基于iTRAQ蛋白质组学技术对前列腺癌血清标志物的筛查

目的:应用同位素标记相对和绝对定量（iTRAQ）蛋白质组学技术筛选前列腺癌血清中的差异表达蛋白质,提供新的候选标志物。方法:收集4组患者的外周血清标本:良性前列腺增生（BPH）（n=10）、高级别前列腺上皮内瘤变（HGPIN）（n=10）、局限性前列腺癌（localized PCa）（n=10）以及伴有远处转移的前列腺癌（metastatic PCa）（n=10）。每组10例患者的血清样本进行等体积混合后,应用iTRAQ技术联合液相串联质谱分析（LC-ESI-MS/MS）对蛋白质进行鉴定和相对定量。结果:在患者外周血清中共鉴定到蛋白质825个。相对于良性前列腺增生,在前列腺癌组中表达差异在1.2倍以上的蛋白质13个,其中9个表达上调,4个表达下调。结论:基于iTRAQ技术的蛋白质组学方法有助于鉴定出前列腺癌相关的差异蛋白质,为进一步探索前列腺癌肿瘤标志物提供了新的思路和线索。     

Proteomics-based signature for human benign prostate hyperplasia and prostate adenocarcinoma

Prostate adenocarcinoma often presents at a late stage, due to a lack of early clinical symptoms and lack of accurate objective markers. This study aimed to identify and validate proteomics-based biomarkers useful for prostate cancer diagnosis and to establish a marker-panel for prostate cancer and benign prostate hyperplasia (BPH). Global protein expression patterns in fresh tissue specimens from 8 patients with prostate carcinoma and 16 with BPH were analyzed by two-dimensional gel electrophoresis. Differentially expressed proteins were identified by MALDI-TOF mass spectrometry. We compared our results with those of published studies and defined a set of common biomarkers. We identified 22 differentially expressed proteins between BPH and prostate carcinomas. The up-regulated proteins in cancer compared to BPH included protein disulfide-isomerase, 14-3-3-protein, Enoyl CoA-hydrase, prohibitin and B-tubulin β-2. Keratin-II, desmin, HSP71, ATP-synthase-β-chain and creatine kinase-β-chain were down-regulated. Survey of the literature showed that 15 of our 22 identified proteins have been previously reported to differ in their expression levels between BPH and prostate cancer by other laboratories. The expression patterns of these biomarkers could successfully cluster BPH and adenocarcinomas as well as prostate cancer of low and high Gleason scores. This study validates protein-biomarkers that can be useful for accurate diagnosis and prognostic monitoring of prostate adenocarcinoma. Despite varied prevalence of the disease between different ethnic populations (i.e., high in Sweden, low in Saudi Arabia); the biomarkers indicate that BPH and prostate cancers are biologically 'homogeneous' in their protein expression patterns across wide geographical regions.     

Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues: implications for prostate carcinogenesis and progression of prostate cancer

OBJECTIVE: Prostate stem cell antigen (PSCA) is a recently defined homolog of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. The objective of the present study was to examine the expression status of PSCA protein and mRNA in clinical specimens of human prostate cancer (PCa) and to validate it as a potential molecular target for diagnosis and treatment of PCa. METHODS: Immunohistochemical (IHC) and in situ hybridization (ISH) analyses of PSCA expression were simultaneously performed on paraffin-embedded sections of 20 benign prostatic hyperplasia (BPH), 20 prostatic intraepithelial neoplasm (PIN) and 48 prostate cancer (PCa) tissues, including 9 androgen-independent prostate cancers. The level of PSCA expression was semiquantitatively scored by assessing both the percentage and intensity of PSCA-positive staining cells in the specimens. We then compared the PSCA expression between BPH, PIN and PCa tissues and analyzed the correlations of PSCA expression level with pathological grade, clinical stage and progression to androgen-independence in PCa. RESULTS: In BPH and low grade PIN, PSCA protein and mRNA staining were weak or negative and less intense and uniform than that observed in high grade PIN (HGPIN) and PCa. Moderate to strong PSCA protein and mRNA expression were noted in 8 of 11 (72.7%) HGPIN and in 40 of 48 (83.4%) PCa specimens examined by IHC and ISH analyses, and their statistical significance was compared with BPH (20%) and low-grade PIN (22.2%) specimens (P < 0.05). The expression level of PSCA increased with a higher Gleason grade, advanced stage and progression to androgen-independence (P < 0.05). In addition, IHC and ISH staining revealed a high degree of correlation between PSCA protein and mRNA overexpression. CONCLUSIONS: Our data demonstrate that PSCA as a new cell surface marker is overexpressed in a majority of cases of human PCa. PSCA expression correlates positively with adverse tumor characteristics, such as increasing pathological grade (poor cell differentiation), worsening clinical stage and androgen-independence and speculatively with prostate carcinogenesis. PSCA may possess prognostic utility and may be a promising molecular target for diagnosis and treatment of PCa.     

Use of multiple biomarkers for a molecular diagnosis of prostate cancer

The identification of biomarkers capable of providing a reliable molecular diagnostic test for prostate cancer (PCa) is highly desirable clinically. We describe here 4 biomarkers, UDP-N-Acetyl-alpha-D-galactosamine transferase (GalNAc-T3; not previously associated with PCa), PSMA, Hepsin and DD3/PCA3, which, in combination, distinguish prostate cancer from benign prostate hyperplasia (BPH). GalNAc-T3 was identified as overexpressed in PCa tissues by microarray analysis, confirmed by quantitative real-time PCR and shown immunohistochemically to be localised to prostate epithelial cells with higher expression in malignant cells. Real-time quantitative PCR analysis across 21 PCa and 34 BPH tissues showed 4.6-fold overexpression of GalNAc-T3 (p = 0.005). The noncoding mRNA (DD3/PCA3) was overexpressed 140-fold (p = 0.007) in the cancer samples compared to BPH tissues. Hepsin was overexpressed 21-fold (p = 0.049, whereas the overexpression for PSMA was 66-fold (p = 0.047). When the gene expression data for these 4 biomarkers was combined in a logistic regression model, a predictive index was obtained that distinguished 100% of the PCa samples from all of the BPH samples. Therefore, combining these genes in a real-time PCR assay represents a powerful new approach to diagnosing PCa by molecular profiling. (Supplemental material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)     

增殖细胞核抗原和p27在前列腺增生和前列腺癌组织中的表达及意义

目的　探讨增殖细胞核抗原 (PCNA)和p2 7蛋白在前列腺增生及前列腺癌组织中的表达 ,及其与肿瘤发生发展的关系。方法　应用免疫组化S P法 ,检测 30例前列腺增生和 37例前列腺癌石蜡包埋存档标本组织中PCNA、p2 7蛋白的表达 ,对其在前列腺增生及前列腺癌不同病理分级、临床分期中的表达进行对比分析和相关性研究。结果　前列腺增生组织的PCNA强阳性表达率(3.3% )与前列腺癌组织 (83.8% )相比 ,差异有显著性 (P <0 .0 1)。前列腺增生组织中p2 7蛋白高表达 ( )率 (70 .0 % )与前列腺癌 (2 7.0 % )相比 ,差异有显著性 (P <0 .0 5 ) ,p2 7蛋白表达与前列腺癌组织的分化程度及临床分期无关 (P >0 .0 5 )。前列腺增生组织中 ,PCNA与p2 7蛋白表达呈负相关 (P <0 .0 1) ;前列腺癌组织中 ,PCNA与p2 7蛋白表达无相关性 (P >0 .0 5 )。结论　p2 7蛋白表达减少或缺失与前列腺肿瘤的发生有关 ,而与恶性肿瘤的进展无关 ,其表达的缺失是前列腺癌重要的阴性预测因子 ;PCNA表达程度不仅与前列腺增生及前列腺癌的发生有关 ,而且与前列腺癌的恶性行为有关 ,PCNA的检测对判断肿瘤的性质、转移及预后有重要的临床意义     

Differential blood-based diagnosis between benign prostatic hyperplasia and prostate cancer: miRNA as source for biomarkers independent of PSA level,Gleason score,or TNM status

Since the benefit of prostate-specific antigen (PSA) screening remains controversial, new non-invasive biomarkers for prostate carcinoma (PCa) are still required. There is evidence that microRNAs (miRNAs) in whole peripheral blood can separate patients with localized prostate cancer from healthy individuals. However, the potential of blood-based miRNAs for the differential diagnosis of PCa and benign prostatic hyperplasia (BPH) has not been tested. We compared the miRNome from blood of PCa and BPH patients and further investigated the influence of the tumor volume, tumor-node-metastasis (TNM) classification, Gleason score, pretreatment risk status, and the pretreatment PSA value on the miRNA pattern. By microarray approach, we identified seven miRNAs that were significantly deregulated in PCa patients compared to BPH patients. Using quantitative real time PCR (qRT-PCR), we confirmed downregulation of hsa-miR-221* (now hsa-miR-221-5p) and hsa-miR-708* (now hsa-miR-708-3p) in PCa compared to BPH. Clinical parameters like PSA level, Gleason score, or TNM status seem to have only limited impact on the overall abundance of miRNAs in patients’ blood, suggesting a no influence of these factors on the expression of deregulated miRNAs.     

A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue

Prostate-specific antigen (PSA) is a widely used serum marker for prostate cancer (PCa), but in the critical diagnostic range of 4-10 ng/ml it has limited specificity for distinguishing early PCa from benign prostatic hyperplasia (BPH). PSA in serum is comprised of a variety of both "free" and "complexed" forms that have been used to improve the specificity of PSA for prostate cancer detection. We previously reported that pro PSA (pPSA), the zymogen or precursor form of PSA, is a component of free PSA in the serum of PCa patients. In the current study, we examined prostate tissues to understand the origin and specificity of pPSA. PSA was immuno-affinity purified from matched sets of prostate tissues including peripheral zone cancer (PZ-C); peripheral zone noncancer; and benign tissue from the transition zone (TZ), the primary site of BPH within the prostate. We found that pPSA is differentially elevated in PZ-C, but is largely undetectable in TZ. N-terminal sequencing revealed that the pPSA was comprised primarily of [-2]pPSA and minor levels of [-4]pPSA, containing pro leader peptides of 2 and 4 amino acids, respectively. The median value of pPSA was 3% in PZ-C and 0% (undetectable) in TZ (P < 0.0026). No pPSA was detected in 13 of 18 transition zone specimens (72%), but only 2 of the 18 matched cancer specimens (11%) contained no measurable pPSA. These results demonstrate that pPSA is more highly correlated with prostate cancer than with BPH. The pPSA in serum may represent a more cancer-specific form of PSA that could help distinguish prostate cancer from BPH.     

Classical and Alternative Nuclear Factor-κB Pathways: A Comparison among Normal Prostate, Benign Prostate Hyperplasia and Prostate Cancer

Nuclear factor-κB (NF-κB) is controlled by the classical and alternative NF-κB pathways, the role of which in prostate cancer (PCa) is not clearly defined. To provide this missing translational link, we compared the classical and alternative NF-κB pathways in normal prostate, benign prostate hyperplasia (BPH) and PCa. Prostate specimens were divided into three groups: group A, PCa (n?=?68); group B, BPH (n?=?60); and group C, normal prostates (n?=?15). The gene expression levels of NF-κB1 and NF-κB2 were determined by real-time quantitative RT-PCR. Additionally, we analyzed the expression and sub-cellular localization of phosphorylated P50 (p-P50) and phosphorylated P52 (p-P52) proteins by immunohistochemical staining. Furthermore, associations were made between NF-κB pathway proteins and patients' prognosis. Compared with BPH and normal prostate tissues, the expression of NF-κB1 gene was differentially down-regulated by >1.5-fold, whereas NF-κB2 gene was differentially up-regulated by >2-fold in PCa tissues. The proportion of p-P50 positive patients in group A (26.5%) was significantly lower than in group B (88.3%, p?=?0.005) and C (100%, p?=?0.002). The proportion of p-P52 positive patients in group A (42.6%) was significantly higher than in group B (11.7%, p?=?0.009) and C (6.7%, p?=?0.008). Comparison of the survival curves in group A according to p-P52 expression showed a significant difference between positive and negative patients. The p-P52 positive patients showed worse prognosis (p?=?0.019). Our findings suggest for the first time that the classical and alternative NF-κB pathways have an important role in PCa. p-P52 might be a predictor of poor prognosis for PCa.     

加兰肽在前列腺癌组织中的表达及其意义

 目的　研究加兰肽（GLA）在前列腺癌组织中的表达及其临床意义。方法　采用免疫组织化学法检测GLA在50例前列腺增生、50例前列腺癌和30例发生骨转移的前列腺癌组织中的表达。结果　GLA在前列腺增生、前列腺癌及骨转移前列腺癌组织中阳性表达率分别为18 %（9／50）、68 %（34／50）和80 %（24／30）,前列腺癌及骨转移组阳性表达率高于前列腺增生组,组间比较差异有统计学意义（χ2值分别为25.5、29.74,均P＜0.01）,但骨转移组与前列腺癌组阳性表达率比较差异无统计学意义（χ2＝1.35,P＞0.05）。结论　GLA在前列腺癌组织中有较高表达,可作为良恶性前列腺疾病的鉴别指标,为前列腺癌的诊断及预测预后提供一定依据。     

Identification of claudin-4 as a marker highly overexpressed in both primary and metastatic prostate cancer

In the quest for markers of expression and progression for prostate cancer (PCa), the majority of studies have focussed on molecular data exclusively from primary tumours. Although expression in metastases is inferred, a lack of correlation with secondary tumours potentially limits their applicability diagnostically and therapeutically. Molecular targets were identified by examining expression profiles of prostate cell lines using cDNA microarrays. Those genes identified were verified on PCa cell lines and tumour samples from both primary and secondary tumours using real-time RT-PCR, western blotting and immunohistochemistry. Claudin-4, coding for an integral membrane cell-junction protein, was the most significantly (P<0.00001) upregulated marker in both primary and metastatic tumour specimens compared with benign prostatic hyperplasia at both RNA and protein levels. In primary tumours, claudin-4 was more highly expressed in lower grade (Gleason 6) lesions than in higher grade (Gleason >or=7) cancers. Expression was prominent throughout metastases from a variety of secondary sites in fresh-frozen and formalin-fixed specimens from both androgen-intact and androgen-suppressed patients. As a result of its prominent expression in both primary and secondary PCas, together with its established role as a receptor for Clostridium perfringens enterotoxin, claudin-4 may be useful as a potential marker and therapeutic target for PCa metastases.     

Expression and significance of microsomal prostaglandin synthase-1 (mPGES-1) and Beclin-1 in the development of prostate cancer

The aim of this study was to investigate the expression and significance of microsomal prostaglandin synthase-1 (mPGES-1) and Beclin-1 in the development of prostate cancer (PCa). Immunohistochemistry was performed on paraffin-embedded sections with rabbit polyclonal against mPGES-1 and Beclin-1 in 40 PCa, 40 benign prostatic hyperplasia (BPH) and 10 normal prostate specimens for this purpose. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied for mRNA expression of mPGES-1 and Beclin-1, while MTT assays were used to ascertain the best working concentration of the mPGES-1 inhibitor (CAY10526). The effect of CAY10526 treatment on expression of Beclin-1 in DU-145 cells was studied using Western blot analysis. Localization of Beclin-1 and mPGES-1 was in endochylema. Significant differences in expression was noted among PCa, BPH and normal issues (P<0.05). Beclin-1 expression inversely correlated with mPGES-1 expression in PCa tissue (P<0.05). CAY10526 could significantly block mPGES-1 expression and the proliferation of DU-145 cells (P<0.05), while increasing Beclin-1 levels (P<0.05). Overexpression of mPGES-1 could decrease the autophagic PCa cell death. Inhibiting the expression of mPGES-1 may lead to DU-145 cell death and up-regulation of Beclin-1. The results suggest that inhibition of mPGES-1 may have therapeutic potential for PCa in the future.     

hK2、Ki-67在前列腺癌组织中的表达及其临床意义

目的探讨hK2、Ki-67基因在前列腺癌组织中的表达和临床意义。方法应用免疫组织化学sP法检测40例前列腺癌和30例前列腺增生组织中hK2和Ki-67基因的表达情况。结果前列腺癌组织中hK2、Ki-67的阳性表达率明显高于前列腺增生组织（P〈0．05）。hK2阳性表达与前列腺癌的Gleason分级有关（P〈0．05）,与临床分期无关（P〉0．05）;Ki-67的阳性表达与Gleason分级无关（P〉0．05）,与临床分期有关（P〈0．05）。hK2和Ki-67在前列腺癌组织中的表达呈正相关（P〈0．05）。结论hK2、Ki-67异常表达与前列腺癌的诊断及预后密切相关,联合检测二者的表达有可能作为前列腺癌诊断和预后评估的指标。     

Prognostication of prostate cancer based on NUCB2 protein assessment: NUCB2 in prostate cancer

Background

Nucleobindin 2 (NUCB2) protein, a novel oncoprotein, is overexpressed in breast cancer. To date, there have been no published data regarding the role of NUCB2 protein expression in prostate cancer (PCa). Therefore, this study was performed to investigate the correlations between NUCB2 protein expression and prognosis in patients with PCa.

Methods

Through immunohistochemistry, NUCB2 protein expression was evaluated in 60 benign prostatic hyperplasia (BPH) specimens and 180 PCa specimens. The correlation of NUCB2 protein expression with clinicopathological parameters was assessed using χ² analysis. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between NUCB2 protein expression and prognosis of PCa patients.

Results

The immunohistochemistry results showed that the expression level of NUCB2 in PCa cases was significantly higher than that in BPH tissues (P < 0.001). Moreover, statistical analysis also showed that high NUCB2 protein expression was positively related to seminal vesicle invasion, lymph node metastasis, angiolymphatic invasion, higher Gleason score, biochemical recurrence (BCR), and higher preoperative prostate-specific antigen (PSA). Furthermore, it was also shown that patients with high NUCB2 protein expression had significantly poorer overall survival and BCR- free survival compared with patients with low expression of NUCB2 protein. Multivariate Cox regression analysis revealed that high NUCB2 protein expression level was an independent prognostic factor for overall survival and BCR-free survival of patients with PCa.

Conclusions

NUCB2 protein expression showed a strong association with the potencies of BCR and progression of PCa, and that may be applied as a novel biomarker for the prediction of BCR, and helpful for improving the diagnosis, prognosis and treatment of PCa.     

CD40和 Id4在前列腺癌中的表达及意义

目的：探讨 CD40和 Id4在前列腺癌中的表达及意义。方法：应用免疫组化技术,选取71例前列腺癌、40例高级别前列腺内瘤病（HGPIN）及30例前列腺增生症（BPH）标本,检测 CD40和 Id4在上述组织中的表达差异。结果：71例前列腺癌标本中,CD40总体阳性表达率达67．6％,且以阳性和强阳性表达为主,阳性表达率显著高于其它两组,差异有统计学意义（P ＜0．05）。前列腺癌组,CD40蛋白阳性表达率随病理组织学分级的升高而升高,在高分化、中分化及低分化期依次是28．6％、68．0％、74．4％,高分化组与其他两组比较差异有统计学意义（P 均＜0．05）;三组中 Id4因子阳性表达率呈逐渐下降趋势,前列腺癌组 Id4阳性表达率与 HGPIN 组、BPH 组两组间分别比较,均有显著差异（P ＜0．05）。在前列腺癌病理分级中,Id4因子阳性表达率随肿瘤病理分级的增高而增加,分别为高分化57．1％、中分化68．0％、低分化76．9％,但三组间进行统计学比较无显著差异（P ＞0．05）。结论：CD40、Id4二者的异常表达在前列腺癌生物学行为中可能起着重要作用,可为将来前列腺癌的生物免疫治疗及基因治疗研究提供新的选择。     

前列腺特异性膜抗原在前列腺癌患者外周血和组织中的表达及意义

目的探讨前列腺特异性膜抗原（PSMA）在前列腺癌患者（PCa）外周血和组织中的表达及其与肿瘤病理分级和临床分期之间的关系。方法采用RT-PCR方法检测前列腺特异性膜抗原（PSMA）在前列腺癌和良性增生患者外周血清中的表达;采用免疫组化法观察PSMA在前列腺不同病变组织中的表达。前列腺癌28例,前列腺上皮内瘤（PIN）7例,良性前列腺增生（BPH）30例。结果血清学检测显示PSMA mRNA在前列腺癌和良性病变组（包括PIN和BPH）患者外周血中阳性率分别为67.9%和8.1%,两者差异具有显著性（P〈0.01）。在局限性癌、局部进展性癌和远处转移癌患者外周血肿瘤细胞中,PSMA mRNA的阳性率分别为58.3%、66.7%和85.7%,随前列腺癌临床分期的进展而逐渐递增（P〈0.05）。在高分化、中分化和低分化前列腺癌中,PSMA mRNA的阳性率分别为87.5%、62.5%和50%,肿瘤分化越差,其阳性率越低（P〈0.05）。组织学检测显示PSMA在PCa、PIN、BPH三种不同前列腺病变组织中的阳性率分别为60.7%、28.6%和20.0%（P〈0.05）,在高、中、低分化前列腺癌组织中PSMA的阳性率分别为100.0%、50.0%和25.0%,与肿瘤Gleason评分之间呈负相关（P〈0.05）。在局限性癌、局部进展性癌和远处转移癌患者肿瘤组织中,PSMA的阳性率分别为58.3%（7/12）、77.8%（7/9）和42.9%（3/7）（P〉0.05）。结论PSMA在前列腺癌组织中明显高表达,并且表达量与前列腺癌临床分期和分化程度（组织学分级）密切相关;检测PSMA可能对前列腺癌诊断、治疗方案的选择及预后评估具有重要价值。     

DNA methylation status is more reliable than gene expression at detecting cancer in prostate biopsy

Background:

We analysed critically the potential usefulness of RNA- and DNA-based biomarkers in supporting conventional histological diagnostic tests for prostate carcinoma (PCa) detection.

Methods:

Microarray profiling of gene expression and DNA methylation was performed on 16 benign prostatic hyperplasia (BPH) and 32 cancerous and non-cancerous prostate samples extracted by radical prostatectomy. The predictive value of the selected biomarkers was validated by qPCR-based methods using tissue samples extracted from the 58 prostates and, separately, using 227 prostate core biopsies.

Results:

HOXC6, AMACR and PCA3 expression showed the best discrimination between PCa and BPH. All three genes were previously reported as the most promising mRNA-based markers for distinguishing cancerous lesions from benign prostate lesions; however, none were sufficiently sensitive and specific to meet the criteria for a PCa diagnostic biomarker. By contrast, DNA methylation levels of the APC, TACC2, RARB, DGKZ and HES5 promoter regions achieved high discriminating sensitivity and specificity, with area under the curve (AUCs) reaching 0.95−1.0. Only a small overlap was detected between the DNA methylation levels of PCa-positive and PCa-negative needle biopsies, with AUCs ranging between 0.854 and 0.899.

Conclusions:

DNA methylation-based biomarkers reflect the prostate malignancy and might be useful in supporting clinical decisions for suspected PCa following an initial negative prostate biopsy.     

Expression analysis of delta-catenin and prostate-specific membrane antigen: their potential as diagnostic markers for prostate cancer

The current approach to prostate cancer diagnosis has major limitations including the inability of prostate-specific antigen (PSA) assays to accurately differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the imprecision of transrectal ultrasound (TRUS) biopsy sampling. We have employed cDNA microarray screening to compare gene expression patterns in BPH and tumour samples to identify expression markers that may be useful in discriminating between these conditions. Screening of 3 individual cDNA arrays identified 8 genes with expression 3-fold greater in 6 tumour tissues than in 1 nontumour sample and 1 BPH sample. Real-time PCR was used to confirm the overexpression of these 8 genes and 12 genes selected from the literature against a panel of 17 tumours and 11 BPH samples. Two genes, delta-catenin (delta-catenin; CTNND2) and prostate-specific membrane antigen (PSMA; FOLH1), were significantly overexpressed in prostate cancer compared to BPH. Prostate epithelial cells stained positively for delta-catenin and PSMA in our prostate cancer tissues, whereas the majority of our BPH tissues were negative for both markers. Thus we have identified delta-catenin (not previously associated with prostatic adenocarcinoma) and confirmed the potential of PSMA as potential candidates for the diagnosis and management of prostate cancer.     

Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression

Prostate cancer (PCa) is the most common form of cancer in American men. Mortality from PCa is caused by the movement of cancer cells from the primary organ to form metastatic tumors at distant sites. Heat shock protein 27 (HSP27) is known to increase human PCa cell invasion and its overexpression is associated with metastatic disease. The role of HSP27 in driving PCa cell movement from the prostate to distant metastatic sites is unknown. Increased HSP27 expression increased metastasis as well as primary tumor mass. In vitro studies further examined the mechanism of HSP27-induced metastatic behavior. HSP27 did not affect cell detachment, adhesion, or migration, but did increase cell invasion. Cell invasion was dependent upon matrix metalloproteinase 2 (MMP-2), whose expression was increased by HSP27. In vivo, HSP27 induced commensurate changes in MMP-2 expression in tumors. These findings demonstrate that HSP27 drives metastatic spread of cancer cells from the prostate to distant sites, does so across a continuum of expression levels, and identifies HSP27-driven increases in MMP-2 expression as functionally relevant. These findings add to prior studies demonstrating that HSP27 increases PCa cell motility, growth and survival. Together, they demonstrate that HSP27 plays an important role in PCa progression.