Hedgehog信号通路与肿瘤

Hedgehog信号通路在胚胎发育中细胞的生长分化、组织器官形成以及成体干细胞的维持和自稳态的保持等方面具有重要作用。同时,Hedgehog信号通路与Wnt信号通路、Notch信号通路等相互作用、密切联系,在肿瘤的发生、发展过程中也起到关键作用。论文综述了Hedgehog信号通路的作用机理,与其他信号通路、蛋白质因子的相互联系,以及在肿瘤研究中所关注的靶位点和小分子化合物抑制剂,对于癌症的预防和治疗具有一定的参考价值。     

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia

The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL⁺ CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL⁺ CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL⁺ cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL⁺ cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.     

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia

The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL⁺ CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL⁺ CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL⁺ cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL⁺ cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.     

Hippo-YAP信号通路在结直肠癌发生发展中的作用

结直肠癌是消化系统常见的恶性肿瘤,发生发展机制复杂。Hippo-YAP信号通路作为肿瘤抑制的一个重要信号通路,具有调节器官大小和维持细胞增殖与凋亡的动态平衡等功能。研究发现Hippo-YAP信号通路可以通过影响细胞的增殖、凋亡等从而参与结直肠癌的发生发展。本文就Hippo-YAP信号通路在结直肠癌中的作用及其机制进行综述。     

Epigenetic regulation of Wnt signaling pathway in urological cancer

Constitutive activation of the Wnt signaling pathway is a common feature of solid tumors and contributes to uncontrolled cell-growth and impaired differentiation. We hypothesized that gene silencing mediated through aberrant promoter methylation of upstream Wnt antagonist genes might result in β-catenin accumulation, resulting in constitutive Wnt activation. Wnt antagonist genes (SFRP1, WIF1, APC and CDH1) and CTNNB1 promoter methylation was examined in genomic DNA extracted from 12 urological cancer cell lines and correlated with CTNNB1 mRNA expression. Promoter methylation status was then assessed in 36 BCa, 30 PCa, 31 RCT, and normal bladder mucosa (15), prostate (10) and renal (5) tissue samples. Finally, CTNNB1 mRNA relative expression levels were correlated with Wnt antagonist gene methylation status in RCT. Methylation was found in at least one Wnt antagonist gene and the CTNNB1 promoter was unmethylated in all cancer cell lines tested. When gene methylation levels were compared between cancer cell lines with high and low CTNNB1 mRNA expression, a trend was found for increased CDH1 promoter methylation levels in the former. BCa and PCa tumors demonstrated high frequency of promoter methylation at all tested genes. In RCT, CTNNB1 was unmethylated in all cases and the overall frequency of promoter methylation at the remainder genes was lower. Interestingly, median CTNNB1 mRNA expression levels were significantly higher in RCTs methylated in at least one Wnt antagonist gene promoter. We concluded that epigenetic deregulation of Wnt pathway inhibitors may contribute to aberrant activation of Wnt signaling pathway in bladder, prostate and renal tumors.     

Epigenetic regulation of estrogen signaling in breast cancer

Estrogen signaling is mediated by ERα and ERβ in hormone dependent, breast cancer (BC). Over the last decade the implication of epigenetic pathways in BC tumorigenesis has emerged: cancer-related epigenetic modifications are implicated in both gene expression regulation, and chromosomal instability. In this review, the epigenetic-mediated estrogen signaling, controlling both ER level and ER-targeted gene expression in BC, are discussed: (1) ER silencing is frequently observed in BC and is often associated with epigenetic regulations while chemical epigenetic modulators restore ER expression and increase response to treatment;(2) ER-targeted gene expression is tightly regulated by co-recruitment of ER and both coactivators/corepressors including HATs, HDACs, HMTs, Dnmts and Polycomb proteins.     

Proteins of the Hedgehog signaling pathway as therapeutic targets against cancer

The Hedgehog pathway plays a crucial role in growth and patterning during embryonic development and is involved in stem cell maintenance and proliferation in adult tissues. Mutations that increase the overall activity of the pathway are often associated with a higher incidence of cancers. This article focuses on the mutations, misfoldings and deregulations of the Hedgehog pathway proteins that have been reported to be involved in different tumors, and on small molecules targeting these proteins shown to slow down the growth of certain tumors in various animal models. We propose that proteomics could be a powerful tool to identify new targets of the Hedgehog pathway, enabling the discovery of effective and novel treatments for cancers.     

Pathways and consequences: Hedgehog signaling in human disease

Signaling pathways that play a fundamental role during development are turning out to underlie many disease states when misregulated. Here, we review some of the recent findings in the Hedgehog (Hh) pathway and the role it plays in different human diseases. We present a summary of the diseases that result from the inactivation or inappropriate activation of the Hh pathway. The human phenotypes generally fit the findings in model organisms and help to identify some potential targets for therapy.     

IGF2: epigenetic regulation and role in development and disease

Insulin-like growth factor II (IGF2) is perhaps the most intricately regulated of all growth factors characterized to date. Its gene is imprinted – only one allele is active, depending on parental origin – and this pattern of expression is maintained epigenetically in almost all tissues. IGF2 activity is further controlled through differential expression of receptors and IGF-binding proteins (IGFBPs) that determine protein availability. This complex and multifaceted regulation emphasizes the importance of accurate IGF2 expression and activity. This review will examine the regulation of the IGF2 gene and what it has revealed about the phenomenon of imprinting, which is frequently disrupted in cancer. IGF2 protein function will be discussed, along with diseases that involve IGF2 overexpression. Roles for IGF2 in sonic hedgehog (Shh) signaling and angiogenesis will also be explored.     

Wnt signaling pathway in osteoporosis: Epigenetic regulation,interaction with other signaling pathways,and therapeutic promises

Wnt is a major signaling pathway involved in multifaceted roles of various biological processes. Bones are dynamic tissues which are able to remodel and maintain the tissue homeostasis. Wnt signaling cascade leads to the promotion of bone formation and suppression of bone resorption, leading to a balance in bone remodeling. Recent evidence has reinforced the inevitable role of Wnt signaling in osteoporosis. The complex genetic and epigenetic regulations of Wnt signaling factors and their interaction with other master signaling pathways such as TGF-β, BMP, PI3K/AKT, and Hedgehog outline their importance in diagnosis and treatment of osteoporosis. In this review, we highlighted the recent advances in function of Wnt signaling-related epigenetic regulation, different signaling pathways interacting with Wnt, and their roles in osteoporosis. Finally, we discussed novel promises in molecular targeted therapy of osteoporosis.     

间质表皮转化因子MET信号通路及其在肿瘤中的研究进展

间质表皮转化因子(Mesenchymal to epithelial transition factor,MET)蛋白作为一种受体酪氨酸激酶,通常存在于上皮细胞中,被HGF等配体激活后,能够参与调控细胞的增殖、凋亡、迁移侵袭和细胞形态等多种生物学功能。随着研究的深入,MET已被证实在多种恶性肿瘤中异常表达或基因扩增,其与肿瘤患者的预后有着密切的关系。因此,针对MET的抑制剂研究发展比较迅速,且其良好的抗肿瘤效果也得到了证实。本文结合目前本实验室的研究,对MET的结构、功能及其抑制剂研究的现状等进行了综述,为今后的研究者提供一个阶段性的数据资料。     

Multiple roles for Hedgehog signaling in zebrafish pituitary development

The endocrine-secreting lobe of the pituitary gland, or adenohypophysis, forms from cells at the anterior margin of the neural plate through inductive interactions involving secreted morphogens of the Hedgehog (Hh), fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) families. To better understand when and where Hh signaling influences pituitary development, we have analyzed the effects of blocking Hh signaling both pharmacologically (cyclopamine treatments) and genetically (zebrafish Hh pathway mutants). While current models state that Shh signaling from the oral ectoderm patterns the pituitary after placode induction, our data suggest that Shh plays a direct early role in both pituitary induction and patterning, and that early Hh signals comes from adjacent neural ectoderm. We report that Hh signaling is necessary between 10 and 15 h of development for induction of the zebrafish adenohypophysis, a time when shh is expressed only in neural tissue. We show that the Hh responsive genes ptc1 and nk2.2 are expressed in preplacodal cells at the anterior margin of the neural tube at this time, indicating that these cells are directly receiving Hh signals. Later (15-20 h) cyclopamine treatments disrupt anterior expression of nk2.2 and Prolactin, showing that early functional patterning requires Hh signals. Consistent with a direct role for Hh signaling in pituitary induction and patterning, overexpression of Shh results in expanded adenohypophyseal expression of lim3, expansion of nk2.2 into the posterior adenohypophysis, and an increase in Prolactin- and Somatolactin-secreting cells. We also use the zebrafish Hh pathway mutants to document the range of pituitary defects that occur when different elements of the Hh signaling pathway are mutated. These defects, ranging from a complete loss of the adenohypophysis (smu/smo and yot/gli2 mutants) to more subtle patterning defects (dtr/gli1 mutants), may correlate to human Hh signaling mutant phenotypes seen in Holoprosencephaly and other congenital disorders. Our results reveal multiple and distinct roles for Hh signaling in the formation of the vertebrate pituitary gland, and suggest that Hh signaling from neural ectoderm is necessary for induction and functional patterning of the vertebrate pituitary gland.     

Hedgehog signaling in gastrointestinal development and disease

The development of the gastrointestinal (GI) tract and its associated parenchymal organs depends on Hedgehog signals from the endoderm to the surrounding mesoderm. During development, Hedgehog signaling is essential for patterning the GI tract along anterior-posterior (A-P), dorsal-ventral (D-V), and radial axes, as well as in maintenance of stem cells. Our knowledge about these roles for Hedgehog signaling is derived from studies of developmental defects that result from disrupted or activated Hedgehog signaling in model organisms including mouse, chick, and frog. These studies provide evidence for distinct roles of specific Hedgehog ligands in GI development. Studies in model organisms have also elucidated how Hedgehog signaling may function in development and function of the GI tract in humans. Several diseases and congenital syndromes are known to result from genetic defects in Hedgehog signaling components, and this pathway may ultimately prove to be an important target for future diagnostic and therapeutic tools.