激活mGlu5通过MAPK信号通路调节肝癌细胞HepG2生长

代谢型谷氨酸受体5（mGlu5）与神经元存活及脑肿瘤发生关系密切.近年发现,mGlu5在肝组织中有表达,并且在肝的病理过程中发挥重要的调节作用.而 mGlu5 是否在肝癌中起作用,目前尚未见报道.本研究选用代谢型谷氨酸受体特异性激动剂二羟基苯甘氨酸(dihydroxyphenylglycine,DHPG)处理肝癌细胞HepG2,从而探讨激活mGlu5对肝癌细胞生长的影响及其机制.结果显示,激活mGlu5能够促进HepG2细胞生长,并激活ERK/JNK通路,抑制p38通路,进而激活转录因子CREB/Elk1和NF-κB.本文揭示了MAPK通路可能参与mGlu5对肝癌细胞生长的调控,为临床提供以mGlu5作为药物靶位点的肝癌治疗新思路.     

Ghrelin Affects Gastric Cancer Progression by Activating AMPK Signaling Pathway

Biochemical Genetics - As the endogenous ligand for the GH secretagogue receptor (GHSR), Ghrelin is aberrant expressed in multiple malignant carcinoma, and involved in regulating a number of...     

Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway

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HMGA2通过激活Wnt信号通路促进结直肠癌细胞增殖

目的:HMGA2(high-mobility group AT-hook 2)一个染色质蛋白,被报道在多种癌症中都发挥重要作用。本文研究染色体蛋白HMGA2对Wnt信号传递的影响,及对结直肠癌细胞增殖的影响。方法:本文通过q RT-PCR和免疫印迹法检测HMGA2在结直肠癌样本中m RNA和蛋白水平。用荧光素酶报告基因系统研究HMGA2对Wnt信号通路的作用。用细胞增殖实验检测HMGA2对结直肠癌细胞增殖的作用。结果:在我们检测的大部分结直肠癌样本里,HMGA2表达水平升高;HMGA2蛋白可上调Wnt信号通路荧光素酶报告基因TOPflash-luciferase的表达,并呈现剂量依赖的形式。降低HMGA2表达可抑制由Wnt3a、Dvl(Dishevelled)、Li Cl以及βcatenin(S37A)引起的TOPflash-luciferase报告基因表达上调作用。此外,SW480中过量表达HMGA2可以促进细胞增殖。结论:HMGA2在结直肠癌中表达升高,HMGA2在结直肠癌中通过增强Wnt信号来促进结直肠癌细胞的增殖。     

Nrf2/ARE信号通路与胃癌耐药关系的研究进展

胃癌是癌症死亡的第二大原因。化疗是胃癌治疗的主要方法之一,胃癌化疗失败的主要原因是对化疗药物的耐受。Nrf2/ARE信号通路与肿瘤耐药的关系是当前的研究热点。转录因子Nrf2作为抗氧化反应中的关键转录因子,可以与抗氧化反应元件ARE结合,正向调节II相解毒酶、抗氧化酶及某些药物转运泵基因等靶基因的表达,诱导胃癌耐药性的产生。该综述整理归纳了Nrf2/ARE信号通路与胃癌耐药之间的关系。     

RABEX-5 Is Upregulated and Plays an Oncogenic Role in Gastric Cancer Development by Activating the VEGF Signaling Pathway

RABEX-5, a guanine-nucleotide exchange factor (GEF) for RAB-5, is implicated in tumorigenesis and in the development of certain human cancers. Here, we report that RABEX-5 promotes tumor growth and the metastatic ability of gastric cancer cells both in vitro and in vivo. Expression of RABEX-5 is significantly higher in gastric cancer tissues and is associated with tumor size and lymph node metastasis. In addition, targeted silencing of RABEX-5 reduced gastric cancer cell proliferation and colony formation in vitro via the induction of a G0/G1 phase arrest, and stimulated gastric cancer cell apoptosis. Knockdown of RABEX-5 also inhibited wound healing, migration and the invasive abilities of gastric cancer cells. The results of in vivo animal experiments were also consistent with these in vitro findings. Silencing of RABEX-5 led to decreased expression of VEGF. These results indicate that RABEX-5 is upregulated and plays an oncogenic role in gastric cancer development by activating the VEGF signaling pathway.     

KiSS1 Inhibits Growth and Invasion of Osteosarcoma Cells through Inhibition of the MAPK Pathway

As a metastasis suppressor, KiSS1 has been implicated in numerous human cancers. However, recent studies have demonstrated that KiSS1 promotes tumor growth and metastasis in breast cancer, and it is unclear about the expression and function of KiSS1 in human osteosarcoma (OS). The aim of the present study was to investigate the role and molecular mechanisms of KiSS1 in human OS. The expression of KiSS1 was assessed by immunohistochemical assay using a tissue microarray procedure in forty cases of OS tissues. A gain-of-function approach was used to observe the effects of lentiviral vector-mediated overexpression of KiSS1 (Lv-KiSS1) on the biological behaviors including proliferative activities and invasive potential of OS MG-63 cells, indicated by MTT and Transwell assays, respectively. The results showed that the expression of KiSS1 protein in OS tissues was significantly lowered compared to that in adjacent non-cancerous tissues (42.5% vs 70.0%, P=0.023), and had negative correlation with distant metastases of the tumor (P=0.019). Overexpression of KiSS1 inhibited proliferation and invasion of OS cells with the decreased expression of p38 MAPK and matrix metalloproteinase-9 (MMP-9). Taken together, our findings indicate that the decreased expression of KiSS1 is correlated with distant metastasis of OS, and KiSS1 may function as a tumor suppressor in OS cells through inhibition of the MAPK pathway, suggesting that KiSS1 may serve as a potential therapeutic target for the treatment of cancer.Key words: KiSS1, osteosarcoma, growth, invasion     

Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway

Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4′-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell–targeted therapy.     

Sonic Hedgehog Signaling Pathway Supports Cancer Cell Growth during Cancer Radiotherapy

Tumor growth after radiotherapy is a commonly recognized cause of therapeutic failure. In this way, we examined tumor cell growth after radiotherapy by establishing a cancer cell growth model in vitro. We accomplished this model by seeding non-irradiated firefly luciferase2 and green fluorescent protein fusion gene (Fluc) labeled living cancer reporter cells onto a feeder layer of irradiated cancer cells. The living tumor cell growth was monitored by bioluminescence imaging. The living reporter cells grew faster when seeded onto lethally irradiated feeder cells than when seeded onto non-irradiated feeder cells or when seeded in the absence of feeder cells. We found that the expression levels of the Shh and Gli1 proteins, both of which are critical proteins in Sonic hedgehog (SHH) signaling, were increased after irradiation and that this expression was positively correlated with reporter cell growth. Moreover, the dying cell stimulation of living tumor cell growth was enhanced by the addition of SHH signaling agonists and inhibited by SHH signaling antagonists. SHH agonists also enhanced reporter cell growth in the absence of irradiated feeder cells, suggesting this mechanism plays a role in feeder cell growth stimulation. Given these results, we conclude that SHH signaling activation plays an important role during tumor repopulation after radiotherapy.     

Notch Pathway Is Activated by MAPK Signaling and Influences Papillary Thyroid Cancer Proliferation

Mutually exclusive genetic alterations in the RET, RAS, or BRAF genes, which result in constitutively active mitogen-activated protein kinase (MAPK) signaling, are present in about 70% of papillary thyroid carcinomas (PTCs). However, the effect of MAPK activation on other signaling pathways involved in oncogenic transformation, such as Notch, remains unclear. In this study, we tested the hypothesis that the MAPK pathway regulates Notch signaling and that Notch signaling plays a role in PTC cell proliferation. Conditional induction of MAPK signaling oncogenes RET/PTC3 or BRAF^T1799A in normal rat thyroid cell line mediated activation of Notch signaling, upregulating Notch1 receptor and Hes1, the downstream effector of Notch pathway. Conversely, pharmacological inhibition of MAPK reduced Notch signaling in PTC cell. Thyroid tumor samples from transgenic mice expressing BRAF^T1799A and primary human PTC samples showed high levels of Notch1 expression. Down-regulation of Notch signaling by γ-secretase inhibitor (GSI) or NOTCH1 RNA interference reduces PTC cell proliferation. Moreover, the combination of GSI with a MAPK inhibitor enhanced the growth suppression in PTC cells. This study revealed that RET/PTC and BRAF^T1799A activate Notch signaling and promote tumor growth in thyroid follicular cell. Taken together, these data suggest that Notch signaling may be explored as an adjuvant therapy for thyroid papillary cancer.     

Nitric Oxide Participates in the Induction of Brain Ischemic Tolerance via Activating ERK1/2 Signaling Pathways

The present study was undertaken to observe in vivo changes of expression and phosphorylation of ERK1/2 proteins during brain ischemic preconditioning and effects of inhibiting generation of nitric oxide (NO) on the changes to determine the role of ERKs in the involvement of NO participating in the acquired tolerance. Fifty-five Wistar rats were used. Brain ischemic preconditioning was performed with four-vessel occlusion for 3 min. Total ERK1/2 proteins and phospho-ERK1/2 in the CA1 hippocampus were assayed with Western immunoblot. Total ERK1/2 proteins did not change in period from 5 min to 5 days of reperfusion after preconditioning stimulus. While the level of phospho-ERK1/2 increased obviously to 223, 237, 300, 385 and 254% of sham level at times of 5 min, 2 h, 1, 3 and 5 days after preconditioning stimulus, respectively (P < 0.01). Administration of L-NAME, an inhibitor of NO synthase, 30 min prior to preconditioning stimulus failed to induce change in total ERK1/2 proteins (P > 0.05). However, phospho-ERK1/2 increased only to 138 and 176% of sham level at 2 h and 3 days after preconditioning stimulus, respectively, when animals were pretreated with L-NAME. The magnitudes of the increase were obviously low compared with those (237 and 385%) in animals untreated with L-NAME at corresponding time points (P < 0.01), which indicated that phosphorylation of ERK1/2 normally induced by preconditioning stimulus was blocked apparently by administration of L-NAME. The results suggested that phosphorylation of ERK1/2, rather than synthesis of ERK1/2 proteins, was promoted in brain ischemic preconditioning, and that the promotion was partly mediated by NO signal pathway.     

Vascular Endothelial Growth Factor-Receptor 1 Inhibition Aggravates Diabetic Nephropathy through eNOS Signaling Pathway in db/db Mice

The manipulation of vascular endothelial growth factor (VEGF)-receptors (VEGFRs) in diabetic nephropathy is as controversial as issue as ever. It is known to be VEGF-A and VEGFR2 that regulate most of the cellular actions of VEGF in experimental diabetic nephropathy. On the other hand, such factors as VEGF-A, -B and placenta growth factor bind to VEGFR1 with high affinity. Such notion instigated us to investigate on whether selective VEGFR1 inhibition with GNQWFI hexamer aggravates the progression of diabetic nephropathy in db/db mice.While diabetes suppressed VEGFR1, it did increase VEGFR2 expressions in the glomerulus. Db/db mice with VEGFR1 inhibition showed more prominent features with respect to, albuminuria, mesangial matrix expansion, inflammatory cell infiltration and greater numbers of apoptotic cells in the glomerulus, and oxidative stress than that of control db/db mice. All these changes were related to the suppression of diabetes-induced increases in PI3K activity and Akt phosphorylation as well as the aggravation of endothelial dysfunction associated with the inactivation of FoxO3a and eNOS-NOx. In cultured human glomerular endothelial cells (HGECs), high-glucose media with VEGFR1 inhibition induced more apoptotic cells and oxidative stress than did high-glucose media alone, which were associated with the suppression of PI3K-Akt phosphorylation, independently of the activation of AMP-activated protein kinase, and inactivation of FoxO3a and eNOS-NOx pathway. In addition, transfection with VEGFR1 siRNA in HGECs also suppressed PI3K-Akt-eNOS signaling.In conclusion, the specific blockade of VEGFR1 with GNQWFI caused severe renal injury related to profound suppression of the PI3K-Akt, FoxO3a and eNOS-NOx pathway, giving rise to the oxidative stress-induced apoptosis of glomerular cells in type 2 diabetic nephropathy.     

Inhibition of Liver Cancer Cell Growth by Triethylsilyl Resveratrol through Targeting Phosphoinositide-3 Kinase Pathway

Doklady Biochemistry and Biophysics - Liver cancer is one of the commonly detected malignancy and third highest cause of deaths caused by cancer worldwide. The current study investigated the effect...     

HCV core通过活化Wnt/β-catenin信号通路诱导肝前体细胞向肝癌干细胞分化

丙型病毒性肝炎（hepatitis C virus,HCV）慢性感染及肝前体细胞向肝癌干细胞分化是原发性肝癌(hepatocellular carcinoma,HCC)的重要致病因素。且Wnt信号参与维持肝癌干细胞特性,但HCV能否通过活化Wnt信号诱导肝前体细胞向肝癌干细胞分化尚不清楚。本室研究发现,在HCV core诱导分化的肝前体细胞中,HCV core抑制成熟肝细胞标志物Alb、CK18的表达,糖原储存能力显著下降（P<0.05）,且上调肝癌干细胞标志物EpCAM、CD133、CD44等表达。另外,HCV core增强β-联蛋白活性及表达水平,促使β-联蛋白向核内聚集,上调其下游靶基因EpCAM、细胞周期蛋白D1、C-myc的表达,沉默β-联蛋白后,Wnt/β-catenin通路其下游靶基因表达明显受到抑制,糖原储存能力部分恢复,荧光共聚焦显示HCV core与β-联蛋白在细胞核内存在共定位。因此,HCV core可能与β-联蛋白相互作用,直接活化Wnt/β-catenin通路,上调其下游靶基因EpCAM等表达,诱导肝前体细胞向肝癌干细胞分化。     

抑制Hedgehog信号通路改变结肠癌细胞基因表达谱

Hedgehog（Hh）信号通路在机体发育和肿瘤发生中发挥着重要作用。在该研究中,Western blot检测三株结肠癌细胞Hedgehog信号通路组分的表达,结果表明三株结肠癌细胞中HT-29细胞Hedgehog信号通路组分较完整。采用MTT和BrdU法检测Hedgehog信号通路膜受体Smo特异性抑制剂环杷明和末端转录因子Gli1/2的特异性抑制剂GANT61对HT-29细胞的影响,提示这两种抑制剂均显著抑制HT-29细胞生存率和细胞增殖率,且GANT61比环杷明更敏感。表达谱芯片检测阻断Hedgehog信号通路后HT-29细胞基因谱的变化,结合生物信息学分析,揭示HT-29细胞经环杷明和GANT61处理后基因表达呈现抑制特征,其差异基因表达主要以下调为主,其中环杷明主要影响细胞内源刺激等,而GANT61主要影响代谢和类固醇合成,并与MAPK信号通路有关联,两者均能影响细胞免疫及凋亡相关通路。这些结果提示,Hh信号通路有可能作为结肠癌的治疗靶点。     

MiR-942-3p as a Potential Prognostic Marker of Gastric Cancer Associated with AR and MAPK/ERK Signaling Pathway

Gastric cancer is a common tumor with high morbidity and mortality. MicroRNA (miRNA) can regulate gene expression at the translation level and various tumorigenesis processes, playing an important role in tumor occurrence and prognosis. This study aims to screen miRNA associated with gastric cancer prognosis as biomarkers and explore the regulatory genes and related signaling pathways. In this work, R language was used for the standardization and differential analysis of miRNA and mRNA expression profiles. Samples were randomly divided into a testing group and a training group. Subsequently, we built the five miRNAs (has-miR-9-3p, has-miR-135b-3p, has-miR-143-5p, has-miR-942-3p, has-miR-196-3p) prognostic modules, verified and evaluated their prediction ability by the Cox regression analysis. They can be used as an independent factor in the prognosis of gastric cancer. By predicting and analyzing potential biological functions of the miRNA target genes, this study found that the AR gene was not only a hub gene in the PPI network, but also associated with excessive survival of patients. In conclusion, this study demonstrated that hsa-miR-942-3p could be a potential prognostic marker of gastric cancer associated with the AR and MAPK/ERK signaling pathways. The results of this study provide insights into the occurrence and development of gastric cancer.