食管黏膜上皮癌变过程中与细胞骨架蛋白tensin同源的磷酸酯酶基因的表达及意义

目的探讨与细胞骨架蛋白tensin同源的磷酸酯酶基因(PTEN)在食管黏膜上皮癌变过程中的表达及意义。方法采用免疫组织化学法检测20例正常食管黏膜、20例食管上皮非典型增生、24例原位癌、44例食管鳞癌组织中PTEN表达情况,并探讨PTEN与食管鳞癌病理分级的关系。结果正常食管黏膜、非典型增生、原位癌及食管鳞癌组织中PTEN蛋白阳性表达率分别为100%、85.00%、70.83%和45.45%,原位癌、食管鳞癌组织中PTEN蛋白阳性率低于正常食管黏膜(P<0.05),食管鳞癌组织中PTEN蛋白阳性率低于原位癌和食管上皮非典型增生组织(P<0.05)。高分化、中分化及低分化食管鳞癌组织中在患者中PTEN蛋白阳性表达率分别为75.00%(15/20)、21.43%(3/14)、20.00%(2/10),高分化食管鳞癌组织中PTEN蛋白阳性表达率显著高于中分化和低分化食管鳞癌组织中(P<0.05),中分化和低分化食管鳞癌组织中PTEN蛋白阳性表达率无明显差异(P>0.05)。结论PTEN表达降低可能与食管鳞状上皮癌变有关,并可能在食管癌早期形成与发展中起有重要的作用。

高糖条件下Tensin在人肾脏系膜细胞上的表达

目的:探讨在高糖刺激的条件下,Tensin在人类肾脏系膜细胞上的表达及变化。方法:体外培养系膜细胞,用含不同浓度的葡萄糖(5mmol/L,30mmol/L)刺激细胞48h、72h和5d。用免疫荧光法观察tensin在人类肾脏系膜细胞上表达及变化,ELISA法检测上清液中纤连蛋白含量。结果:高糖刺激下系膜细胞tensin的表达随着培养时间的延长逐渐增多,且纤连蛋白的分泌也随培养时间的延长而增加。结论:高糖刺激下tensin在人类肾脏系膜细胞的细胞膜上表达增加,在细胞外基质增多的发生机制中起重要作用。

肾消康对糖尿病肾病大鼠肾损伤的保护作用及对tensin表达的影响

目的:探讨肾消康对糖尿病肾病(DN)的保护作用及机理。方法:建立糖尿病肾病大鼠模型,以肾消康治疗,观察各组大鼠的血糖、尿素氮、肌酐、24h尿微量白蛋白的数值及tensin的表达。结果:正常大鼠肾脏tensin表达很弱,DN大鼠肾脏tensin表达明显增强(与正常对照组相比P<0.01,有统计学意义),肾消康对DN大鼠肾脏组织tensin的表达有下调作用(与模型组相比P<0.01,有统计学意义)。同时肾消康能有效降低血糖、尿素氮、肌酐、尿微量白蛋白。结论:肾消康能够调节血糖水平,下调ten-sin的表达,降低尿素氮、肌酐、尿微量白蛋白,从而防止肾纤维化及延缓肾衰。

Nerve growth factor pretreatment against glutamate-induced hippocampal neuronal injury Action mechanism of phosphatase and tensin homologue deleted on chromosome 10

BACKGROUND： Nerve growth factor （NGF） attenuates glutamate-induced injury to hippocampal neurons, and the human tumor suppressor gene phosphatase and tensin homologue deleted on chromosome 10 （PTEN） promotes neuronal apoptosis. However, effects of PTEN in NGF-mediated neuroprotection against glutamate excitotoxicity remain poorly understood. OBJECTIVE： To investigate the relationship between NGF inhibition of glutamate-induced injury and PTEN. DESIGN, TIME AND SE＇I＇rlNG： The randomized, controlled, in vitro study was performed at the Department of Pathophysiology, Medical School of Nantong University, China from October 2007 to March 2008. MATERIALS： Glutamate, NGF, 4, 6-diamidino-2-phenyl-indolediacetate, 3-[4, 5-dimethylthiazol-2-yl]- 2, 5-diphenyl tetrazoliumbromide （M-I-F）, and lactate dehydrogenase kit （Sigma, USA）, fluorescence microscope and inverted phase contrast microscope （Olympus, Japan） were used in this study. METHODS： Hippocampal neurons were obtained from newborn （〈 24 hours） Sprague Dawley rats and cultured for 7 days. The control group was not treated with any intervention factor, the glutamate group was treated with glutamate （0.2 mmol/L）, and NGF groups were treated with NGF （10, 50, 100, and 200 μg/L, respectively） prior to glutamate treatment. MAIN OUTCOME MEASURES： The MTT and lactate dehydrogenase assays were applied to evaluate viability of hippocampal neurons. Morphological changes in hippocampal neurons were observed using an inverted phase-contrast microscope, and neuronal apoptosis was detected by 4, 6-diamidino-2- phenyl-indolediacetate staining. PTEN mRNA and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot analysis, respectively. RESULTS： Glutamate （0.2 mmol/L） induced significantly decreased neuronal viability and greater lactate dehydrogenase efflux compared with the control group （P 〈 0.01）. However, compared with the glutamate group, cell viability significantly increased and lactate dehydrogenase efflux decreased in the NGF group with increasing NGF concentrations （P 〈 0.05 or P 〈 0.01）. The apoptotic ratio and PTEN mRNA and protein expression decreased in the NGF group compared with the glutamate group （P 〈 0.01）. CONCLUSION： Pretreatment with NGF exerted neuroprotective effects against glutamate-induced injury, partially through inhibition of PTEN expression and neuronal apoptosis.

Expression of phosphatase and tensin homolog deleted on chromosome ten in liver of athymic mice with hepatocellular carcinoma and the effect of Fuzheng Jiedu Decoction

AIM： To explore the expression of phosphatase and tensin homolog deleted on chromosome ten （PTEN） in liver of athymic mice with hepatocellular carcinoma （HCC） and the effect of Fuzheng Jiedu Decoction （FJD）. METHODS： Forty eight male BALB/c athymic mice models were built by Bel-7402 with an indirect method. After 24 h of postoperation, the 48 athymic mice were distributed randomly into 4 groups： A, B, C, D, each group had 12 athymic mice. Group A were were treated by intragastric administration with FT207 （Tegafur） for 4 wk. Group B, C and D were treated by intragastric administration with FJD （complex prescription of Chinese crude drug） that had been delegated into 3 kinds of density as the low, middle, and high for 4 wk. At last, athymic mice were put to death, live time, volume of tumors, exponent of tumors and the tumor metastasis in livers were observed; and PTEN was detected in hepatic tissue, latero-cancer tissue and cancer tissue by immunohistochemistry. RESULTS： Four weeks later, the total survival rate in treatment group （A ＋ B ＋ C） was 50% and higher than the control group （0%） treated by FT207, （P 〈 0.01）. The survival rate in group A, B, C was higher than in group D, and except group A with D, there was significant differentces （Fisher＇s Exact Test P = 0.05 or 0.01）. And no differences were observed between the treatment groups and the control group in volume of tumors and exponent of tumors （P 〉 0.05）. Tumor metastasis in livers of the treatment group was less than the controls （Fisher＇s Exact Test, P = 0.021）. The result of immunohistochemistry showed that the intensity of PTEN in latero-cancer tissue was the highest, and then the hepatic tissue, the lowest was cancer tissue （Kruskal- Wallis test, X^2 = 60.67, P = 0.000）. It also showed that the intensity of PTEN in treatment groups （A, B, C） was higher than the control group （D） （F = 5.90, P = 0.002 in hepatic tissue and F = 15.99, P = 0.000 in latero-cancer tissue and X^2 = 26.08, P = 0.000 in cancer tissue）, and group B is the highest in the treatment groups （P 〈 0.05, r = 0.01. respectively）. However, there was no significant statistic difference between group A and group C （P 〉 0.05）. CONCLUSION： FJD can prolong the survival time and decrease tumor metastasis in livers of these experimental mice. Mechanisms of FJD healing HCC may partially be explained by enhancing the expression of PTEN in liver.

phosphatase and tensin homolog is a differential diagnostic marker between nonalcoholic and alcoholic fatty liver disease

AIM: To investigate the protein expression of phosphatase and tensin homolog (PTEN) in human liver biopsies of patients with alcoholic and non-alcoholic liver disease.METHODS: PTEN protein expression was assessed by immunohistochemistry in formalin-fixed, paraffin-embedded liver sections of patients with non-alcoholic fatty liver disease (NAFLD) (n = 44) or alcoholic liver disease (ALD) (n = 25). Liver resections obtained from 3 healthy subjects candidate for partial liver donation served as controls. Histological evaluations were performed by two experienced pathologists, and diagnoses established based on international criteria. The intensity of the PTEN staining in nuclei was compared between steatotic and non-steatotic areas of each liver fragment analyzed. For each liver specimen, the antibody-stained sections were examined and scored blindly by three independent observers, who were unaware of the patients&#x02019; clinical history.RESULTS: In healthy individuals, PTEN immunostaining was intense in both the cytoplasm and nuclei of all hepatocytes. However, PTEN was strongly downregulated in both the nucleus and the cytoplasm of hepatocytes from steatotic areas in patients with NAFLD, independently of the disease stage. In contrast, no changes in PTEN protein expression were observed in patients with ALD, regardless of the presence of steatosis or the stage of the disease. The degree of PTEN downregulation in hepatocytes of patients with NAFLD correlated with the percentage of steatosis (r = 0.3061, P = 0.0459) and the BMI (r = 0.4268, P = 0.0043). Hovewer, in patients with ALD, PTEN expression was not correlated with the percentage of steatosis with or without obesity as a confounding factor (P = 0.5574). Finally, PTEN expression level in steatotic areas of ALD patients was significantly different from that seen in steatotic areas of NAFLD patients (P &#x0003c; 0.0001).CONCLUSION: PTEN protein expression is downregulated early in NAFLD, but not in ALD. PTEN immunohistochemical detection could help in the differential diagnosis of NAFLD and ALD.

Is NEDD4-1 a negative regulator of phosphatase and tensin homolog in gastric carcinogenesis?

The expression of phosphatase and tensin homolog (PTEN ), a tumor suppressor gene, is frequently downregulated in gastric carcinomas due to mutation, loss of heterozygosity, and promoter hypermethylation. However, it is unknown if additional mechanisms may account for the down-regulation of PTEN expression. While neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) is believed to be a potential dual regulator of PTEN, there are conflicting reports regarding their interaction. To gain further insight into the role of NEDD4-1 and its association with PTEN in gastric carcinoma development, we measured the protein expression of NEDD4-1 and PTEN in gastric mucosae with various pathological lesions and found that NEDD4-1 increased from normal gastric mucosa to intestinal metaplasia and decreased from dysplasia to gastric carcinoma. These changes did not correlate with PTEN expression changes during gastric carcinogenesis. Moreover, we found similar results in protein levels in the primary tumors and adjacent non-tumorous tissues. These results differ from a previous report showing that expression of NEDD4-1 is up-regulated in gastric carcinomas, and show a more complex pattern of NEDD4-1 gene expression during gastric carcinogenesis.

Rapid construction of phosphatase and tensin homolog-deleted on chromosome ten gene recombinant adenovirus using the AdEasy system

Recent studies have shown that phosphatase and tensin homolog-deleted on chromosome ten （PTEN） gene plays an important role in ischemic brain damage and synaptic plasticity. The AdEasy system, which has been widely used, greatly simplifies preparation of recombinant adenovirus. Therefore, recombinant defective adenovirus vector carrying human PTEN tumor suppressor gene （Ad-PTEN） was constructed using the AdEasy-1 system and was transfected into HEK293 cells for packaging and amplification. Infection efficiency and expression intensity were observed in primary cultured rat hippocampal neurons infected with Ad-PTEN in vitro. Results revealed a cytopathic effect in green fluorescent protein expression, which increased with prolonged time. After three cycles of amplification, the adenovirus titer was increased to an adequate titer for infecting hippocampal neurons. The entire process typically requires 4-5 weeks for completion. Results suggested that recombinant defective adenovirus vector carrying the PTEN gene was successfully and rapidly constructed using the AdEasy system.

Dual regulatory role for phosphatase and tensin homolog in specification of intestinal endocrine cell subtypes

AIM:To investigate the impact of phosphatase and tensin homolog(Pten) in the specification of intestinal enteroendocrine subpopulations.METHODS:Using the Cre/loxP system,a mouse with conditional intestinal epithelial Pten deficiency was generated.Pten mutant mice and controls were sacrificed and small intestines collected for immunofluorescence and quantitative real-time polymerase chain reaction.Blood was collected on 16 h fasted mice by cardiac puncture.Enzyme-linked immunosorbent assay was used to measure blood circulating ghrelin,somatostatin(SST) and glucose-dependent insulinotropic peptide(GIP) levels.RESULTS:Results show an unexpected dual regulatory role for epithelial Pten signalling in the specification/differentiation of enteroendocrine cell subpopulations in the small intestine.Our data indicate that Pten positively regulates chromogranin A(CgA) expressing subpopulations,including cells expressing secretin,ghrelin,gastrin and cholecystokinin(CCK).In contrast,Pten negatively regulates the enteroendocrine subtype specification of non-expressing CgA cells such as GIP and SST expressing cells.CONCLUSION:The present results demonstrate that Pten signalling favours the enteroendocrine progenitor to specify into cells expressing CgA including those producing CCK,gastrin and ghrelin.

Antagonizing adipose tissue-derived exosome miR-103-hepatocyte phosphatase and tensin homolog pathway alleviates autophagy in non-alcoholic steatohepatitis:A trans-cellular crosstalk

BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.

Increased tensin 4 expression is related to the histological type of gastric cancer

BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors worldwide.Tensin 4(TNS4)is an adhesive protein belonging to the tensin family.This protein is located in focal adhesion sites.The TNS4 gene is considered an oncogene in numerous cancers.This protein plays an important role in adhesion,migration and proliferation of cells.AIM To evaluate expression of TNS4 protein in GC tissues and analysis of the clinical and histopathological parameters as well as the overall survival rate of patients.METHODS The expression of TNS4 was assessed in 89 patients using immunohistochemistry.RESULTS Positive expression of TNS4 was observed in 49 of 89 patients(55.06%).Higher TNS4 expression was more common in GC tumors with a diameter≥5 cm(P=0.040).We demonstrated that an increase in TNS4 expression was more frequent in tumors of the histological type without mucinous components than in tumors from mucosal cancers(P=0.023).Furthermore,TNS4 expression was higher in moderately differentiated tumors than in poorly differentiated and non-differentiated tumors(P=0.002).Increased TNS4 expression was also noted in the intestinal type of GC according to Lauren’s classification(P=0.020).No statistically significant correlation was found between the expression of TNS4 and the overall survival rate of patients.CONCLUSION TNS4 expression was significantly higher in tumors with a diameter≥5 cm of the moderately differentiated intestinal type(according to Lauren’s classification)of GC without a mucinous component.Therefore,increased TNS4 expression is related to the histological type of GC with a better prognosis.

Phosphatase and tensin homolog expression related to cetuximab effects in colorectal cancer patients: A meta-analysis

AIM: To investigate the correlation between expression of phosphatase and tensin homolog (PTEN) and cetuximab effects in colorectal cancer. METHODS: We searched PubMed, EMBASE and ASCO to identify eligible studies. Finally, 8 randomized control studies were included in the meta-analysis. STATA 10.0 Software was used to investigate heterogeneity among individual studies and to summarize all the studies. Risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the strength of the association. RESULTS: Compared with 20 of 266 patients with loss of PTEN, 206 of 496 patients with intact PTEN protein expression had a better objective response rate to cetuximab-based therapy (RR, 4.75; 95% CI, 2.59-8.72; P < 0.001). PTEN positivity was associated with better progression-free survival (PFS) (HR, 0.675; 95% CI, 0.473-0.964; P = 0.031) but not with better overall survival (OS) (HR, 0.608; 95% CI, 0.411-0.899; P = 0.013). In patients with KRAS wild-type status, PTEN positivity did not predict a longer PFS or OS (PFS: HR, 0.707; 95% CI, 0.440-1.138; P = 0.154; OS: HR, 0.943; 95% CI, 0.646-1.377; P = 0.761). CONCLUSION: Expression of PTEN is related to the effect of cetuximab in colorectal cancer patients and should be considered in treatment with cetuximab.

Phosphatase and tensin homology deleted in chromosome 10,hypoxia-inducible factor-1 alpha gene expression in colorectal adenoma and adenocarcinoma and their relation to vascular endothelial growth factor protein expression

To examine phosphatase and tensin homology deleted in chromosome 10 (PTEN),hypoxia-inducible factor-1 alpha (HIF-1 alpha) gene expressions and their relation to vascular endothelial growth factor(VEGF) protein expression in the patients with human colorectal adenomas and adenocarcinomas.Methods The expression of PTEN,HIF-1 alpha gene was detected by using in situ hybridization,and the VEGF expression levels by immunohistochemistry in colorectal adenomas and primary colorectal adenocarcinoma.Results Strong expression of HIF-1 alpha was detectable in the majority of colorectal dadenocarcinoma,particularly surrounding areas of necrosis in adenocarcinoma.PTEN,HIF-1 alpha mRNA and VEGF protein were positive in 51.6%,67.7% and 59.7% respectively in 62 cases of adenocarcinomas,and 77.8%,44.4% and 33.3% respectively in 18 cases of adenomas.The positive rate of VEGF was higher in the patients with colorectal adenocarcinomas than that in those with adenomas,whereas that of PTEN mRNA was contrary.HIF-1 mRNA expression was correlated significantly with lymph node metastasis,liver metastasis,Duke’s stage and recurrence.During colorectal tumor progression,the expression of HIF-1 alpha mRNA was positively correlated with the VEGF protein expression (χ2= 4.751 ,P<0.05),but negatively with the PTEN mRNA expression(χ2=21.84,P<0.01).Conclusion The absence or low expression of PTEN and the increased levels of HIF-1α and VEGF may paly an important role in carcinogenesis and progression of colorectal carcinoma.These results suggest that VEGF upregulated by HIF-1 alpha gene may be involved in angiogenesis of colorectal adenocarcinoma.4 refs,1 tab.

Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy

Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia(AML)in recent years,chemotherapy still remains the mainstay of treatment and the overall survival is poor in most patients.Here,we demonstrated the antileukemia activity of a novel small molecular compound NL101,which is formed through the modification on bendamustine with a suberanilohydroxamic acid(SAHA)radical.NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells.It induces DNA damage and caspase 3-mediated apoptosis.A genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)library screen revealed that phosphatase and tensin homologous(PTEN)gene is critical for the regulation of cell survival upon NL101 treatment.The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome(MDS)cells,accompanied by the activation of protein kinase B(AKT)signaling pathway.The inhibition of mammalian target of rapamycin(mTOR)by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death.These findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.

Tensin1蛋白与胃癌临床病理特征及预后的关系

目的：探讨Tensin1蛋白表达水平与胃癌临床病理特征及预后的关系。方法：采用回顾性病例对照研究方法。收集2011年7月31日至2013年12月31日江苏大学附属医院收治的163例胃癌患者的临床病理资料。收集患者的术后胃癌组织和对应癌旁组织病理学标本，石蜡切片包埋，并行免疫组织化学染色检测。观察指标：（1）胃癌组织和癌旁组织中Tensin1蛋白表达情况。（2）胃癌组织中Tensin1蛋白表达与患者临床病理因素的关系。（3）随访和生存情况。（4）胃癌患者的预后因素分析。采用电话方式进行随访，了解患者生存情况。随访时间截至2017年1月1日。偏态分布的计量资料采用M（范围）表示。计数资料采用双侧χ^2或配对χ^2检验。采用KaplanMeier法绘制生存曲线计算生存率，Log-rank检验进行生存分析。单因素及多因素分析采用COX比例风险模型。结果：（1）胃癌组织和癌旁组织中Tensin1蛋白表达情况：免疫组织化学染色检测显示Tensin1蛋白在胃癌组织和癌旁组织细胞中主要表达于细胞质。163例患者，胃癌组织中154例Tensin1蛋白表达阳性（66例高表达、88例低表达），9例表达阴性；癌旁组织中79例Tensin1蛋白表达阳性（37例高表达、42例低表达），84例表达阴性；两者Tensin1蛋白表达阳性比例和表达水平比较，差异均有统计学意义（χ^2=64.65，12.93，P〈0.05）。（2）胃癌组织中Tensin1蛋白表达与患者临床病理因素的关系：胃癌患者术后发生和未发生肿瘤转移患者胃癌组织中Tensin1蛋白高表达率分别为31.34%（21/67）和46.88%（45/96），两者比较，差异有统计学意义（χ^2=3.95，P〈0.05）。（3）随访和生存情况：163例患者术后均获得随访，随访时间为3.3-64.7个月，中位随访时间为28.7个月。66例胃癌组织中Tensin1蛋白高表达患者3年累积无病生存率和累积总体生存率分别为63.12%和74.22%；97例胃癌组织中Tensin1蛋白低表达＋阴性表达患者3年累积无病生存率和累积总体生存率分别为47.30%和55.74%；两者上述指标比较，差异均有统计学意义（χ^2=4.58，4.11，P〈0.05）。亚组生存分析结果显示：肿瘤最大直径≥5 cm、神经和（或）脉管侵犯、TNM分期Ⅲ期的胃癌组织中Tensin1蛋白高表达患者的3年累积无病生存率分别为45.98%、62.79%、52.75%；Tensin1蛋白低表达＋阴性表达患者分别为18.11%、31.10%、32.80%，上述生存情况比较，差异均有统计学意义（χ^2=5.85，7.89，4.96，P〈0.05）； Tensin1蛋白高表达患者3年累积总体生存率分别为66.00%、75.75%、67.93%，Tensin1蛋白低表达＋阴性表达患者分别为30.74%、40.15%、44.67%，上述生存情况比较，差异均有统计学意义（χ^2=7.59，9.62，4.32，P〈0.05）。（4）胃癌患者的预后因素分析，单因素分析结果显示：肿瘤最大直径、组织学分级、神经和（或）脉管侵犯、术后TNM分期、术后辅助化疗及Tensin1蛋白表达水平是影响胃癌患者预后的相关因素（风险比=3.66，2.45，2.17，3.36，0.41，0.54，95%可信区间：2.09-6.41，1.43-4.19，1.17-4.04，1.52-7.41，0.23-0.72，0.31-0.96， P〈0.05）。多因素分析结果显示：肿瘤最大直径≥5 cm、组织学分级为Ⅲ级是影响胃癌患者预后的独立危险因素（风险比=3.21，2.17，95%可信区间：1.63-6.32，1.18-3.99，P〈0.05）；术后辅助化疗和Tensin1蛋白高表达是影响胃癌患者预后的独立保护因素（风险比=0.50，0.44，95%可信区间：0.28-0.90，0.24-0.82，P〈0.05）。结论：Tensin1蛋白高表达可能抑制胃癌转移，是胃癌独立的保护性预后因素。

糖尿病肾病大鼠肾脏Tensin表达的变化

目的 观察tensin在糖尿病肾病（DN）大鼠肾脏中的表达，探讨其在DN肾小球纤维化中的作用。方法 链脲佐菌素（STZ）诱导大鼠DN，间接免疫荧光组织化学方法观察DN大鼠肾脏tensin的表达。结果 糖尿病肾病大鼠的肾脏tensin表达明显增加（与正常对照组相比P〈0．01，有统计学意义），阳性表达主要位于系膜细胞胞浆内。结论 tensin在糖尿病肾病大鼠系膜细胞中高表达可能参与了糖尿病肾病过程中肾小球纤维化的形成。

Tensin的研究进展

Tensin是一种位于胞浆灶性粘附区的磷酸蛋白，它包含了一个磷酸酪氨酸结合（PTB）区域和一个Src同源区2区域（SH2）。Tensin通过整合素、纽蛋白和灶性粘附激酶（FAK）的粘附复合物影响肾小球系膜细胞产生细胞外基质，它在肌肉再生、细胞迁移中起关键作用。因此，tensin可以作为对肾脏疾病、创口愈合、癌症等进行干预治疗的靶点。

Involvement of phosphatase and tensin homolog-induced putative kinase 1–Parkin-mediated mitophagy in septic acute kidney injury

Background:Studies have reported mitophagy activation in renal tubular epithelial cells(RTECs)in acute kidney injury(AKI).Phosphatase and tensin homolog-induced putative kinase 1(PINK1)and E3 ubiquitin-protein ligase Parkin are involved in mitophagy regulation;however,little is known about the role of PINK1-Parkin mitophagy in septic AKI.Here we investigated whether the PINK1-Parkin mitophagy pathway is involved in septic AKI and its effects on cell apoptosis in vitro and on renal functions in vivo.Methods:Mitophagy-related gene expression was determined using Western blot assay in human RTEC cell line HK-2 stimulated with bacterial lipopolysaccharide(LPS)and in RTECs from septic AKI rats induced by cecal ligation and perforation(CLP).Autophagy-related ultrastructural features in rat RTECs were observed using electron microscopy.Gain-and loss-of-function approaches were performed to investigate the role of the PINK1-Parkin pathway in HK-2 cell mitophagy.Autophagy activators and inhibitors were used to assess the effects of mitophagy modulation on cell apoptosis in vitro and on renal functions in vivo.Results:LPS stimulation could significantly induce LC3-II and BECN-1 protein expression(LC3-II:1.72±0.05 vs.1.00±0.05,P<0.05;BECN-1:5.33±0.57 vs.1.00±0.14,P<0.05)at 4 h in vitro.Similarly,LC3-II,and BECN-1 protein levels were significantly increased and peaked at 2 h after CLP(LC3-II:3.33±0.12 vs.1.03±0.15,P<0.05;BECN-1:1.57±0.26 vs.1.02±0.11,P<0.05)in vivo compared with those after sham operation.Mitochondrial deformation and mitolysosome-mediated mitochondria clearance were observed in RTECs from septic rats.PINK1 knockdown significantly attenuated LC3-II protein expression(1.35±0.21 vs.2.38±0.22,P<0.05),whereas PINK1 overexpression markedly enhanced LC3-II protein expression(2.07±0.21 vs.1.29±0.19,P<0.05)compared with LPS-stimulated HK-2 cells.LPS-induced proapoptotic protein expression remained unchanged in autophagy activator-treated HK-2 cells and was significantly attenuated in PINK1-overexpressing cells,but was remarkably upregulated in autophagy inhibitor-treated and in PINK1-depleted cells.Consistent results were observed in flow cytometric apoptosis assay and in renal function indicators in rats.Conclusion:PINK1-Parkin-mediated mitophagy might play a protective role in septic AKI,serving as a potential therapeutic target for septic AKI.

Phosphatase and Tensin Homologue Genetic Polymorphisms and their Interactions with Viral Mutations on the Risk of Hepatocellular Carcinoma

Background： Chronic hepatitis B virus （HBV） infection is the major cause of hepatocellular carcinoma （HCC）. Some HBV mutants and dysregulation of phosphatase and tensin homolog （PTEN） may promote the development of HCC synergistically. We aimed to test the effects of PTEN genetic polymorphisms and their interactions with important HBV mutations on the development of HCC in HBV-infected subjects. Methods： Quantitative po[ymerase chain reaction was applied to genotype PTEN polymorphisms （rs1234220, rs2299939, rsl234213） in 1012 healthy controls, 302 natural clearance subjects, and 2011 chronic H BV-infected subjects including 1021 HCC patients. HBV mutations were determined by sequencing. The associations of PTEN polymorphisms and their interactions with HBV mutations with HCC risk were assessed using multivariate logistic regression analysis. Results： Rs1234220 C allele was significantly associated with HCC risk compared to healthy controls （adjusted odds ratio [AOR] = 1.35, 95% confidence interval [CI] = 1,07-1.69） and HCC-free HBV-infected subjects （AOR = 1.27, 95% CI = 1.01-1 .57）. rsl234220 C allele was significantly associated with increased frequencies of HCC-risk A 1652G, C 1673T, and C 1730G mutations in genotype B H BV-in fected subjects. Rs2299939 GT genotype was inversely associated with HCC risk in HBV-infected patients （AOR 0.75, 95% CI 0.62-0.92）. The interaction of rs2299939 variant genotypes （GT＋TT） with A3054T mutation significantly increased HCC risk （AOR = 2.41, 95% CI = 1.08-5.35）; whereas its interaction with C3116T mutation significantly reduced HCC risk （AOR = 0.34, 95% CI 0.18-0.66）. These significant effects were only evident in males alter stratification. Conclusions： PTEN polymorphisms and their interactions with HBV mutations may contribute to hepatocarcinogenesis in males. The host-virus interactions are important in identifying HBV-infected subjects who are more likely to develop HCC.

Nuclear miR-665 aggravates heart failure via suppressing phosphatase and tensin homolog transcription

Although numerous miRNAs have been discovered,their functions in the different subcellular organelles have remained obscure.In this study,we found that miR-665 was enriched in the nucleus of cardiomyocytes,and then investigated the underlying role of nuclear miR-665 in heart failure.RNA fluorescence in situ hybridization assays in human heart tissue sections and primary cardiomyocytes showed that miR-665 was localized in the nucleus of cardiomyocytes.Increased expression of nuclear miR-665 was observed not only in the cardiomyocytes isolated from the heart of mice treated in vivo by transverse aortic constriction(TAC),but also in phenylephrine(PE)-treated cultured cardiomyocytes in vitro.To further explore the role of miR-665 in heart failure,a type 9 recombinant adeno-associated virus(rAAV)system was employed to manipulate the expression of miR-665 in mice.Overexpression of miR-665 aggravated TAC-induced cardiac dysfunction,while down-expression of miR-665 showed opposite effects.Bioinformatic prediction and biological validation confirmed that the PTEN(phosphatase and tensin homolog)gene was one of the targets of miR-665 in the nucleus.Furthermore,restoring PTEN expression significantly eliminated the destructive effects of miR-665 over-expression in TAC-induced cardiac dysfunction.Our data showed that nuclear miR-665 aggravates heart failure via inhibiting PTEN expression,which provided a therapeutic approach for heart failure.