Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila

Apparent defects in cell polarity are often seen in human cancer. However, the underlying mechanisms of how cell polarity disruption contributes to tumor progression are unknown. Here, using a Drosophila genetic model for Ras-induced tumor progression, we show a molecular link between loss of cell polarity and tumor malignancy. Mutation of different apicobasal polarity genes activates c-Jun N-terminal kinase (JNK) signaling and downregulates the E-cadherin/beta-catenin adhesion complex, both of which are necessary and sufficient to cause oncogenic Ras(V12)-induced benign tumors in the developing eye to exhibit metastatic behavior. Furthermore, activated JNK and Ras signaling cooperate in promoting tumor growth cell autonomously, as JNK signaling switches its proapoptotic role to a progrowth effect in the presence of oncogenic Ras. Our finding that such context-dependent alterations promote both tumor growth and metastatic behavior suggests that metastasis-promoting mutations may be selected for based primarily on their growth-promoting capabilities. Similar oncogenic cooperation mediated through these evolutionarily conserved signaling pathways could contribute to human cancer progression.     

Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

Pleiotrophin (PTN, Ptn) is an 18kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn, it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway in PTN-stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTPbeta/zeta signaling pathway; we now demonstrate that ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the ;;dotted" pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTPbeta/zeta signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.     

组蛋白赖氨酸特异性去甲基化酶1A在肿瘤发生发展中的作用

组蛋白赖氨酸特异性去甲基化酶1A (Histone lysine-specific demethylase 1A,KDM1A)作为组蛋白赖氨酸特异性去甲基化酶(Histonelysine-specificdemethylase)家族的一员,在信号传导、染色体重构、胚胎发育、造血和糖脂代谢等生物学过程中起着重要的作用。近年来的研究及临床证据表明,KDM1A的表达与肿瘤的发生发展密不可分,通过与不同的复合物结合并介导不同的下游信号通路,对多种肿瘤的生长增殖起着关键的调节作用,例如前列腺癌、乳腺癌、肺癌和肝癌等。在大多数情况下,KDM1A在肿瘤的发生发展中扮演着促癌基因角色。文中结合近年来有关文献,阐述了KDM1A在多种肿瘤发生及发展中的研究进展,总结了其作用机制,并对以KDM1A为靶点的抑癌治疗的应用前景进行了展望。     

Role of TGF-β signaling regulatory microRNAs in the pathogenesis of colorectal cancer

Transforming growth factor β (TGF-β) modulates tumor progression by regulating cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. Biological and pharmacological agonists/antagonists, the interplay between intracellular signaling pathways, and microRNAs (miRNAs) control the initiation and activation of the TGF-β signaling pathway. It has been proposed that the expression profiles of tumor suppressor and oncogenic TGF-β miRNAs may be used for the classification, diagnosis, and prognosis of human malignancies. Deregulated miRNAs and aberrant activation of TGF-β signaling are frequently found in human colorectal cancers (CRCs), but a little is known about their mechanisms of action in the development and progression of colorectal carcinoma. This review summarizes the current knowledge of the role of TGF-β signaling regulatory miRNAs in the pathogenesis of CRC for a better understanding and hence better management of this disease.     

Epiregulin promotes growth and metastasis of gastric cancer via the ERK/JNK/p38 signaling pathway

Epiregulin (EREG) is a ligand of the epidermal growth factor receptor. It belongs to the ErbB family of ligands found overexpressed in various cancers such as colon cancer and lung carcinoma and is likely to play diverse oncogenic roles in several other cancer types. However, little is known about the mechanisms of EREG in the pathogenesis of gastric cancer (GC). The present study was undertaken to investigate whether EREG influences the development and progression in GC. The results revealed that EREG was found to be overexpressed in human GC cells lines. Moreover, EREG induced cell migration, invasion, and proliferation, and inhibited apoptosis in vitro. The study also found that EREG depletion inhibited tumor growth in vivo. Our findings indicated that EREG activated the ERK/JNK/p38 signaling pathway and PI3K/Akt signaling pathways to promote GC malignant progression. Overall, this study suggests that EREG may promote GC development and progression through the ERK/JNK/p38 and PI3K/Akt signaling pathways, which may improve our understanding of the molecular mechanism of EREG in GC. Thus, EREG may be a potential target for GC treatment.     

INHBA gene silencing inhibits gastric cancer cell migration and invasion by impeding activation of the TGF-β signaling pathway

Gastric cancer (GC) is the fourth largest cancer in the world, with a 5-year survival rate of <30%. Thus, this study intends to investigate the effects of inhibin βA (INHBA) gene silencing on the migration and invasion of GC cells via the transforming growth factor-β (TGF-β) signaling pathway. Initially, this study determined the expression of INHBA and the TGF-β signaling pathway-related genes in GC tissues. After that, to assess the effect of INHBA silencing on GC progression, GC cells were transfected with short hairpin RNAs that targeted INHBA in order to detect the expression of INHBA and the TGF-β signaling pathway-related genes, as well as cell migration, invasion, and proliferation abilities. Finally, a tumor xenograft model in nude mice was constructed to verify the effect that the silencing of INHBA had on tumor growth. Highly expressed INHBA and activated TGF-β signaling pathways were observed in GC tissues. In response to shINHBA-1 and shINHBA-2, the TGF-β signaling pathway was inhibited in GC cells, whereas the GC cell migration, invasion, proliferation, and tumor growth were significantly dampened. On the basis of the observations and findings of this study, INHBA gene silencing inhibited the progression of GC by inactivating the TGF-β signaling pathway, which provides a potential target in the treatment of GC.     

Oncogenes and Tumor Suppressor Genes

Breast cancer progression involves multiple genetic events, which can activate dominant-acting oncogenes and disrupt the function of specific tumor suppressor genes. This article describes several key oncogene and tumor suppressor signaling networks that have been implicated in breast cancer progression. Among the tumor suppressors, the article emphasizes BRCA1/2 and p53 tumor suppressors. In addition to these well characterized tumor suppressors, the article highlights the importance of PTEN tumor suppressor in counteracting PI3K signaling from activated oncogenes such as ErbB2. This article discusses the use of mouse models of human breast that recapitulate the key genetic events involved in the initiation and progression of breast cancer. Finally, the therapeutic potential of targeting these key tumor suppressor and oncogene signaling networks is discussed.Karyotypic and epidemiological analyses of mammary tumors at various stages suggest that breast carcinomas become increasingly aggressive through the stepwise accumulation of genetic changes. The majority of genetic changes found in human breast cancer fall into two categories: gain-of-function mutations in proto-oncogenes, which stimulate cell growth, division, and survival; and loss-of-function mutations in tumor suppressor genes that normally help prevent unrestrained cellular growth and promote DNA repair and cell cycle checkpoint activation. Epigenetic deregulation also contributes to the abnormal expression of these genes. For example, genes that encode enzymes involved in histone modification are mutated in primary renal cell carcinoma (Dalgliesh et al. 2010; van Haaften et al. 2009). In addition, the involvement of noncoding RNAs in tumorigenesis and tumor metastasis has been recently documented (Croce 2009; Shimono et al. 2009). These can act as oncogenes or tumor suppressor genes, depending on the context. Here, we discuss genes that are frequently altered in breast cancer, focusing on ErbB2, PI3K (phosphatidylinositol 3 kinase) pathways, TP53, BRCA1/2, and PTEN (phosphatase and tensin homolog deleted on chromosome 10). Genetically engineered mouse models are emphasized because these provide a wealth of biological information. We consider in detail genetic and biochemical studies that have shown that oncogenic proteins and tumor suppressors provide a critical balance in regulation of key pathways that control cell number and cell behavior.     

Immune and nonimmune mechanisms mediate the mental stress-induced tumor growth in a xenograft model of breast cancer

Excess mental stress may harm health, and even accelerate cancer initiation and progression. One fourth of breast cancer patients suffer mental stress including anxiety, sadness, or depression, which negatively affect prognosis and survival. However, the regulatory mechanism is yet to be determined. Herein, we applied unpredictable stress stimuli to the breast tumor-bearing mice to establish a xenograft model of breast cancer suffering mental stress, followed by behavioral tests, tumor growth tracking, immune analysis, miRNA screening, and tumor cell proliferation analysis as well. As a result, increased stress hormone levels in serum, decreased percentage of T and NK cells in both blood and tumor samples and accelerated tumor growth in vivo were observed in the mice exposed to mental stress. Promoted cell proliferation was observed in both primary tumor cells derived from the stressed mice and 4T1 breast cancer cells treated with stress hormone corticosterone. In addition, a subset of miRNAs including miR-326, 346, 493, 595, 615, and 665 were identified through a miRNA screening with downregulation in tumors of the stressed mice. CCND1 was identified as a common target gene of miR-346 and miR-493, the top two most significantly downregulated miRNAs by stress exposure. The stress-miRNA-CCND1 signaling regulation of the tumor cell proliferation was further validated in 4T1 cells treated with corticosterone in vitro. GO terms and KEGG pathways analyses on the target genes of miR-346 and miR-493 revealed their involvement in the regulation of human cancer and neuron system, indicating the importance of non-coding genome in mediating the mental stress-induced cancer regulation. In conclusion, this study not only explored immune and nonimmune mechanisms through which mental stress exposure contributes to tumor growth in breast cancer, but also suggested a new therapeutic strategy for cancer patients suffering mental stress.Subject terms: Breast cancer, Disease model, miRNAs     

Pre-Clinical Applications of Transgenic Mouse Mammary Cancer Models

Breast cancer is a leading cause of cancer morbidity and mortality. Given that the majority of human breast cancers appear to be due to non-genetic factors, identifying agents and mechanisms of prevention is key to lowering the incidence of cancer. Genetically engineered mouse models of mammary cancer have been important in elucidating molecular pathways and signaling events associated with the initiation, promotion, and the progression of cancer. Since several transgenic mammary models of human breast cancer progress through well-defined cancer stages, they are useful pre-clinical systems to test the efficacy of chemopreventive and chemotherapeutic agents. This review outlines several oncogenic pathways through which mammary cancer can be induced in transgenic models and describes several types of preventive and therapeutic agents that have been tested in transgenic models of mammary cancer. The effectiveness of farnesyl inhibitors, aromatase inhibitors, differentiating agents, polyamine inhibitors, anti-angiogenic inhibitors, and immunotherapeutic compounds including vaccines have been evaluated in reducing mammary cancer and tumor progression in transgenic models.     

Expression and function of the insulin receptor substrate proteins in cancer

The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do not contain any intrinsic kinase activity, but rather serve as scaffolds to organize signaling complexes and initiate intracellular signaling pathways. As common intermediates of multiple receptors that can influence tumor progression, the IRS proteins are positioned to play a pivotal role in regulating the response of tumor cells to many different microenvironmental stimuli. Limited studies on IRS expression in human tumors and studies on IRS function in human tumor cell lines and in mouse models have provided clues to the potential function of these adaptor proteins in human cancer. A general theme arises from these studies; IRS-1 and IRS-4 are most often associated with tumor growth and proliferation and IRS-2 is most often associated with tumor motility and invasion. In this review, we discuss the mechanisms by which IRS expression and function are regulated and how the IRS proteins contribute to tumor initiation and progression.     

TMEFF2 modulates the AKT and ERK signaling pathways

The transmembrane protein with epidermal growth factor (EGF) and two follistatin (FS) motifs 2 (TMEFF2) has a limited tissue distribution with strong expression only in brain and prostate. While TMEFF2 is overexpressed in prostate cancer indicating an oncogenic role, several studies indicate a tumor suppressor role for this protein. This dual mode of action is, at least in part, the result of metalloproteinase-dependent shedding that generates a soluble TMEFF2 ectodomain with a growth promoting function. While recent studies have shed some light on the biology of different forms of TMEFF2, little is known about the molecular mechanisms that influence its oncogenic/tumor suppressive function. In several non-prostate cell lines, it has been shown that a recombinant form of the TMEFF2 ectodomain can interact with platelet derived growth factor (PDGF)-AA to suppress PDGF receptor signaling and can promote ErbB4 and ERK1/2 phosphorylation. However, the role of the full length TMEFF2 in these pathways has not been examined. Using prostate cell lines, here we examine the role of TMEFF2 in ERK and Akt activation, two pathways implicated in prostate cancer progression and that have been shown to cross talk in several cancers. Our results show that different forms of TMEFF2 distinctly affect Akt and ERK activation and this may contribute to a different cellular response of either proliferation or tumor suppression.     

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.     

Hypoxia regulates cross-talk between Syk and Lck leading to breast cancer progression and angiogenesis

Hypoxia is a key parameter that controls tumor angiogenesis and malignant progression by regulating the expression of several oncogenic molecules. The nonreceptor protein-tyrosine kinases Syk and Lck play crucial roles in the signaling mechanism of various cellular processes. The enhanced expression of Syk in normal breast tissue but not in malignant breast carcinoma has prompted us to investigate its potential role in mammary carcinogenesis. Accordingly, we hypothesized that hypoxia/reoxygenation (H/R) may play an important role in regulating Syk activation, and Lck may be involved in this process. In this study, we have demonstrated that H/R differentially regulates Syk phosphorylation and its subsequent interaction and cross-talk with Lck in MCF-7 cells. Moreover, Syk and Lck play differential roles in regulating Sp1 activation and expressions of melanoma cell adhesion molecule (MelCAM), urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF) in response to H/R. Overexpression of wild type Syk inhibited the H/R-induced uPA, MMP-9, and VEGF expression but up-regulated MelCAM expression. Our data also indicated that MelCAM acts as a tumor suppressor by negatively regulating H/R-induced uPA secretion and MMP-9 activation. The mice xenograft study showed the cross-talk between Syk and Lck regulated H/R-induced breast tumor progression and further correlated with the expressions of MelCAM, uPA, MMP-9, and VEGF. Human clinical specimen analysis supported the in vitro and in vivo findings. To our knowledge, this is first report that the cross-talk between Syk and Lck regulates H/R-induced breast cancer progression and further suggests that Syk may act as potential therapeutic target for the treatment of breast cancer.     

CMTM家族成员在肿瘤细胞中的分子机制及潜在临床价值

恶性肿瘤已成为危害人类健康的重要杀手,针对肿瘤的研究也成为当今医学界的热点.含有MARVEL跨膜结构域的趋化素样因子基因家族(CKLF-like MARVEL transmembrane domain containing family of genes,CMTM family),原名人类趋化素样因子超家族(chemo...     

Wnt基因/Wnt信号通路与乳腺癌

Wnt蛋白是一组调控胚胎形成期间细胞间信号传导的高度保守的分泌信号分子.在过去的几年里,由Wnt蛋白触发的不同信号通路已经得到了详尽的研究.Wnt基因与Wnt信号通路组成分子的突变可引起发育缺陷,异常的Wnt信号传导可导致人类疾病包括肿瘤的发生.许多证据都表明,Wnt信号通路的失调与乳腺癌的发生发展密切相关.micro...