Stathmin! An immunohistochemical analysis of the novel marker in Oral Squamous Cell Carcinoma and Oral Leukoplakia.

Background: Stathmin is an intracellular phosphoprotein that controls the microtubule dynamics by further regulating proper attachment and alignment of chromosomes in a dividing cell. Thus, any mutation or aberrantly expressed protein that reduces the fidelity of spindle assembly will enhance chromosomal instability contributing to aneuploidy. Oral Squamous Cell Carcinoma is an extensively studied malignancy that occurs due to accumulated genetic changes due to carcinogens. The current study is done to evaluate the stathmin role and its expression in OSCC and Oral epithelial dysplasia (OED). Objective: The aim of the present study is to evaluate the role of stathmin in OSCC and Oral dysplasia and also to correlate the expression of Stathmin with respect to the different histopathological grades of OED and OSCC. Materials and Methods: 30 neutral buffered formalin fixed, paraffin embedded (FFPE) tissues of Oral Leukoplakia/OED and 30 FFPE tissues of OSCC were subjected to immunohistochemistry with stathmin antibody. Five fields of each case with 300 cells were examined and a mean percentage of positive–stained slides were determined. The percentages were recorded accordingly with their respective histological grades. The results were analysed statistically. Results: The results of the present study demonstrated higher mean values of stathmin in tissues with OSCC (2.50) compared to leukoplakia (2.11) and normal tissues (0.00) with a high level of statistical significance (0.0001). There is also an increase in the percentage levels of stathmin with increase in the histological grade of differentiation in OSCC as well as leukoplakia. Conclusion: The present study found a statistical correlation between increased grades of the disease with expression levels of stathmin. This confirms that stathmin expression can contribute to disease progression and that stathmin might have a potential role as an early diagnostic biomarker and can be a therapeutic target for OSCC.     

Overexpression of cIAP2 contributes to 5-FU resistance and a poor prognosis in oral squamous cell carcinoma

Background:

Resistance to 5-fluorouracil (5-FU) is a major obstacle in treating oral squamous cell carcinoma (OSCC). However, little is known about apoptosis resistance, which contributes to 5-FU resistance in OSCC.

Methods:

We focussed on the cellular inhibitor of apoptosis protein 2 (cIAP2) on the basis of a DNA microarray data using parental and 5-FU-resistant OSCC cell lines. The effects of cIAP2 downregulation on 5-FU sensitivity and apoptosis were evaluated. An immunohistochemical analysis of cIAP2 and related proteins, cIAP1 and X-linked IAP, was performed in 54 OSCC patients who were treated with 5-FU-based chemoradiotherapy and surgery.

Results:

The downregulation of cIAP2 significantly enhanced the sensitivity of the 5-FU-resistant cells to 5-FU, with a significant increase in apoptosis. The immunohistochemical analysis demonstrated a high cIAP2 tumour expression to significantly correlate with the pathological response to chemoradiotherapy. Furthermore, a Cox regression analysis revealed the cIAP2 expression status (hazard ratio, 4.91; P=0.037) and the pathological response to chemoradiotherapy (hazard ratio, 0.418; P=0.016) to be significant prognostic factors for OSCC patients.

Conclusion:

These novel findings demonstrate that cIAP2 may represent a potentially useful therapeutic target for improving the treatment and survival of OSCC patients, particularly in the setting of 5-FU resistance.     

Decrease of Bcl-xL/Bcl-2-associated death promoter in hepatocellular carcinoma indicates poor prognosis

Bcl-xL/Bcl-2-associated death promoter (Bad) is a proapoptotic member of Bcl-2 family and plays a key role in tumor development. To explore the expression of Bad and its clinical significance in hepatocellular carcinoma (HCC), we analyzed a large cohort of 437 HCC samples by tissue microarray (TMA)-based immunohistochemistry. Our data showed that Bad expression was markedly decreased in 50.6% (221/437) of HCC tissues, compared with the adjacent nontumorous tissues. Bad expression was closely associated with adverse clinical characters such as clinical stage (P=0.007), tumor size (P=0.008), vascular invasion (P=0.024), tumor differentiation (P=0.018) and AFP level (P=0.039). Furthermore, Kaplan-Meier analysis indicated that low Bad expression was significantly correlated to overall survival (P<0.0001) but not disease-free survival (P=0.587) and recurrence-free survival (P=0.707) of patients with HCC. Stratified survival analysis further confirmed the prognostic value of Bad. Moreover, multivariate analyses revealed that Bad was an independent indicator of overall survival in HCC (hazard ration=0.589, 95% confidence interval: 0.483-0.717, P<0.0001). Collectively, our data suggest that Bad is down-regulated in HCC and serves as a promising biomarker for poor prognosis of patients with this fatal disease.     

Association of RGS20 expression with the progression and prognosis of renal cell carcinoma

Regulator of G protein signaling 20 (RGS20) has been shown to be highly expressed in various types of cancer. The present study aimed to investigate the effects of RGS20 in patients with renal cell carcinoma (RCC) and in RCC cells. Bioinformatics analysis was performed to analyze the role of RGS20 in RCC. Quantitative PCR and western blotting were used to determine the mRNA and protein expression levels of RGS20 in cells, respectively. After RGS20 inhibition, the proliferation, apoptosis, migration and invasiveness of A-498 cells were tested using MTT assay, EdU assay, propidium iodide staining, Annexin V-FITC/PI kit, wound healing assay and Transwell assay. High RGS20 expression was closely associated with the progression and immune infiltration of RCC, and may be considered as an independent indicator of poor prognosis in RCC. After knocking down RGS20, the proliferation, migration and invasiveness of cells were impaired, the cell cycle was arrested at the G₀/G₁ phase, and the level of apoptosis was increased. In addition, the mRNA expression levels of securin, CDC20 and cyclin B1 were decreased in RGS20-knockdown cells. RGS20 expression was significantly associated with the infiltration level of activated CD4 T cells, type 1 T helper cells and activated dendritic cells. In summary, RGS20 expression was associated with RCC progression and poor prognosis; thus, it may be used to estimate the prognosis of RCC and may serve as a new potential treatment strategy for RCC.     

High expression of aldolase A is associated with tumor progression and poor prognosis in hepatocellular carcinoma

BackgroundAldolase A (ALDOA), a key glycolytic enzyme, has been reported to play an important role in lung, pancreatic, and colorectal cancer. However, the role and mechanism of ALDOA in hepatocellular carcinoma (HCC) are still unclear. This study aimed to study the role and potential mechanism of ALDOA in HCC.MethodsThe changes in expression level and clinical implications of ALDOA in HCC were studied through bioinformatics and online databases. The prognostic role of ALDOA was investigated by Kaplan-Meier and Cox regression survival analysis. We explored the potential mechanism of ALDOA in the development of HCC by gene set enrichment analysis (GSEA).ResultsThe expression level of ALDOA was significantly increased in HCC compared with adjacent normal tissues (P<0.001). The expression level of ALDOA was significantly associated with tumor, node, metastasis (TNM) stage, histologic grade, and p53 mutation (all P<0.05). Prognostically, HCC patients with high expression of ALDOA indicated poorer prognosis and shorter survival time. In addition, univariate and multivariate Cox regression analysis further suggested that overexpression of ALDOA was an independent prognostic risk factor (P<0.05). Furthermore, the nomogram was developed based on ALDOA expression and tumor TNM stage. Besides, ALDOA DNA copy gain and methylation were associated with ALDOA upregulation in HCC. Finally, GSEA suggested that high expression of ALDOA was associated with glucose catabolic process, cell cycle, DNA replication, E2F1 pathways, protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathways, and CD4 T cell related immune biological processes.ConclusionsThere is a close relationship between ALDOA and HCC progression, and ALDOA may be a novel prognostic biomarker and a promising drug target for the treatment of HCC.     

基于TCGA数据库分析肝细胞肝癌组织中HMMR表达与患者临床特征及预后的相关性

目的:研究透明质酸介导的运动受体（hyaluronan-mediated motility receptor,HMMR）的表达与肝细胞肝癌（hepatocellular carcinoma,HCC）的发生发展以及预后的关系。方法:在本研究中,我们通过从癌症基因组图谱(the cancer genome atlas,TCGA)数据库中下载HCC有关的数据进行生物信息学分析,探讨HMMR表达在HCC发生、发展和预后中的价值。根据HMMR mRNA表达的中位值将患者分为两组(HMMR高表达组和HMMR低表达组),应用Kruskal-Wallis检验和Logistic回归分析HMMR表达与患者临床特征之间的关系,利用Kaplan-Meier和Cox分析观察HMMR表达对HCC患者生存的影响,并进行PPI蛋白互作网络、GO富集和KEGG通路分析。最后通过实时荧光定量PCR(quantitative real-time PCR,qRT-PCR)验证HMMR mRNA在HCC组织样本中的表达。结果:HCC组织中HMMR的高表达与组织学分级(G3 vs G1,OR=2.675)、癌组织阶段(Ⅲ vs Ⅰ,OR=2.509）、T分期(T4 vs T1,OR=3.568)相关(P均<0.05)。Kaplan-Meier生存分析显示,HMMR高表达的HCC预后比HMMR低表达的患者差(P=6.858E-05)。Cox分析显示HMMR高表达是总体生存（overall survival,OS）的危险因素（HR:1.166,95%CI:1.027~1.324,P=0.018）。PPI蛋白互作、GO富集和KEGG通路分析鉴定了与HMMR存在相互作用的10个基因,分别为:FAM83D、CD44、TPX2、PLK4、AURKA、PLK1、NEK2、CDK1、BUB1及DLGAP5,它们主要富集在有丝分裂细胞周期相变的调控、细胞周期过程、ECM-受体相互作用、FoxO信号通路、EB病毒感染等。qRT-PCR结果显示,HMMR mRNA在HCC癌组织中高表达（P＜0.05）。结论:HMMR mRNA的高表达与HCC的发生发展密切相关,是HCC预后不良的独立危险因素。     

DF3 epitope expression on MUC1 mucin is associated with tumor aggressiveness,subsequent lymph node metastasis,and poor prognosis in patients with oral squamous cell carcinoma

BACKGROUND:

DF3/MUC1 mucin is expressed in various cancer tissues, and many in vitro studies have suggested that it may play a role in the aggressive behavior of malignant tumors. However, to the best of the authors' knowledge, the relation between DF3/MUC1 expression and outcome has not yet been investigated in patients with oral squamous cell carcinoma (OSCC). The objective of the current study was to evaluate the prognostic significance of DF3/MUC1 expression in patients with OSCC.

METHODS:

The expression profile of DF3/MUC1 in OSCC tissues from 206 patients was examined using immunohistochemistry. Its prognostic significance in OSCC was statistically analyzed on the basis of detailed clinicopathologic factors.

RESULTS:

DF3/MUC1 expression was found to be significantly correlated with tumor aggressiveness, such as pathologic lymph node metastasis (P = .002), advanced tumor stage (P = .02), diffuse invasion of cancer cells (P = .03), and vascular invasion (P = .01). Respectively, the overall survival (OS)and disease‐free survival (DFS) rates were significantly worse for patients with DF3/MUC1 expression compared with those without DF3/MUC1 expression (P = .001 and P = .0003, respectively). Multivariate analysis demonstrated that DF3/MUC1 expression was an independent prognostic factor for both OS and DFS (P = .04 for both). In addition, DF3/MUC1 expression was found to be an independent risk factor for subsequent regional lymph node metastasis (P = .03).

CONCLUSIONS:

Aberrant expression of DF3/MUC1 is an independent prognostic factor indicating poor prognosis in patients with OSCC. DF3/MUC1 expression is a risk factor for subsequent lymph node metastasis in patients with OSCC and therefore may represent an indication for elective neck dissection. Patients with OSCC demonstrating positive expression of DF3/MUC1 should be followed carefully. Cancer 2012. © 2012 American Cancer Society.     

Overexpression of SPAG9 correlates with poor prognosis and tumor progression in hepatocellular carcinoma

Sperm-associated antigen 9 (SPAG9) was reported as a novel biomarker for several cancers and associated with the malignant behavior of cancer cells. However, its expression pattern and biological role in human hepatocellular carcinoma (HCC) have not been reported. In the present study, we analyzed SPAG9 expression in human HCC tissues by immunohistochemistry and found that SPAG9 overexpression is correlated with tumor stage (p?p?=?0.019), tumor size (p?=?0.034), AFP levels (p?=?0.006), and tumor relapse (p?=?0.0017). Furthermore, SPAG9 overexpression is correlated with poor overall survival (p?p?=?0.002). Transfection of SPAG9 small interfering RNA (siRNA) was performed in Bel-7402 cell line. Colony formation and MTT showed that SPAG9 siRNA knockdown inhibited HCC cell proliferation. We also found that SPAG9 depletion could increase cell apoptosis. In addition, the level of cyclin D1 and cyclin E protein expression was downregulated after siRNA treatment. In conclusion, SPAG9 is overexpressed in human HCC and serves as a prognostic marker. SPAG9 contributes to cancer cell growth through regulation of cyclin proteins.     

Overexpression of platelet-derived growth factor receptor alpha promotes tumor progression and indicates poor prognosis in hepatocellular carcinoma

Dysregulation of platelet-derived growth factor receptor alpha (PDGFRα) has been documented in various cancers. However, its role in hepatocellular carcinoma (HCC) remains unknown. We and others have examined that upregulation of PDGFRα might be involved in hepatocarcinogenesis. Here, we report that PDGFRα plays a critical role in HCC progression and prognosis. The expression of PDGFRα was markedly higher in human HCC compared to adjacent liver tissues. Although PDGFRA mRNA was decreased in HCC, PDGF-A mRNA was dramatically increased in HCC. Overexpression of PDGFRα was strongly correlated with microvessel density (MVD) of HCC (p<0.05), as well as macroscopic vascular invasion of the tumors (p<0.05). HCC patients with high PDGFRα expression displayed a shorter overall survival and a higher recurrence rate than those with low PDGFRα expression (p<0.05, respectively). Additionally, stable overexpression of PDGFRα in hepatoma cells promoted cell proliferation, migration, invasion and epithelial-mesenchymal transition in vitro. Similarly, an in vivo assay showed that PDGFRα overexpression in hepatoma cells exhibited remarkably tumorigenic potential in tumor size and weight in vivo, which displayed markedly elevated MVD than controls. Thus, our study provided the evidence that PDGFRα may serve as a candidate prognostic marker and a novel therapeutic target for HCC.     

TIPE1在皮肤鳞状细胞癌中的表达及意义

目的:研究TIPE1在皮肤鳞状细胞癌中的表达变化情况。方法:采用免疫组化方法检测31例皮肤鳞状细胞癌组织和31例正常皮肤组织中TIPE1的表达情况。结果:在正常皮肤组织中,TIPE1弱表达于表皮基底层及棘层下部,在表皮全层表达的阳性率为23.20%。在皮肤鳞状细胞癌中,可见TIPE1高表达于大部分的癌细胞中,阳性率为77.41%。TIPE1在皮肤鳞状细胞癌中的表达显著高于正常皮肤组织(P＜0.05)。结论:TIPE1可能参与皮肤鳞状细胞癌的发生和发展。