novel biomarker for the prediction of BCR, and helpful for improving the diagnosis, prognosis and treatment of PCa.     

Nucleobindin 2 in human breast carcinoma as a potent prognostic factor

It is well-known that estrogens immensely contribute to the progression of human breast carcinoma, but their detailed molecular mechanisms remain largely unclear. In this study, we identified nucleobindin 2 (NUCB2) as a gene associated with recurrence based on microarray data of estrogen receptor (ER)-positive breast carcinoma cases (n = 10), and subsequent in vitro study showed that NUCB2 expression was upregulated by estradiol in ER-positive MCF-7 cells. However, NUCB2 has not yet been examined in breast carcinoma, and its significance remains unknown. Therefore, we further examined the biological functions of NUCB2 in breast carcinoma using immunohistochemistry and in vitro studies. NUCB2 immunoreactivity was detected in carcinoma cells in 77 of 161 (48%) breast cancer cases, and positively associated with lymph node metastasis and ER status of the patients. In addition, NUCB2 status was significantly associated with an increased risk of recurrence and adverse clinical outcome of the patients using both univariate and multivariate analyses. Results of siRNA transfection experiments showed that NUCB2 significantly increased cell proliferation, and migration and invasion properties in both MCF-7 and ER-negative SK-BR-3 cells. These results suggest that NUCB2 is upregulated by estrogens and plays an important role, especially in the process of metastasis, in breast carcinomas. NUCB2 status is considered a potent prognostic factor in human breast cancer.     

The biochemical and clinical implications of phosphatase and tensin homolog deleted on chromosome ten in different cancers

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is widely known as a tumor suppressor gene. It is located on chromosome 10q23 with 200 kb, and has dual activity of both protein and lipid phosphatase. In addition, as a targeted gene in multiple pathways, PTEN has a variety of physiological activities, such as those regulating the cell cycle, inducing cell apoptosis, and inhibiting cell invasion, etc. The PTEN gene have been identified in many kinds of cancers due to its mutations, deletions and inactivation, such as lung cancer, liver cancer, and breast cancer, and they are closely connected with the genesis and progression of cancers. To a large extent, the tumor suppressive function of PTEN is realized through its inhibition of the PI3K/AKT signaling pathway which controls cells apoptosis and development. In addition, PTEN loss has been associated with the prognosis of many cancers, such as lung cancer, liver cancer, and breast cancer. PTEN gene is related to many cancers and their pathological development. On the basis of a large number of related studies, this study describes in detail the structure, regulation, function and classical signal pathways of PTEN, as well as the relationship between various tumors related to PTEN. In addition, some drug studies targeting PTEN/PI3K/AKT/mTOR are also introduced in order to provide some directions for experimental research and clinical treatment of tumors.     

Targeting hedgehog in cancer stem cells: how a paradigm shift can improve treatment response

The integration of developmental biology and cancer therapeutics has revolutionized the understanding of tumor proliferation. Cell-signaling pathways first recognized for their importance in embryogenesis have begun to inspire the scientific community to investigate new avenues in cancer initiation and growth. Other ground-breaking discoveries provided evidence for a revisit to the theory of cancer stem cells, which has long-term implications for the efficient and lasting elimination of cancer. This paradigm shift involves a change from viewing the malignant tumor as a perpetually mutating mass of clonogenic cells to seeing it as an organ mistakenly created by mutations that disrupt cell-signaling pathways in stem cells. As researchers find more evidence of the essential involvement of these signaling pathways in cancer formation and maintenance, the link between tumorigenesis and aberrant stem cell activation can be more clearly drawn. One such pathway is the hedgehog (Hh)-signaling pathway, which is important in growth and differentiation during embryogenesis and for proper functioning in many adult tissues. Investigation of this pathway and its involvement in cancer has already led to drug development that could eradicate basal cell carcinoma, the most common type of cancer in humans. Future research focused on Hh and related signaling pathways involved in cancer might improve treatment response in malignancies resistant to traditional therapy.     

Metastasis and stem cell pathways

Recent studies have described a small population of self-renewing and multipotent cells within tumors termed “cancer stem cells.” These cells share many traits with somatic and embryonic stem cells and are thought to be responsible for driving tumor progression in a growing list of neoplastic diseases. Cells within solid tumors encounter hypoxia due to poor vascular function. Both long-standing and emerging data describe hypoxic effects on somatic and embryonic stem cells, and it is likely that hypoxia also has profound effects on cancer stem cells. These effects include the activation of pathways that induce the dedifferentiation of cancer cells, the maintenance of stem cell identity, and increased metastatic potential. Hypoxia may contribute to tumor progression by specifically impacting these pathways in cancer stem cells.     

Targeted agents in the treatment of pancreatic cancer: history and lessons learned

PURPOSE OF REVIEW: The treatment of pancreatic cancer is an ongoing challenge with minimal substantive improvement in patient outcomes despite many randomized phase III clinical trials evaluating multiple agents, both alone and in combination. Such disappointing outcomes clearly call for broadening the scope of pharmacologic approaches to managing this disease. With increasing insight into pathways within tumor cells that are related to tumor growth and spread, and development of 'targeted therapies' against these pathways, much attention has turned to the use of these agents, alone or coupled with chemotherapy, in the treatment of pancreatic cancer. RECENT FINDINGS: Several targeted agents have been studied in patients with pancreatic cancer. Of the agents studied, the only agent that has shown to provide a modest but significant benefit in survival for these patients is erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. SUMMARY: From trials done to date, minimal benefit has been found with the addition of targeted agents in the treatment of pancreatic cancer. More potential pathways remain to be targeted, however, and there are a plethora of new agents to be tested. Due to the likelihood that different pathways drive the development and growth of different tumors of the same site of origin the inclusion of biomarker studies to correlate with treatment effect may be a necessary component of clinical trials to learn how to best tailor therapy to the patient.     

Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More

Calorie restriction (CR), or a diet modification aiming to reduce the total intake of calories by 20%–40%, has been shown to increase longevity across multiple species. Recently, there has been growing interest in investigating the potential role of CR as a treatment intervention for age-related diseases, such as cancer, because an increasing body of literature has demonstrated a metabolic component to both carcinogenesis and tumor progression. In fact, many of the molecular pathways that are altered with CR are also known to be altered in cancer. Therefore, manipulation of these pathways using CR can render cancer cells, and most notably breast cancer cells, more susceptible to standard cytotoxic treatment with radiation and chemotherapy. In this review article we demonstrate the laboratory and clinical evidence that exists for CR and show compelling evidence through the molecular pathways CR induces about how it may be used as a treatment in tandem with radiation therapy to improve our rates of disease control.     

Mechanisms of tumor escape from the immune system: adenosine-producing Treg, exosomes and tumor-associated TLRs

Human tumors utilize many different mechanisms of immunosuppression to prevent immune cells from exercising their antitumor activities. These mechanisms, which enable the tumor to escape from the host immune system and to progress, are being intensively investigated in hope of finding therapeutically safe and effective inhibitors able to counteract tumor-induced immunosuppression. Three of more recently discovered tumor-related suppression mechanisms, i.e. accumulations of adenosine-producing regulatory T-cells (Treg) in the tumor microenvironment, release by tumors of suppressive microvesicles (TMV) and expression of toll-like receptors (TLR) on the tumor cell surface, are described in this review. All contribute in a varying degree to creating a milieu favorable for the tumor and unfavorable for immune effector cells. Tumor escape has been a major problem in cancer immunotherapy and it has been held responsible for the failure of many immune interventions in cancer. For this reason, it is important to study and understand the various suppressive pathways human tumors utilize. Future antitumor immunotherapies are likely to include inhibitors of tumor-induced suppression with the goal of restoring antitumor immune responses in patients with cancer.