MiR-27a-3p enhances the cisplatin sensitivity in hepatocellular carcinoma cells through inhibiting PI3K/Akt pathway

MicroRNAs (miRNAs) play an important role in drug resistance, and it is reported that miR-27a-3p regulated the sensitivity of cisplatin in breast cancer, lung cancer and ovarian cancer. However, the relationship between miR-27a-3p and chemosensitivity of cisplatin in hepatocellular carcinoma (HCC) was unclear, especially the underlying mechanism was unknown. In the present study, we analyzed miR-27a-3p expression levels in 372 tumor tissues and 49 adjacent tissues in HCC samples from TCGA database, and found that the miR-27a-3p was down-regulated in HCC tissues. The level of miR-27a-3p was associated with metastasis, Child–Pugh grade and race. MiR-27a-3p was regarded as a favorable prognosis indicator for HCC patients. Then, miR-27a-3p was overexpressed in HepG2 cell, and was knocked down in PLC cell. Next, we conducted a series of in vitro assays, including MTT, apoptosis and cell cycle assays to observe the biological changes. Further, inhibitor rate and apoptosis rate were detected with pre- and post-cisplatin treatment in HCC. The results showed that overexpression of miR-27a-3p repressed the cell viability, promoted apoptosis and increased the percentage of cells in G₀/G₁ phase. Importantly, overexpression of miR-27a-3p significantly increased the inhibitor rate and apoptosis rate with cisplatin intervention. Besides, we found that miR-27a-3p added cisplatin sensitivity potentially through regulating PI3K/Akt signaling pathway. Taken together, miR-27a-3p acted as a tumor suppressor gene in HCC cells, and it could be useful for modulating cisplatin sensitivity in chemotherapy.     

过表达微小RNA-130a-3P对LPS诱导心肌细胞损伤的干预作用及其机制*

目的: 探讨miRNA-130a-3p对脂多糖(LPS)诱导的心肌细胞自噬与凋亡的影响及分子机制。方法: H9C2心肌细胞随机分为5组,即正常对照组,LPS模型组,miRNA阴性对照组(miRNA-negative control组),miRNA-130a-3p mimics组(过表达miRNA-130a-3p),miRNA-130a-3p mimics+LY294002组(过表达miRNA-130a-3p + PI3K抑制)。LPS模型组即终浓度为10 μg/ml的LPS诱导24 h,miRNA阴性对照组与miRNA-130a-3p mimics组是利用lipo3000将阴性对照miRNA及miRNA-130a-3p mimics转染至H9C2细胞,培养24 h后,再将LPS加入培养基中培养24 h。miRNA-130a-3p mimics + LY294002组是利用lipo3000将miRNA-130a-3p mimics转染至H9C2细胞,同时在培养基中加入10 μmol/L(终浓度)的LY294002,培养24 h后,再将浓度为10 μg/ml的LPS加入培养基中培养24 h。所有实验均重复5次以上。利用RT-qPCR检测细胞中miRNA-130a-3p mRNA的表达水平,利用CCK-8实验检测细胞活性,利用ELISA实验检测细胞培养液中肿瘤坏死因子-α(TNF-α),白细胞介素-6(IL-6),白细胞介素-1β (IL-1β)的含量,利用比色法检测细胞培养液中超氧化物歧化酶(SOD)、乳酸脱氢酶(LDH)的含量;利用Western blot检测细胞中p-PI3K蛋白,p-AKT蛋白,Bax蛋白,Bcl-2蛋白,cleaved-caspase-3蛋白,LC3蛋白,p62蛋白的表达水平。结果: 结果显示,与正常组相比较,LPS模型细胞中miRNA-130a-3p mRNA水平,p-PI3K蛋白与p-AKT蛋白的水平显著低于正常对照组(P<0.01);与LPS组相比较,miRNA-130a-3p mimics组细胞中p-PI3K,p-AKT蛋白的表达显著升高(P<0.01,P<0.05);与正常对照组相比较,LPS组细胞活性显著降低,细胞培养液中TNF-α,IL-6,IL-1β及 LDH的含量显著升高(P<0.01), SOD的含量显著降低(P<0.01),细胞中Bax蛋白,cleaved caspase-3蛋白,p62蛋白的表达显著升高(P<0.01),Bcl-2蛋白的表达和LC3II/I的比率显著降低(P<0.01);与LPS组相比较,miRNA-130a-3p mimics可提高细胞活性,降低细胞培养液中TNF-α,IL-6,IL-1β及LDH的含量(P<0.01,P<0.05),提高SOD的含量(P<0.05),降低细胞中Bax蛋白,cleaved caspase-3蛋白,p62蛋白的表达(P<0.01),促进Bcl-2蛋白的表达(P<0.01),提高LC3II/I的比率(P<0.05);与miRNA-130a-3p mimics组相比较,miRNA-130a-3p mimics+LY294002组,可部分逆转miRNA-130a-3p mimics对细胞的作用。结论: 过表达miRNA-130a-3p可部分通过激活PI3K/AKT信号通路促进细胞的自噬与抑制细胞凋亡,减轻LPS诱导的心肌细胞损伤。     

Placenta-derived exosomal miR-135a-5p promotes gestational diabetes mellitus pathogenesis by activating PI3K/AKT signalling pathway via SIRT1

Most people are aware of gestational diabetes mellitus (GDM), a dangerous pregnancy complication in which pregnant women who have never been diagnosed with diabetes develop chronic hyperglycaemia. Exosomal microRNA (miRNA) dysregulation has been shown to be a key player in the pathophysiology of GDM. In this study, we looked into how placental exosomes and their miRNAs may contribute to GDM. When compared to exosomes from healthy pregnant women, it was discovered that miR-135a-5p was elevated in placenta-derived exosomes that were isolated from the maternal peripheral plasma of GDM women. Additionally, we discovered that miR-135a-5p encouraged HTR-8/SVneo cell growth, invasion and migration. Further research revealed that miR-135a-5p activates HTR-8/SVneo cells' proliferation, invasion and migration by promoting PI3K/AKT pathway activity via Sirtuin 1 (SIRT1). The transfer of exosomal miR-135a-5p generated from the placenta could be viewed as a promising agent for targeting genes and pertinent pathways involved in GDM, according to our findings.     

Erianin induces triple-negative breast cancer cells apoptosis by activating PI3K/Akt pathway

Background: Triple-negative breast cancer (TNBC) is a refractory subtype of breast cancer, 25–30% of which have dysregulation in the PI3K/AKT pathway. The present study investigated the anticancer effect of erianin on TNBC cell line and its underlying mechanism.Methods: After treatment with erianin, MTT assay was employed to determine the MDA-MB-231 and EFM-192A cell proliferation, the nucleus morphological changes were observed by DAPI staining. The cell cycle and apoptotic proportion were detected by flow cytometry. Western blot was performed to determine the cell cycle and apoptosis-related protein expression and PI3K pathways. Finally, the antiproliferative activity of erianin was further confirmed by adding or not adding PI3K agonists SC79.Results: Erianin inhibited the proliferation of MDA-MB-231 and EFM-192A cells in a dose-dependent manner, the IC₅₀ were 70.96 and 78.58 nM, respectively. Erianin could cause cell cycle arrest at the G₂/M phase, and the expressions of p21 and p27 were up-regulated, while the expressions of CDK1 and Cyclin B1 were down-regulated. Erianin also induced apoptosis via the mitochondrial pathway, with the up-regulation of the expression of Cyto C, PARP, Bax, active form of Caspase-3, and Caspase-9. Furthermore, p-PI3K and p-Akt expression were down-regulated by erianin. After co-incubation with SC79, the cell inhibition rate of erianin was decreased, which further confirmed that the attenuated PI3K/Akt pathway was relevant to the pro-apoptotic effect of erianin.Conclusions: Erianin can inhibit the proliferation of TNBC cells and induce cell cycle arrest and apoptosis, which may ascribe to the abolish the activation of the PI3K/Akt pathway.     

Autophagy participates in the protection role of 1,25-dihydroxyvitamin D3 in acute myocardial infarction via PI3K/AKT/mTOR pathway

Vitamin D deficiency is associated with acute myocardial infarction (AMI); thus we aimed to explore improvement effects of 1,25-dihydroxyvitamin D3 (VD3) on the AMI and its potential mechanism. AMI models were constructed using male C57/BL6J mice and randomly treated with normal saline or VD3, using sham rats as control. Heart functions, myocardial damage, apoptosis, and inflammation were evaluated. Cardiomyocytes isolated from 3-day-old suckling mice were used for in vitro verification. After VD3 treatment, AMI-induced cardiac dysfunction was reversed with better cardiac function parameters. VD3 treatment reduced inflammatory cell infiltration and myocardial infarction area accompanied by the reduction of inflammatory factors and myocardial infarction markers compared with the AMI group. VD3 treatment obviously alleviated AMI-induced myocardial apoptosis, along with Bcl-2 upregulation and downregulation of caspase-3, caspase-9, and Bax. Both in vivo and in vitro experiments revealed that VD3 enhanced the expression of LC3II and Beclin-1 and decreased soluble p62. Furthermore, VD3 enhanced the AMI-caused inhibition of PI3K, p-AKT, and p-mTOR expression, which was conversely reversed by the addition of 3-methyladenine in vitro. The study highlights the improvement effects of VD3 on cardiac functions. We proposed a potential mechanism that VD3 protects against myocardial damage, inflammation, and apoptosis by promoting autophagy through PI3K/AKT/mTOR pathway.     

Annexin A3 gene silencing promotes myocardial cell repair through activation of the PI3K/Akt signaling pathway in rats with acute myocardial infarction

Acute myocardial infarction (AMI), as a severe consequence of coronary atherosclerotic heart disease, always contributes to the loss of myocardial cells. Mounting evidence shows that annexin protects the myocardium from ischemic injury. In this study, we examine the inhibition of annexin A3 (ANXA3) on AMI through the phosphatidylinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. We selected rats to build an AMI model which was then assigned into different groups. The hemodynamic parameters after transfection were detected by using enzyme-linked immunosorbent assay. The effect of silencing of ANXA3 on inflammatory reaction and the PI3K/Akt signaling pathway was assessed. Rats transfected with ANXA3-short hairpin RNA had alleviated hemodynamics, inflammatory reaction, decreased infarct size, α-smooth muscle actin, Collagen I, and Collagen III as well as an increased vascular endothelial growth factor. Silencing ANAX3 would promote repair and healing of myocardial tissue by activation of the PI3K/Akt signaling pathway. Collectively, our study provides evidence that the downregulation of ANXA3 promotes the repair and healing of myocardial tissues by activating the PI3K/Akt signaling pathway.     

Duvelisib attenuates bleomycin-induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K-δ and PI3K-γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose-dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.     

Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway

Nicorandil exerts myocardial protection through its antihypoxia and antioxidant effects. Here, we investigated whether it plays an anti‐apoptotic role in diabetic cardiomyopathy. Sprague‐Dawley rats were fed with high‐fat diet; then single intraperitoneal injection of streptozotocin was performed. Rats with fasting blood glucose (FBG) higher than 11.1 mmol/L were selected as models. Eight weeks after the models were built, rats were treated with nicorandil (7.5 mg/kg day and 15 mg/kg day respectively) for 4 weeks. H9c2 cardiomyocytes were treated with nicorandil and then stimulated with high glucose (33.3 mmol/L). TUNEL assay and level of bcl‐2, bax and caspase‐3 were measured. 5‐HD was used to inhibit nicorandil. Also, PI3K inhibitor (Miltefosine) and mTOR inhibitor (rapamycin) were used to inhibit PI3K/Akt pathway. The results revealed that nicorandil (both 7.5 mg/kg day and 15mg/kg day) treatment can increase the level of NO in the serum and eNOS in the heart of diabetic rats compared with the untreated diabetic group. Nicorandil can also improve relieve cardiac dysfunction and reduce the level of apoptosis. In vitro experiments, nicorandil (100 µmol) can attenuate the level of apoptosis stimulated by high glucose significantly in H9C2 cardiomyocyte compared with the untreated group. The effect of nicorandil on apoptosis was blocked by 5‐HD, and it was accompanied with inhibition of the phosphorylation of PI3K, Akt, eNOS, and mTOR. After inhibition of PI3K/Akt pathway, the protective effect of nicorandil is restrained. These results verified that as a NO donor, nicorandil can also inhibit apoptosis in diabetic cardiomyopathy which is mediated by PI3K/Akt pathway.     

α‐Lipoic acid inhibits sevoflurane‐induced neuronal apoptosis through PI3K/Akt signalling pathway

Sevoflurane is a widely used anaesthetic agent, including in anaesthesia of children and infants. Recent studies indicated that the general anaesthesia might cause the cell apoptosis in the brain. This issue raises the concerns about the neuronal toxicity induced by the application of anaesthetic agents, especially in the infants and young children. In this study, we used Morris water maze, western blotting and immunohistochemistry to elucidate the role of α‐lipoic acid in the inhibition of neuronal apoptosis. We found that sevoflurane led to the long‐term cognitive impairment in the young rats. This adverse effect may be caused by the neuronal death in the hippocampal region, mediated through PI3K/Akt signalling pathway. We also showed that α‐lipoic acid offset the effect of sevoflurane on the neuronal apoptosis and cognitive dysfunction. This study elucidated the potential clinical role of α‐lipoic acid, providing a promising way in the prevention and treatment of long‐term cognitive impairment induced by sevoflurane general anesthesia. Copyright © 2016 John Wiley & Sons, Ltd.     

Calcium and integrin binding protein 1 (CIB1) induces myocardial fibrosis in myocardial infarction via regulating the PI3K/Akt pathway

Myocardial infarction (MI) is a severe coronary artery disease resulted from substantial and sustained ischemia. Abnormal upregulation of calcium and integrin binding protein 1 (CIB1) has been found in several cardiovascular diseases. In this study, we established a mouse model of MI by permanent ligation of the left anterior descending coronary artery. CIB1 was upregulated in the heart of MI mice. Notably, CIB1 knockdown by intramuscular injection of lentivirus-mediated short hairpin RNA (shRNA) targeting Cib1 improved cardiac function and attenuated myocardial hypertrophy and infarct area in MI mice. MI-induced upregulation of α-SMA, vimentin, Collagen I, and Collagen III, which resulted in collagen production and myocardial fibrosis, were regressed by CIB1 silencing. In vitro, cardiac fibroblasts (CFs) isolated from mice were subjected to angiotensin II (Ang II) treatment. Inhibition of CIB1 downregulated the expression of α-SMA, vimentin, Collagen I, and Collagen III in Ang II-treated CFs. Moreover, CIB1 knockdown inhibited Ang II-induced phosphorylation of PI3K-p85 and Akt in CFs. The effect of CIB1 knockdown on Ang II-induced cellular injury was comparable to that of LY294002, a specific inhibitor of the PI3K/Akt pathway. We demonstrated that MI-induced cardiac hypertrophy, myocardial fibrosis, and cardiac dysfunction might be attributed to the upregulation of CIB1 in MI mice. Downregulation of CIB1 alleviated myocardial fibrosis and cardiac dysfunction by decreasing the expression of α-SMA, vimentin, Collagen I, and Collagen III via inhibiting the PI3K/Akt pathway. Therefore, CIB1 may be a potential target for MI treatment.     

Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells

We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose‐ and time‐dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in magnolol‐treated cells. Treatment of PC‐3 cells with an apoptosis‐inducing concentration of magnolol (60 µM) resulted in a rapid decrease in the level of phosphorylated Akt leading to inhibition of its kinase activity. Magnolol treatment (60 µM) also caused a decrease in Ser(¹³⁶) phosphorylation of Bad (a proapoptotic protein), which is a downstream target of Akt. Protein interaction assay revealed that Bcl‐xL, an anti‐apoptotic protein, was associated with Bad during treatment with magnolol. We also observed that during treatment with magnolol, translocation of Bax to the mitochondrial membrane occurred and the translocation was accompanied by cytochrome c release, and cleavage of procaspase‐8, ‐9, ‐3, and poly(ADP‐ribose) polymerase (PARP). Similar results were observed in human colon cancer HCT116Bax^+/? cell line, but not HCT116Bax^?/? cell line. Interestingly, at similar concentrations (60 µM), magnolol treatment did not affect the viability of normal human prostate epithelial cell (PrEC) line. We also observed that apoptotic cell death by magnolol was associated with significant inhibition of pEGFR, pPI3K, and pAkt. These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)‐mediated signaling transduction pathways. J. Cell. Biochem. 106: 1113–1122, 2009. © 2009 Wiley‐Liss, Inc.     

Duvelisib attenuates bleomycin‐induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K‐δ and PI3K‐γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin‐induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin‐induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose‐dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.     

Resveratrol suppresses the epithelial-to-mesenchymal transition in PC-3 cells by down-regulating the PI3K/AKT signaling pathway

Resveratrol possesses a wide spectrum of pharmacological properties and has been an ideal alternative drug for the treatment of different cancers, including prostate cancer. However, the mechanisms by which resveratrol inhibits the growth of prostate cancer are still not fully elucidated. To understand the effect of resveratrol on the apoptosis and the epithelial-to-mesenchymal transition (EMT) of prostate cancer as well as its related mechanism, we investigated the potential use of resveratrol in PC-3 prostate cancer cells in vitro using real-time PCR, fluorescence-activated cell sorting, Western blotting, etc. Resveratrol suppresses the PC-3 prostate cancer cell growth and induces apoptosis. Resveratrol also influences the expression of EMT-related proteins (increased E-cadherin and decreased Vimentin expression). Finally, resveratrol also suppressed Akt phosphorylation in PC-3 cells. This study indicates that resveratrol may be a potential anti-cancer treatment for prostate cancer; moreover, it provides new evidence that resveratrol suppresses prostate cancer growth and metastasis.     

Germacrone improves liver fibrosis by regulating the PI3K/AKT/mTOR signalling pathway

Liver fibrosis is a primary threat to public health, owing to limited therapeutic options. Germacrone (GM) has been shown to exert various curative effects against human diseases, including liver injury. The aim of this study was to investigate the pharmacological effects of GM in the pathophysiology of hepatic fibrosis and determine its potential mechanisms of action. A liver fibrosis rat model was established via carbon tetrachloride (CCl₄) treatment, and LX-2 cells were stimulated with TGF-β1. The effects of GM on liver fibrosis and its relationship with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway were investigated. In the CCl₄ fibrosis-induced rat model, GM improved histological damage, inhibited the activity of hepatic α-smooth muscle actin and improved serum alanine aminotransferase and aspartate aminotransferase levels in a dose-dependent manner. GM potently inhibited hepatic stellate cells (HSCs) growth and epithelial–mesenchymal transition (EMT) progression, as reflected by the altered expression of proliferative (Ki-67, PCNA and cleaved caspase-3) and EMT-related (E-cadherin and vimentin) proteins. In TGF-β1-stimulated LX-2 cells, GM significantly inhibited the survival and activation of HSCs and induced cell apoptosis. GM also suppressed the migration ability and reversed the EMT process in HSCs. Following GM treatment, the phosphorylation of the PI3K, AKT and mTOR proteins was reduced in the liver of CCl₄-treated rats and TGF-β1-stimulated LX-2 cells, indicating that GM may attenuate hepatic fibrosis via the PI3K/AKT/mTOR signalling pathway. These outcomes highlight the anti-fibrotic effects of GM and suggest that it is a potential therapeutic agent for the treatment of liver fibrosis.     

RhoGDI2与PI3K/Akt/mTOR信号通路在肺癌细胞中的相关性研究

目的探讨肿瘤转移相关因子RhoGDI2与PI3K/Akt/mTOR信号通路在肺癌侵袭转移过程中的作用及相关机制。方法利用PI3K/Akt/mTOR信号通路上特异性的抑制剂,采用MTT法,伤口愈合实验及侵袭实验观察不同浓度药物对肺癌95D细胞生长侵袭转移能力的影响,通过Western Blot方法观察RhoGDI2蛋白水平的变化。结果PI3K抑制剂LY294002及mTOR抑制剂Rapamycin都能抑制肺癌细胞95D的侵袭转移能力,联合应用抑制作用更强。PI3K抑制剂LY294002处理组RhoGDI2蛋白的表达量增加,且随浓度增加RhoGDI2蛋白表达也增加。mTOR抑制剂Rapamycin组,在低浓度时增加RhoGDI2蛋白的表达,但增大Rapamycin的浓度,RhoGDI2蛋白的表达反而降低。低浓度LY294002组和Rapa-mycin组联合应用可以明显增加RhoGDI2蛋白的表达。结论PI3K/Akt/mTOR信号通路中Akt的活化与RhoGDI2密切相关,RhoGDI2可能直接或间接通过与Akt的相互作用参与调节肺癌的侵袭转移的过程。     

Surface chemistry induces mitochondria-mediated apoptosis of breast cancer cells via PTEN/PI3K/AKT signaling pathway

Tumor cell can be significantly influenced by various chemical groups of the extracellular matrix proteins. However, the underlying molecular mechanisms involved in the interaction between cancer cells and functional groups in the extracellular matrix remain unknown. Using chemically modified surfaces with biological functional groups (CH₃, NH₂, OH), it was found that hydrophobic surfaces modified with CH₃ and NH₂ suppressed cell proliferation and induced the number of apoptotic cells. Mitochondrial dysfunction, cytochrome c release, Bax upregulation, cleaved caspase-3 and PARP, and Bcl-2 downregulation indicated that hydrophobic surfaces with CH₃ and NH₂ triggered the activation of intrinsic apoptotic signaling pathway. Cells on the CH₃- and NH₂-modified hydrophobic surfaces showed downregulated expression and activation of integrin β1, with a subsequent decrease of focal adhesion kinase (FAK) activity. The RhoA/ROCK/PTEN signaling was then activated to inhibit the phosphorylation of PI3K and AKT, which are essential for cell proliferation. However, pretreatment of MDA-MB-231 cells with SF1670, a PTEN inhibitor, abolished the hydrophobic surface-induced activation of the intrinsic pathway. Taken together, the present results indicate that CH₃- and NH₂-modified hydrophobic surfaces induce mitochondria-mediated apoptosis by suppressing the PTEN/PI3K/AKT pathway, but not OH surfaces. These findings are helpful to understand the interaction between extracellular matrix and cancer cells, which might provide new insights into the mechanism potential intervention strategies for tumor prognosis.     

GHR is involved in gastric cell growth and apoptosis via PI3K/AKT signalling

Growth hormone receptor (GHR), the cognate receptor of growth hormone (GH), is a membrane bound receptor that belongs to the class I cytokine receptor superfamily. GH binding GHR induces cell differentiation and maturation, initiates the anabolism inside the cells and promotes cell proliferation. Recently, GHR has been reported to be associated with various types of cancer. However, the underlying mechanism of GHR in gastric cancer has not been defined. Our results showed that silence of GHR inhibited the growth of SGC-7901 and MGC-803 cells, and tumour development in mouse xenograft model. Flow cytometry showed that GHR knockout significantly stimulated gastric cancer cell apoptosis and caused G1 cell cycle arrest, which was also verified by Western blot that GHR deficiency induced the protein level of cleaved-PARP, a valuable marker of apoptosis. In addition, GHR deficiency inhibited the activation of PI3K/AKT signalling pathway. On the basis of the results, that GHR regulates gastric cancer cell growth and apoptosis through controlling G1 cell cycle progression via mediating PI3K/AKT signalling pathway. These findings provide a novel understanding for the role of GHR in gastric cancer.