Overexpression of nucleolin and different expression sites both related to the prognosis of gastric cancer

The aim of this study was to investigate the expression of nucleolin in tumorous tissues and corresponding non‐malignant tissues in gastric cancer (GC), and the correlation of different expression sites with clinicopathologic parameters and prognosis. Immunohistochemistry was used for detecting the expression levels of nucleolin in GC tissues and corresponding non‐malignant tissues from 124 gastrectomy specimens with stage I–III. Staining results were correlated with clinicopathologic features and survival. Both GC tissues and corresponding non‐malignant tissues showed nucleolar staining for nucleolin. Nucleolin expression was higher in GC tissues than in non‐malignant tissues. Among the 124 GCs, 85 (68.5%) were nucleolin‐high. No significant correlation between nucleolin expression and other clinicopathologic parameters was found. The Cox univariate analysis indicated that both cytoplasmic staining and nucleolar staining of nucleolin expression correlated with patients' prognosis (log‐rank, p < 0.0001; p = 0.0075, respectively). It was concluded in the study that nucleolin was overexpressed in GCs. A high level of nucleolar expression of nucleolin was an independent prognostic marker for better survival while high cytoplasmic staining was closely associated with worse prognosis for GC patients.     

胃癌中hMSH2、PTEN和PCNA表达的相关性及意义

目的：探讨胃癌中错配修复基因 hMSH2与 PTEN、PCNA 表达的关系及意义。方法：采用免疫组织化学 SP 法检测胃癌、癌旁和胃炎粘膜中 hMSH2、PTEN 和 PCNA 的表达。结果：(1)hMSH2和 PCNA 在癌组织的表达阳性率均显著高于非癌组织;PTEN 在癌组织的表达阳性率显著低于非癌组织。(2)PTEN 在低分化癌和有淋巴结转移的病例表达阳性率显著低于高分化癌和无转移者。PCNA 在低分化癌和有淋巴结转移的病例表达阳性率显著高于高分化癌和无转移者。(3)hMSH2与 PCNA 蛋白表达呈显著性正相关;PTEN 与 PCNA 蛋白表达呈显著性负相关。结论：hMSH2的高表达及 hMSH2与 PCNA 表达的相互影响与胃癌的发生可能有关;检测3种蛋白有助于判断胃癌的恶性程度和生物学行为。     

Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma

Jang K‐S, Song Y S, Jang S‐H, Min K‐W, Na W, Jang S M, Jun Y J, Lee K H, Choi D & Paik S S
(2010) Histopathology 56, 229–239 Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma Aims: Tumour suppressor phosphatase and tensin homologue (PTEN) is an important negative regulator for the PIP3/Akt signalling pathway that promotes cell proliferation and inhibits apoptosis. Inactivation of PTEN by mutation, deletion and promoter hypermethylation has been demonstrated in a range of cancers. The aim was to investigate whether the loss of nuclear PTEN protein expression correlates with conventional clinicopathological parameters and patient survival. Methods and results: Immunohistochemistry staining for PTEN was performed on a tissue microarray of 19 samples of normal colonic mucosa, 14 adenomatous polyps, 482 adenocarcinomas and 56 metastatic lymph nodes. All 19 normal colonic mucosa samples (100%) were positive and 12 (85.7%) out of 14 adenomatous polyps were positive for PTEN. However, only 241 (50.0%) of the 482 colorectal adenocarcinomas and 26 (46.4%) of the 56 metastatic lymph nodes were positive for PTEN. Loss of PTEN expression was related to defective mismatch repair protein expression and colonic localization rather than rectal localization. On univariate survival analysis, patients with PTEN? adenocarcinoma revealed a poor overall and disease‐free survival (P = 0.030 and P = 0.046, respectively). On multivariate analysis, a significant difference was observed in patients with stage II cancer that was not observed in other stages. Conclusions: Nuclear PTEN expression gradually decrease during the normal–adenoma–adenocarcinoma–metastasis sequence, which suggests an important role for PTEN in carcinogenesis. Moreover, loss of nuclear PTEN expression was a marker of poor clinical outcome in patients with stage II colorectal cancer.     

Increased MT2-MMP expression in gastric cancer patients is associated with poor prognosis

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that contribute to tumorigenesis and metastasis due to their ability to degrade the extracellular matrix (ECM) and basement membrane. In despite of many reports in other solid tumors, the role of membrane type-2 MMP (MT2-MMP) in gastric cancer (GC) remains to be elucidated. The aim of this study was to investigate MT2-MMP expression in human GC tissue microarray (TMA) samples using immunohistochemistry (IHC). We found that MT2-MMP expression in tumor tissues was significantly higher compared to peritumoral tissues (P < 0.01). However, there were no statistically significant differences between MT2-MMP expression and clinicopathological parameters. In addition, univariate and multivariate Cox regression analysis showed GC patients with high MT2-MMP expression have poor overall survival (OS) compared to patients with low MT2-MMP expression (P = 0.013, P = 0.040, respectively). In conclusion, MT2-MMP is involved in GC invasion and metastasis and may serve as an independent prognostic factor for GC patients.     

Long non-coding RNA CCAT2 is up-regulated in gastric cancer and associated with poor prognosis

Introduction: Dysregulation of long non-coding RNAs (lncRNAs) play important roles in tumor progression. The aim of our study was to explore the clinicopathologic and prognostic significance of lncRNA CCAT2 expression in human gastric cancer. Methods: Expression levels of lncRNA CCAT2 in 85 pairs of gastric cancer and adjacent non-tumor tissues were detected by quantitative real-time PCR (qRT-PCR). In order to determine its prognostic value, overall survival and progression-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results: Expression levels of lncRNA CCAT2 in gastric cancer tissues were significantly higher than those in adjacent non-tumor tissues. By statistical analyses, high lncRNA CCAT2 expression was observed to be closely correlated with higher incidence of lymph node metastasis and distance metastasis. Moreover, patients with high lncRNA CCAT2 expression had shorter overall survival and progression-free survival compared with the low lncRNA CCAT2 group. Multivariate analyses indicated that high lncRNA CCAT2 expression was an independent poor prognostic factor for gastric cancer patients. Conclusions: Our results suggested that up-regulation of lncRNA CCAT2 was correlated with gastric cancer progression, and lncRNA CCAT2 might be a potential molecular biomarker for predicting the prognosis of patients.     

Tertiary lymphoid structures and gastric cancer prognosis

Tertiary lymphoid structures (TLSs) are part of immune response against cancer. Their high density and high diameter have been shown to be associated with prognosis in different cancer types. The aim of this study was to examine the prognostic significance of TLS density and diameter in gastric cancer and reproducibility of their assessments. TLS densities and maximal TLS diameter were assessed from hematoxylin–eosin (HE) stained slides of 721 surgically treated gastric cancer patients from two hospitals in Finland. Mortality hazard ratios (HRs) for TLS densities and maximal TLS diameter were analyzed. TLS densities and maximal TLS diameter were assessed with moderate interobserver agreement (Cohen's kappa 0.50–0.62). Maximal TLS density was not associated with survival (adjusted HR 0.85, 95% CI 0.70–1.02) and neither was hotspot TLS density (adjusted HR 0.85, 95% CI 0.70–1.02). High maximal TLS diameter was associated with longer survival in overall study population (adjusted HR 0.74, 95% CI 0.61–0.89) and in diffuse type subgroup (adjusted HR 0.65, 95% CI 0.50–0.85). In conclusion, high maximal TLS diameter is associated with improved survival in gastric cancer and can be assessed from HE-stained slides. Its prognostic value might be limited to diffuse histological type.     

EZH2 promotes gastric cancer cells proliferation by repressing p21 expression

EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and promotes carcinogenesis by epigenetically silencing many tumor suppressor genes. Increased EZH2 expression is a marker of advanced and metastatic in many cancers, including lung, prostate and breast cancer, and it has been considered as a potential novel therapeutic target. However, the clinical significance and molecular mechanisms of EZH2 controlling gastric cancer cell proliferation and invasion are not well documented. In this study, immunohistochemical analysis was conducted to investigate the EZH2 expression in gastric cancer. We found that EZH2 levels were increased in gastric cancer tissues compared with adjacent normal tissues. Moreover, patients with high levels of EZH2 expression had a relatively poor prognosis. Furthermore, knockdown of EZH2 expression by siRNA could impair cell proliferation and invasion both in vitro and vivo. Finally, we found that EZH2 influences gastric cancer cells proliferation partly through regulating p21 expression. Our findings present that EZH2 over-expression can be identified as a poor prognostic biomarker in gastric cancer.     

Elevated epiregulin expression predicts poor prognosis in gastric cancer

Epiregulin (EREG) is a novel family member of EGF-like ligands and have elevated expression in a variety of human cancers. EREG expression promotes tumor progression and metastasis and reduces patient survival. However, the expression of EREG and its prognostic value are not clear in gastric cancer (GC). We assessed EREG mRNA and protein expression in GC tissues from Chinese patients using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining of tissue microarray, and analyzed the correlation between the level of EREG expression and patient clinical characteristics and prognosis. We found that EREG expression was significantly higher in GC tissues than in matched adjacent noncancerous tissues. High EREG protein expression in GC was significantly associated with TNM stage including tumor size, lymph node metastases and distant metastases as well as poor overall survival. These finding demonstrate that EREG is an independent prognostic biomarker for GC.     

Aberrant Cdx2 expression in endometrial lesions with squamous differentiation: important role of Cdx2 in squamous morula formation

Only a few reports have described Cdx2 expression in endometrial lesions of the uterus. Our aim was to determine whether Cdx2 expression is related to squamous differentiation in endometrial lesions. Furthermore, we examined whether there is any correlation between Cdx2 and beta-catenin, a well-known marker of aberrant nuclear accumulation in endometrial squamous foci secondary to mutation. We performed immunohistochemical analysis of 225 cases (29 normal endometrium, 28 nonproliferative conditions, 21 polyps, 46 hyperplasias, and 101 endometrioid carcinomas) that included 72 cases (4 polyps, 16 hyperplasias, and 52 carcinomas) showing morular or keratinizing squamous differentiation (SD(+)). Normal endometrium and nonproliferative conditions showed no staining for Cdx2. Whereas there was a low rate of Cdx2 positivity in SD(-) polyps (5.9%) and hyperplasias (10%), all SD(+) lesions expressed Cdx2 (P < .001). Thirty-eight (73%) of the SD(+) carcinomas were positive for Cdx2, whereas only 6 SD(-) cases (14.0%) were positive (P < .001). Furthermore, the larger the number of squamous foci, the greater the number of Cdx2-positive cells that was found. The labeling indices of Cdx2 were significantly higher in morular components than in keratinizing or glandular ones (P < .001). There was a strong correlation of the labeling indices of Cdx2 and beta-catenin in squamous foci of hyperplasias and carcinomas. Using immunofluorescence, we confirmed the coexpression of the 2 markers. The Cdx2 protein is expressed frequently in endometrial lesions with squamous differentiation, especially morular-type differentiation, and correlates strongly with nuclear beta-catenin expression. These facts suggest that Cdx2 plays an important role in squamous morula formation.     

Advanced gastric cancer and prognosis

Summary The morphological features of 158 gastric carcinomas were analyzed in an attempt to identify patterns best correlated with prognosis. To this end, the depth of infiltration, vascular invasion, intra- and perineoplastic lymphocytic infiltrate, lymph node metastases and number of metastatic lymph nodes were evaluated according to the several classifications for advanced gastric cancer. A good correlation between prognosis and histological features of malignancy were observed, as well as different five-year survival rates for Mulligan, Lauren and Ming histotypes However, when the influence of each single morphological criteria of malignancy was examined, these differences disappeared for Mulligan and Lauren histotypes. On the other hand, the better prognosis for Ming expanding type carcinomas appeared unrelated to any individual feature of malignancy.     

Overexpression of metabolic markers HK1 and PKM2 contributes to lymphatic metastasis and adverse prognosis in Chinese gastric cancer

Hexokinase 1 (HK1) and pyruvate kinase M2 (PKM2) are two key regulators in glycosis and oncogenic markers in cancers. In the present study, we investigated the expression profile by Western blotting and immunohistochemistry and determined their prognostic values in the gastric cancer. Expression of HK1 and PKM2 was remarkably increased in gastric cancer tissues and was significantly associated lymphatic metastasis and advanced TNM staging. In the COX regression model, HK1 and TNM stage were analyzed as adverse prognostic indicators in gastric cancer. Furthermore, patients with HK1 expression showed remarkable shorter survival duration in both lymphatic metastasis cohort and advanced staging cohort. Our results suggest that overexpression of PKM2 and HK1, especially the latter, significantly associates with lymphatic metastasis, advanced clinical staging and unfavorable prognosis in gastric cancer.     

Fascin expression is related to poor survival in gastric cancer

Fascin is an actin‐binding protein that provides mechanical support and cell motility, and involves cancer cell metastasis. We investigated fascin protein expression in gastric cancer and assessed their relationship with clinicopathologic parameters and survival rates. In addition, we researched galectin‐3 protein expression to study fascin action mechanisms. We performed immunohistochemisty with fascin and galectin‐3 antibodies in 471 gastric carcinomas, using tissue microarrays. Fascin was positive in 14.9% (70/471) of the samples, and fascin expression was related to worse survival rates (P < 0.001), high clinical stage (P < 0.001), high T stage (P < 0.001), nodal metastasis (P < 0.001), lymphovascular invasion (P= 0.001) and the intestinal type of Lauren classification (P= 0.015). Galectin‐3 protein expression was positive in 83.9% (395/471) of the samples and was reversely correlated with fascin protein expression (P= 0.020). Galectin‐3 expression was related to low clinical stage (P < 0.001), but not to survival rates in multivariate analysis. In multivariate analysis, fascin expression was related to worse survival rates (HR = 1.56, P= 0.036), and can be an independent poor prognostic factor in gastric cancer.     

胃腺癌IGFBP4的表达与患者预后的关系

目的探讨胃腺癌中胰岛素样生长因子结合蛋白4(IGFBP4)的表达情况及预后意义。方法免疫组织化学技术检测2000年1月至2006年12月间401例胃癌术后标本中IGFBP4的表达,并探讨IGFBP4表达与临床病理参数及预后相关性。结果结果显示401例患者中208例(51.9%)IGFBP4表达下调,且在低分化胃腺癌、T4a/b、及Ⅲ/Ⅳ期胃癌患者中表达下调明显。生存分析显示IGFBP4低表达与较差的预后相关(P<0.001)。多因素分析显示IGFBP4可作为一个独立预后风险因素(HR=2.175,P<0.001)。结论 IGFBP4在胃腺癌中表达下调,提示预后不良。