A case of Cowden syndrome diagnosed from multiple gastric polyposis

Cowden syndrome is a rare autosomal dominant disorder that is characterized by multiple hamartomas in a variety of tissues and this is associated with germline mutations in the phosphatase and tensin homologue (PTEN) gene, which is the tumor suppressor gene located on chromosome 10q23.3. It is characterized by multiple hamartomatous neoplasms of the skin, oral mucosa, gastrointestinal (GI) tract, bones, central nervous system, eyes, and genitourinary tract. Cowden syndrome does not have increased risk of GI malignancy; however, it has an increased risk of breast, thyroid and endometrial cancer development. Here the authors report a rare case of Cowden syndrome incidentally diagnosed from multiple gastric polyposis. A 29-year-old woman presented with multiple gastric polyps. The laboratory results were normal except for mild anemia, with a hemoglobin level of 11.9 g/dL. Esophagogastroduodenoscopy revealed multiple gastric, duodenal polyps and esophageal acanthosis. Colonoscopy revealed possible hamartomatous polyps in the rectum. Under the suspicion of Cowden syndrome, sonography of the thyroid and breasts was carried out, which revealed multiple thyroid masses. Subsequent fine-needle aspiration biopsy revealed the presence of clusters of follicular epithelial cells, and due to the possibility of malignancy, the patient underwent total thyroidectomy. The pathology was reported as invasive follicular carcinoma. A gene study by direct sequencing showed the presence of a PTEN mutation (c.633C > A /p.Cys211*).     

PTEN在胃癌中的研究进展

第10号染色体同源缺失性磷酸酶-张力蛋白基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)是继p533之后发现的另一重要的抑癌基因,其编码的蛋白质可调控多种细胞信号转导通路或功能分子,构成一个复杂的网络系统,在调控细胞增殖与凋亡、迁移与黏附...     

抑癌基因PTEN和Ki-67抗原在人脑胶质瘤中的表达及意义

为探讨抑癌基因PTEN和Ki-67抗原表达与脑胶质瘤发生发展的关系，采用免疫组织化学法检测了82例人脑胶质瘤中PTEN和Ki-67的表达情况。结果显示，PTEN阳性染色定位于细胞浆，82例标本中，有48例（58．54％）PTEN呈阳性表达，高分化肿瘤（I级和Ⅱ级）的阳性表达率（75．61％）明显高于低分化（Ⅲ级和Ⅳ级）肿瘤（41．46％），P＜0．005。Ki-67呈明显核染色，各级胶质瘤均有表达，低分化肿瘤（75．61％）明显高于高分化肿瘤（24．39％），P＜0．005。PTEN与Ki-67表达呈负相关（P＜0．01）。认为PTEN突变或缺失在人脑胶质瘤的发生发展中起重要作用，Ki-67可作为反映胶质瘤细胞增殖潜能的指标。PTEN和Ki-67表达与肿瘤分化程度密切相关，联合检测PTEN和ki-67在胶质瘤中的表达，有助于对肿瘤细胞增殖能力、分化程度做出正确评价，指导临床治疗及估计患者预后。     

Curcumin cytotoxicity is enhanced by PTEN disruption in colorectal cancer cells

AIM:To investigate the effects of phosphatase and tensin homolog deleted on chromosome 10(PTEN) deficiency on the cytotoxicity of chemotherapeutic agents toward colorectal cancer cells.METHODS:PTEN-deficient colorectal cancer(CRC) cells were generated by human somatic cell gene targeting using the adeno-associated virus system. The cytotoxic effects of compounds including curcumin,5-fluorouracil(5-FU),dihydroartemisinin(DHA),irinotecan(CPT-11)and oxaliplatin(OXA) on cancer cells were determined using the MTT assay. Enhanced cytotoxicity of curcumin in PTEN-deficient CRC cells was observed,and this was confirmed using clonogenic assays. Apoptosis and cell cycle progression were analyzed by flow cytometry.Levels of apoptosis and cell cycle-related proteins were examined by Western blotting.RESULTS:We developed an isogenic set of CRC cell lines that differed only in their PTEN status. Using this set of cell lines,we found that disruption of the PTEN gene had no effect on the sensitivity of CRC cells to5-FU,CPT-11,DHA,or OXA,whereas PTEN disruption increased the sensitivity of CRC cells to curcumin. Loss of PTEN did not alter the curcumin-induced apoptosis in CRC cells. However,PTEN deficiency led to an altered pattern of curcumin-mediated cell cycle arrest.In HCT116 PTEN+/+cells,curcumin caused a G2/M phase arrest,whereas it caused a G0/G1 phase arrest in HCT116 PTEN-/-cells. Levels of cell cycle-related proteins were consistent with these respective patterns of cell cycle arrest.CONCLUSION:Curcumin shows enhanced cytotoxicity toward PTEN-deficient cancer cells,suggesting that it might be a potential chemotherapeutic agent for cancers harboring PTEN mutations.     

染色体缺失磷酸酶及张力蛋白同源物对胰腺癌细胞系细胞周期和增殖能力的影响

目的探讨10号染色体缺失的磷酸酶及张力蛋白同源物(PTEN)对胰腺癌细胞质(ASPC-1)血管内皮生长因子(VEGF)蛋白表达、细胞周期和增殖的影响.方法将质粒pEAK8-PTEN和pEAK8分别转染指数生长期的胰腺癌细胞株(ASPC-1),挑选阳性细胞克隆,扩增培养,用RT-PCR、Western印迹、流式细胞术、生长速率等方法分别检测PTEN对ASPC-1细胞VEGF蛋白、细胞周期及增殖能力的影响.结果ASPC-1细胞转染后,PTEN mRNA表达量是转染前的3倍;ASPC-1、ASPC-1-pEAK8、ASPC-1-pEAK8-PTEN细胞PTEN蛋白表达量分别为13.2、12.6和21.6,VEGF蛋白表达量分别为17.2、16.5和13.1,转染后较转染前降低.细胞周期显示,ASPC-1-pEAK8-PTEN细胞较ASPC-1、ASPC-1-pEAK8细胞G2/M、S期细胞增多,Gl期细胞减少,并出现少量凋亡细胞(P＜0.01).ASPC-1-pEAK8-PTEN细胞生长曲线平缓,生长速度较另两种细胞明显降低.结论 PTEN可使ASPC-1细胞VEGF蛋白表达下降,细胞阻滞在G2/M期,抑制肿瘤细胞增殖.     

核PTEN和Survivin蛋白在胃癌组织芯片中的表达及意义

目的:探讨核PTEN和Survivin蛋白在胃癌组织芯片中的表达、临床病理学特征及其意义.方法:在116例胃癌35例正常胃黏膜组织芯片上,应用免疫组织化学En Vision法检测核PTEN和Survivin表达水平,分析核PTEN和Survivin在胃癌的表达与患者淋巴结转移状态、Lauren's分型等的关系及其相互关系.结果:核PTEN和Survivin在正常胃黏膜组织中表达率为100%,核PTEN在胃癌组织中的阳性表达率为51.7%(60/116):Survivin的阳性表达率为44.0%(51/116),核PTEN和Survivin与患者淋巴结转移状态相关(P<0.05),同时,核PTEN还和肿瘤分化程度、Lauren's分型密切相关(P<0.05).核PTEN和Survivin二者之间呈正相关(r=0.088,P=0.001).结论:胃癌组织中存在核PTEN和Survivin低表达:同时检测胃癌组织中的核PTEN和Survivin的表达对判断肿瘤的恶性程度和估计预后有一定意义.     

PTEN过表达及其突变对体外活化肝星状细胞凋亡的影响

目的 探讨过表达的野生型PTEN及其突变体G129E对体外培养的活化肝星状细胞(HSC)增殖、凋亡的影响及其机制.方法 体外培养活化的HSC,以腺病毒为载体将野生型PTEN基因及其突变体G129E基因瞬时转染HSC;四甲基偶氮唑盐(MTT)法检测HSC增殖;末端转移酶标记技术(TUNEL)及流式细胞术测定HSC凋亡;Western印迹及实时荧光定量PCR方法 检测HSC PTEN表达;Western印迹测定HSC Bcl-2及Bax表达.结果 外源性野生型PTEN基因及G129E基因成功转染体外活化HSC,并引起HSC的Bax表达增加,Bcl-2表达下降(P<0.01).过表达的野生型PTEN及G129E明显抑制HSC增殖,在转染HSC后48 h、72 h的增殖抑制率分别为14.03%、23.12%和9.52%、12.63%.野生型PTEN基因及G129E基因转染HSC后72 h,HSC凋亡率均显著增加(P<0.01).在上述作用中野生型PTEN均明显强于其突变体G129E.结论 过表达的野生型PTEN及其突变体G129E通过降低Bcl-2/Bax途径诱导体外活化HSC凋亡,并抑制其增殖;并且,野生型PTEN的作用明显强于G129E.     

PTEN、Akt和pAkt蛋白在肝细胞癌组织中的表达及其与预后的关系

目的:探讨人肝细胞癌组织中PTEN、Akt和pAkt蛋白的表达及其预后价值.方法:应用免疫组织化学方法检测78例肝细胞癌组织及21例正常肝组织中PTEN、Akt和pAkt蛋白的表达,分析其与肝细胞癌临床病理特征及预后的关系.结果:在肝细胞癌组织中,PTEN蛋白的表达率显著低于正常肝组织(42.3%vs90.5%,P<0.05),Akt及pAkt蛋白的表达率显著高于正常肝组织(66.7%vs33.3%;43.6%vs9.5%,均P<0.05).PTEN蛋白的表达水平与肿瘤直径、门静脉癌栓、侵及周围脏器或淋巴结转移及TNM分期有关(均P<0.05);Akt及pAkt蛋白的表达水平与肿瘤直径、侵及周围脏器或淋巴结转移及TNM分期有关(均P<0.05).PTEN与Akt蛋白表达呈负相关(r=-0.385,P=0.000),与pAkt蛋白表达呈负相关(r=-0.334,P=0.003).PTEN蛋白高表达患者术后生存率明显高于低表达患者(P=0.000),Akt、pAkt蛋白高表达患者术后生存率明显低于低表达患者(P=0.000).COX模型多因素分析结果显示,TNM分期及pAkt蛋白的表达是影响肝细胞癌预后的独立因素...     

胃癌组织PTEN、VEGF和MVD的表达及意义

目的观察胃癌组织中第10染色体缺失与张力蛋白同源的磷酸酶基因(PTEN)、血管内皮生长因子(VEGF)、微血管密度(M VD)表达,探讨其与胃癌生物学行为的关系。方法用免疫组化法检测60例胃癌标本中PTEN、VEGF、M VD的表达,分析各指标与胃癌临床病理学特征的关系。结果①胃癌组织中PTEN的阳性表达率为46.7%,VEGF为66.6%,M VD为(64±26)条/HP;PTEN的表达与患者的术后生存时间呈正相关(r=0.556,P<0.01),与肿瘤大小、分型、淋巴结转移、分期有关(P均<0.05),与VEGF的表达无相关性(r=-0.136,P>0.05);VEGF和PTEN对胃癌患者预后有不同的影响。②VEGF和M VD的表达与胃癌的大小、分型、分化程度、浸润深度、淋巴结转移、分期有关(P均<0.05);与患者的术后生存时间呈负相关(r=-0.398,P<0.05)。结论PTEN、VEGF、M VD的表达与胃癌生物学行为及预后有密切关系。     

慢性低氧性肺动脉高压大鼠肺动脉内PTEN蛋白表达的变化

目的 通过观察慢性低氧性肺动脉高压大鼠肺动脉内人第10号染色体缺失的磷酸酶及张力蛋白同源的基因（PTEN）蛋白表达水平的变化,初步探讨PTEN在慢性低氧性肺动脉高压的发生、发展过程中所起的作用.方法 将6周龄健康雄性SD大鼠,随机分为正常对照组、低氧1d、3d、7d、14d和21d组,除对照组外,其他各组先建立慢性低氧肺动脉高压大鼠模型,然后检测各组大鼠右心室收缩压（right ventricle systolic pressure,RVSP）和右心室肥厚指数（right ventricle hypertrophy index,RVHI）,采用HE染色观察肺动脉病理学改变,采用Western blot技术检测肺动脉内PTEN蛋白的表达水平.结果 ①与正常对照组（23.76±0.82）mmHg相比,低氧暴露1d、3d、7d、14 d、21d后RVSP均明显上升（P＜0.05）;RVHI低氧3d、7d、14 d、21d组均较正常对照组（100％）明显上升（P＜0.05）;低氧暴露3d、7d和21d组肺动脉中膜明显增厚、管腔明显变小.②PTEN和p-PTEN在正常对照组和低氧各组均有表达.低氧各组肺动脉内PTEN蛋白的表达较对照组下降,但差异无统计学意义（P＞0.05）;而p-PTEN蛋白与PTEN总蛋白表达量的比值随低氧时间的延长有上升趋势,且在慢性低氧21d组（1.71±0.25）较正常对照组（1.00）明显增高（P＜0.05）.结论 PTEN蛋白表达的降低和p-PTEN蛋白表达的增高可能参与了大鼠慢性低氧性肺动脉高压的发生和发展过程.     

Expression of FAK and PTEN in Bronchioloalveolar Carcinoma and Lung Adenocarcinoma

Bronchioloalveolar carcinoma (BAC) is classified as a subset of lung adenocarcinoma but has a distinct clinical presentation, tumor biology, response to therapy, and prognosis compared with other subtypes of lung adenocarcinoma. This study was designed to investigate the clinicopathological differences between BAC and adenocarcinoma and the expression of focal adhesion kinase (FAK) and phosphatase and tensin homologue (PTEN) and their clinical significance in BAC and adenocarcinoma. A retrospective analysis was performed on 77 patients with BAC and 172 patients with pure adenocarcinoma seen during the period from January 1998 to December 2000. All patients underwent lobectomy or pneumonectomy and systematic lymph node dissection. Paraffin-embedded tissue blocks from these patients were obtained and expressions of PTEN and FAK were evaluated by using immunohistochemical staining. Clinicopathological characteristics and survival outcome were reviewed and compared between patients with BAC and adenocarcinoma. Lymph node status, clinical symptoms, CT appearance and expression of FAK were different between BAC and adenocarcinoma. The overall survival of BAC was better than that of adenocarcinoma. In patients with FAK(−), the overall survival was not different between BAC and adenocarcinoma. In patients with adenocarcinoma, the overall survival was better for FAK(−) compared with FAK(+). Expression of PTEN had a prognostic significance in patients with BAC and adenocarcinoma. BAC and adenocarcinoma have different clinicopathological presentations. Expression of FAK has some effect on such differences and affects survival of lung adenocarcinoma. Expression of PTEN can predict outcome of resected lung adenocarcinoma and BAC.     

Colonic manifestations of PTEN hamartoma tumor syndrome: Case series and systematic review

AIM:To investigate our clinical experience with the colonic manifestations of phosphatase and tensin homolog on chromosome ten(PTEN)hamartoma tumor syndrome(PHTS)and to perform a systematic literature review regarding the same.METHODS:This study was approved by the appropriate institutional review board prior to initiation.A clinical genetics database was searched for patients with PHTS or a component syndrome that received gastrointestinal endoscopy or pathology interpretation at our center.These patient’s records were retrospectively reviewed for clinical characteristics(including family history and genetic testing),endoscopy results and pathology findings.We also performed a systematic review of the literature for case series of PHTS or component syndromes that reported gastrointestinal manifestations and investigations published after consensus diagnostic criteria were established in 1996.These results were compiled and reported.RESULTS:Eight patients from our institution met initial inclusion criteria.Of these,5 patients underwent4.2 colonoscopies at mean age 45.8±10.8 years.All were found to have colon polyps during their clinical course and polyp histology included adenoma,hyperplastic,ganglioneuroma and juvenile.No malignant lesions were identified.Two had multiple histologic types.One patient underwent colectomy due to innumerable polyps and concern for future malignant potential.Systematic literature review of PHTS patients undergoing endoscopy revealed 107 patients receiving colonoscopy at mean age 37.4 years.Colon polyps were noted in92.5%and multiple colon polyp histologies were reported in 53.6%.Common polyp histologies included hyperplastic(43.6%),adenoma(40.4%),hamartoma(38.3%),ganglioneuroma(33%)and inflammatory(24.5%)polyps.Twelve(11.2%)patients had colorectal cancer at mean age 46.7 years(range 35-62).Clinical outcomes secondary to colon polyposis and malignancy were not commonly reported.CONCLUSION:PHTS has a high prevalence of colon polyposis with multiple histologic types.It should be considered a mixed polyposis syndrome.Systematic review found an increased prevalence of colorectal cancer and we recommend initiating colonoscopy for colorectal cancer surveillance at age 35 years.     

转染外源性PTEN基因人胃癌细胞生长情况及其对化疗药物敏感性的观察

目的观察转染外源性PTEN基因人胃癌细胞的生长情况及其对化疗药物敏感性的影响。方法人胃癌BGC823细胞转染PEAK8空载质粒和PEAK8-PTEN质粒,稳定表达后予足叶乙甙和阿霉素干预;RT—PCR法检测PTENmRNA表达,MTT法检测细胞生长活力,流式细胞术分析细胞周期。结果转染PEAK8-PTEN质粒的BGC823细胞PTEN mRNA强表达,明显高于转染空载质粒和未转染细胞;PTEN转染后肿瘤细胞存活率下降（P〈0．05）,联合化疗药细胞存活率更低（P〈0．01）;转染PTEN加两种化疗药处理后均出现G2／M为0,细胞阻断于S期。结论转染PTEN基因的人胃癌BGC823细胞生长受抑制,对化疗药敏感性增加。     

沉默miR-216a对四氯化碳诱导的肝纤维化模型大鼠的保护作用及机制研究

目的 探究沉默miR-216a对四氯化碳(CCl4)诱导的肝纤维化模型大鼠的作用及机制.方法 从50只大鼠中随机选取10只作为正常组,其余40只采用腹腔注射含CCl4的橄榄油溶液方法构建肝纤维化模型大鼠.将造模成功的30只大鼠随机分为模型组、对照组和沉默组,每组各10只,对照组尾静脉注射含空载质粒的腺病毒,沉默组尾静脉...     

Impact of KRAS mutation and PTEN expression on cetuximab-treated colorectal cancer

AIM:To investigate the prognostic value of KRAS mutation,and phosphatase and tensin (PTEN) expression in Chinese metastatic colorectal cancer metastatic colorectal cancer (mCRC) patients treated with cetuximab.METHODS:Ninety Chinese mCRC patients treated with cetuximab were evaluated for KRAS mutation and PTEN protein expression by DNA sequencing of codons 12 and 13 and immunohistochemistry,respectively.We then selected 61 patients treated with cetuximab,either in combination with chemotherapy,or alone as a second-line or third-line regimen to assess whether KRAS mutation or PTEN protein expression is associated with the response and the survival time of mCRC patients treated with cetuximab.RESULTS:KRAS mutation was found in 30 (33.3%) tumor samples from the 90 patients,and positive PTEN expression was detected in 58 (64.4%) of the 90 patients.Among the 61 patients who were treated with cetuximab as a second-line or third-line regimen,the resistance to cetuximab was found in 22 patients with KRAS mutation and in 39 patients without KRAS mutation,with a response rate of 4.5% and 46.1% respectively (P=0.001),a shorter median progression-free survival (PFS) time of 14 ± 1.3 wk and 32 ± 2.5 wk respectively (P < 0.001),a median overall survival (OS) time of 11 ± 1.2 mo and 19 ± 1.8 mo respectively (P < 0.001),as well as in 24 patients with negative PTEN expression and in 37 patients with positive PTEN expression respectively (P < 0.001),with a responsive rate of 4.2% and 48.6% respectively,a shorter median PFS survival time of 17 ± 2.0 wk and 28 ± 1.9 wk respectively (P=0.07),and a median OS time of 11 ± 1.3 mo and 18 ± 1.9 mo respectively (P=0.004).Combined KRAS mutation and PTEN expression analysis showed that the PFS and OS time of patients with two favorable prognostic factors were longer than those of patients with one favorable prognostic factor or no favorable prognostic factor (P < 0.001).CONCLUSION:KRAS mutation and PTEN protein expression are significantly correlated with the response ra     

腋窝淋巴结阴性乳腺癌组织中PTEN、p-Akt、P-gp表达及意义

目的进一步探讨磷酸化Akt（p-Akt）、人第10号染色体缺失的磷酸酶及张力蛋白同源的基因（PTEN）及多药耐药蛋白P-糖蛋白（P-gp）在乳腺癌发生、发展中的作用。方法采用免疫组化法检测81份腋窝淋巴结阴性（LNN）乳腺浸润性癌组织标本中p-Akt、FIEN及P-gp表达,采用四格表的,检验、确切概率法和Cox比例风险模型分析三者与乳腺癌临床病理因素的关系。结果LNN乳腺癌组织中p-Akt阳性表达率明显高于癌旁组织（P=0．034）;PTEN阳性表达率显著低于癌旁组织（P=O．001）;p-Akt过表达与PTEN低表达均与肿瘤分化、雌激素受体（ER）阴性、复发转移和5年生存率有关。P-gp在LNN乳腺癌组织中阳性表达率为39．5％,与肿瘤复发转移显著有关。多因素分析发现,p-Akt和PTEN是影响预后的独立因素,且p-Akt与P-gp表达呈正相关（r=0．548,P=0．045）。结论p-Akt、PTEN及P-gp均参与了乳腺癌的发生、发展,检测三者水平有助于患者预后判断。