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Hedgehog信号通路调控骨形成及BMSCs成骨分化的研究进展
RESEARCH PROGRESS OF Hedgehog SIGNALING PATHWAY IN REGULATING BONE FORMATION AND OSTEOGENIC DIFFERENTIATION OF BONE MESENCHYMAL STEM CELLS
 [PDF]

迟博婧,刘光源,邢磊,田发明
- , 2016, DOI: 10.7507/1002-1892.20160318
Abstract: 目的综述Hedgehog信号通路对骨形成及BMSCs成骨分化的调控及其分子机制。 方法查阅近年来Hedgehog通路在体内、体外及离体研究中对骨形成及BMSCs成骨分化调控的相关文献,并对其作用机制进行分析总结。 结果Hedgehog信号通路在体外研究中可通过激活下游关键分子Smoothened(Smo)及Gli1促进BMSCs成骨分化,并可通过IGF激活mTORC2-Akt信号产生类似作用;Hedgehog信号特殊结构鞭毛内运输蛋白80通过激活经典Hh-Smo-Ptch1-Gli信号、抑制非经典Hh-Gαi-RhoA应力纤维信号,调节成骨细胞的分化;应用新型Hedgehog信号激动剂Oxy133可激活Hedgehog信号。Hedgehog信号还可协同BMP及Wnt信号通路调控成骨关键分子Runx2促进细胞的成骨分化和基质矿化,并在体内研究及骨移植模型中促进骨形成及骨缺损修复愈合。 结论Hedgehog信号通路通过对自身或对其他信号及关键分子的调节对骨形成及BMSCs成骨分化进行调控,对Hedgehog信号进行靶向调控或可作为治疗某些骨相关疾病(如骨质疏松症和骨折愈合)的潜在研究方向及新靶点。
ObjectiveTo summarize the research progress of the effects and mechanisms of Hedgehog signaling pathway in regulating bone formation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). MethodsThe related literature concerning the regulations and mechanism of Hedgehog signaling pathway in osteogenic differentiation of BMSCs and bone formation in vivo, in vitro, and ex vivo studies in recent years was analyzed and summarized. ResultsThe in vitro studies indicate that Hedgehog signaling pathway can promote osteogenic differentiation of BMSCs via activation of key molecules Smoothened (Smo) and Gli1 which are downstream of Hedgehog signaling, and Hedgehog signaling can activate mTORC2-Akt signaling by upregulation of insulin-like growth factor which has similar effects. Hedgehog signaling regulates osteoblast differentiation via activation of Hh-Smo-Ptch1-Gli signaling pathway and inhibition of Hh-Gαi-RhoA stress fibre signaling. Hedgehog signaling can regulate key molecules of osteogenesis Runx2 for promoting osteogenic differentiation and matrix mineralization by synergism of bone morphogenetic protein and Wnt signaling, and promotes bone formation and repair and healing for bone defect and bone graft model in vivo. ConclusionHedgehog signaling can regulate bone formation and osteogenic differentiation of BMSCs via activation of Hedgehog signaling and other signaling pathways. Hedgehog signaling pathway may be a potential target for developing treatment for bone related diseases of osteoporosis and fracture healing disorders.
Hedgehog Signaling Regulates Telomerase Reverse Transcriptase in Human Cancer Cells  [PDF]
Tapati Mazumdar, Ranjodh Sandhu, Maha Qadan, Jennifer DeVecchio, Victoria Magloire, Akwasi Agyeman, Bibo Li, Janet A. Houghton
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075253
Abstract: The Hedgehog (HH) signaling pathway is critical for normal embryonic development, tissue patterning and cell differentiation. Aberrant HH signaling is involved in multiple human cancers. HH signaling involves a multi-protein cascade activating the GLI proteins that transcriptionally regulate HH target genes. We have previously reported that HH signaling is essential for human colon cancer cell survival and inhibition of this signal induces DNA damage and extensive cell death. Here we report that the HH/GLI axis regulates human telomerase reverse transcriptase (hTERT), which determines the replication potential of cancer cells. Suppression of GLI1/GLI2 functions by a C-terminus truncated GLI3 repressor mutant (GLI3R), or by GANT61, a pharmacological inhibitor of GLI1/GLI2, reduced hTERT protein expression in human colon cancer, prostate cancer and Glioblastoma multiforme (GBM) cell lines. Expression of an N-terminus deleted constitutively active mutant of GLI2 (GLI2ΔN) increased hTERT mRNA and protein expression and hTERT promoter driven luciferase activity in human colon cancer cells while GANT61 inhibited hTERT mRNA expression and hTERT promoter driven luciferase activity. Chromatin immunoprecipitation with GLI1 or GLI2 antibodies precipitated fragments of the hTERT promoter in human colon cancer cells, which was reduced upon exposure to GANT61. In contrast, expression of GLI1 or GLI2ΔN in non-malignant 293T cells failed to alter the levels of hTERT mRNA and protein, or hTERT promoter driven luciferase activity. Further, expression of GLI2ΔN increased the telomerase enzyme activity, which was reduced by GANT61 administration in human colon cancer, prostate cancer, and GBM cells. These results identify hTERT as a direct target of the HH signaling pathway, and reveal a previously unknown role of the HH/GLI axis in regulating the replication potential of cancer cells. These findings are of significance in understanding the important regulatory mechanisms that determine the functions of HH/GLI signaling in cancer cells.
Akt Regulates Drug-Induced Cell Death through Bcl-w Downregulation  [PDF]
Michela Garofalo, Cristina Quintavalle, Ciro Zanca, Assunta De Rienzo, Giulia Romano, Mario Acunzo, Loredana Puca, Mariarosaria Incoronato, Carlo M. Croce, Gerolama Condorelli
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0004070
Abstract: Akt is a serine threonine kinase with a major role in transducing survival signals and regulating proteins involved in apoptosis. To find new interactors of Akt involved in cell survival, we performed a two-hybrid screening in yeast using human full-length Akt c-DNA as bait and a murine c-DNA library as prey. Among the 80 clones obtained, two were identified as Bcl-w. Bcl-w is a member of the Bcl-2 family that is essential for the regulation of cellular survival, and that is up-regulated in different human tumors, such as gastric and colorectal carcinomas. Direct interaction of Bcl-w with Akt was confirmed by immunoprecipitation assays. Subsequently, we addressed the function of this interaction: by interfering with the activity or amount of Akt, we have demonstrated that Akt modulates the amount of Bcl-w protein. We have found that inhibition of Akt activity may promote apoptosis through the downregulation of Bcl-w protein and the consequential reduction in interaction of Bcl-w with pro-apoptotic members of the Bcl-2 family. Our data provide evidence that Bcl-w is a new member of the Akt pathway and that Akt may induce anti-apoptotic signals at least in part through the regulation of the amount and activity of Bcl-w.
Sonic Hedgehog Signaling Inhibition Provides Opportunities for Targeted Therapy by Sulforaphane in Regulating Pancreatic Cancer Stem Cell Self-Renewal  [PDF]
Mariana Rodova, Junsheng Fu, Dara Nall Watkins, Rakesh K. Srivastava, Sharmila Shankar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046083
Abstract: Dysregulation of the sonic hedgehog (Shh) signaling pathway has been associated with cancer stem cells (CSC) and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN), an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway. Thus Sulforaphane potentially represents an inexpensive, safe and effective alternative for the management of pancreatic cancer.
Sonic Hedgehog and Notch Signaling Can Cooperate to Regulate Neurogenic Divisions of Neocortical Progenitors  [PDF]
Richa K. Dave,Tammy Ellis,Melissa C. Toumpas,Jonathan P. Robson,Elaine Julian,Christelle Adolphe,Perry F. Bartlett,Helen M. Cooper,Brent A. Reynolds,Brandon J. Wainwright
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014680
Abstract: Hedgehog (Hh) signaling is crucial for the generation and maintenance of both embryonic and adult stem cells, thereby regulating development and tissue homeostasis. In the developing neocortex, Sonic Hedgehog (Shh) regulates neural progenitor cell proliferation. During neurogenesis, radial glial cells of the ventricular zone (VZ) are the predominant neocortical progenitors that generate neurons through both symmetric and asymmetric divisions. Despite its importance, relatively little is known of the molecular pathways that control the switch from symmetric proliferative to differentiative/neurogenic divisions in neural progenitors.
MicroRNA-486-3p Regulates γ-Globin Expression in Human Erythroid Cells by Directly Modulating BCL11A  [PDF]
Valentina Lulli, Paolo Romania, Ornella Morsilli, Paolo Cianciulli, Marco Gabbianelli, Ugo Testa, Alessandro Giuliani, Giovanna Marziali
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060436
Abstract: MicroRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNAs target. The functional relevance of microRNAs has been proven in normal and malignant hematopoiesis. While analyzing miRNAs expression profile in unilineage serum-free liquid suspension unilineage cultures of peripheral blood CD34+ hematopoietic progenitor cells (HPCs) through the erythroid, megakaryocytic, granulocytic and monocytic pathways, we identified miR-486-3p as mainly expressed within the erythroid lineage. We showed that miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3′UTR. Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of γ-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced γ-globin expression. Thus, miR-486-3p regulating BCL11A expression might contributes to fetal hemoglobin (HbF) modulation and arise the question as to what extent this miRNA might contribute to different HbF levels observed among β-thalassemia patients. Erythroid cells, differentiated from PB CD34+ cells of a small cohort of patients affected by major or intermedia β-thalassemia, showed miR-486-3p levels significantly higher than those observed in normal counterpart. Importantly, in these patients, miR-486-3p expression correlates with increased HbF synthesis. Thus, our data indicate that miR-486-3p might contribute to different HbF levels observed among thalassemic patients and, possibly, to the clinical severity of the disease.
Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover  [PDF]
Shoujun Huang equal contributor,Zhao Zhang equal contributor,Chunxia Zhang equal contributor,Xiangdong Lv equal contributor,Xiudeng Zheng,Zhenping Chen,Liwei Sun,Hailong Wang,Yuanxiang Zhu,Jing Zhang,Shuyan Yang,Yi Lu,Qinmiao Sun,Yi Tao,Feng Liu,Yun Zhao ,Dahua Chen
PLOS Biology , 2013, DOI: 10.1371/journal.pbio.1001721
Abstract: Hedgehog signaling plays conserved roles in controlling embryonic development; its dysregulation has been implicated in many human diseases including cancers. Hedgehog signaling has an unusual reception system consisting of two transmembrane proteins, Patched receptor and Smoothened signal transducer. Although activation of Smoothened and its downstream signal transduction have been intensively studied, less is known about how Patched receptor is regulated, and particularly how this regulation contributes to appropriate Hedgehog signal transduction. Here we identified a novel role of Smurf E3 ligase in regulating Hedgehog signaling by controlling Patched ubiquitination and turnover. Moreover, we showed that Smurf-mediated Patched ubiquitination depends on Smo activity in wing discs. Mechanistically, we found that Smo interacts with Smurf and promotes it to mediate Patched ubiquitination by targeting the K1261 site in Ptc. The further mathematic modeling analysis reveals that a bidirectional control of activation of Smo involving Smurf and Patched is important for signal-receiving cells to precisely interpret external signals, thereby maintaining Hedgehog signaling reliability. Finally, our data revealed an evolutionarily conserved role of Smurf proteins in controlling Hh signaling by targeting Ptc during development.
Apoptosis and gastric carcinogenesis: Immunohistochemical analysis of Bax and Bcl-2 proteins  [cached]
P. Chatzipantelis,P. Konstantinou,D. Voros,V. Smyrniotis
Annals of Gastroenterology , 2007,
Abstract: Aim: Our aim was to evaluate the role of Bax and Bcl-2 apoptosis- related proteins in the carcinogenesis of the stomach. Materials and Methods: 80 biopsy specimens and 50 surgical specimens of chronic gastritis, atrophic gastritis, intestinal metaplasia, gastric dysplasia and gastric cancer were studied. Routine hematoxyline and eosin sections were evaluated and classified according to the latest diagnostic criteria. Immunohistochemical methods were used for detection of Bax and Bcl-2. Results: The expression of Bax in precancerous lesions and in gastric cancer was distributed as follows: chronic gastritis 100% (80/80 cases), atrophic gastritis 60% (39/65 cases), intestinal metaplasia 55% (28/50 cases), dysplasia 25% (10/40 cases), intestinal type adenocarcinoma 40% (12/30 cases), and diffuse type adenocarcinoma 15% (3/20 cases). Bcl-2 expression was as follows: chronic gastritis 0%, atrophic gastritis 35% (23/65 cases), intestinal metaplasia 90% (45/50 cases), dysplasia 100% (40/40 cases), intestinal type adenocarcinoma 83.3% (25/30 cases), and diffuse type adenocarcinoma 70% (14/20 cases). Conclusions: Our findings demonstrate the high expression of Bcl-2 in precancerous lesions (intestinal metaplasia, dysplasia) and in gastric cancer; at the same time the suppression of Bax in these diseases is evident. This highlights the major role of Bcl-2 and the contradicting role of Bax in early carcinogenesis. Key Words: apoptosis, gastric carcinogenesis, Bax, Bcl-2
Expression of apoptosis related genes bax, bcl-2 and bcl-X in human gastric cancer: early results of an investigation  [cached]
Domenico D'Ugo,Riccardo Ricci,Stefania Boccia,Roberto Persiani
Italian Journal of Public Health , 2005, DOI: 10.2427/5991
Abstract: Background. Evidences indicate an involvement of apoptosis related genes in gastric carcinogenesis. We studied the gene and protein expression patterns of bcl-2, bax and bcl-X in samples of gastric adenocarcinoma. The apoptotic index values, histological type, differentiation grade, cancer stage and lymph node status were statistically analysed for possible correlations with expressional data. Methods. Thirty specimens of gastric cancer and respective normal control gastric mucosa were collected from patients with the diagnosis of gastric adenocarcinoma who underwent a curative gastrectomy. bcl-2, bax and bcl-XL mRNA and protein levels were respectively determined by reverse transcription PCR (RT-PCR) and western blot using monoclonal antibodies for immunodetection. Results and conclusions.We observed a significant suppression of bax with an increase of bcl-XL at protein and mRNA levels. The presence of lymph node metastases was statistically related to the loss of bax overexpression. Bcl-XL was mostly up-regulated in intestinal/mixed types of gastric carcinoma. The expression patterns described confirm the role for these apoptosis genes in gastric adenocarcinoma.
Mutations in the Hedgehog Pathway Genes SMO and PTCH1 in Human Gastric Tumors  [PDF]
Xi-De Wang, Hector Inzunza, Han Chang, Zhenhao Qi, Beihong Hu, Daniel Malone, John Cogswell
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054415
Abstract: The causal role of the hedgehog pathway in cancer has been best documented in basal cell carcinoma of the skin. To assess potential DNA alterations of the hedgehog pathway in gastric cancer, we sequenced SMO and PTCH1 genes in a set of 39 gastric tumors. Tumors were classified by histology based on the Lauren classification and Sanger sequencing was performed to obtain full length coding sequences. Genomic instability was evident in these tumors as a number of silent or missense mutations were found. In addition to those that are potential germline polymorphisms, we found three SMO missense mutations, and one PTCH1 frameshift mutation that are novel and have not been documented in basal cell carcinoma. Mutations were found in both intestinal and diffuse type gastric tumors as well as in tumors that exhibit both intestinal and diffuse features. mRNA expression of hedgehog pathway genes was also examined and their levels do not indicate unequivocal higher pathway activity in tumors with mutations than those without. In summary, SMO and/or PTCH1 mutations are present at low frequency in different histologic subtypes of gastric tumors and these do not appear to be driver mutations.
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