High CD10 expression in lymph node metastases from surgically treated prostate cancer independently predicts early death

Patients with nodal positive prostate cancers are an important cohort with poorly defined risk factors. CD10 is a cell surface metallopeptidase that has been suggested to play a role in prostate cancer progression. CD10 expression was evaluated in 119 nodal positive prostate cancer patients using tissue microarrays constructed from primary tumors and lymph node metastases. All patients underwent radical prostatectomy and standardized extended lymphadenectomy. They had no neoadjuvant therapy and received deferred androgen deprivation. In the primary tumor, high CD10 expression was significantly associated with earlier death from disease when compared with low CD10 expression (5-year survival 73.7% vs. 91.8%; p = 0.043). In the metastases, a high CD10 expression was significantly associated with larger total size of metastases (median 11.4 vs. 6.5 mm; p = 0.015), earlier death of disease (5-year survival 71.5% vs. 87.3%; p = 0.017), and death of any cause (5-year survival 70.0% vs. 87.2%; p = 0.001) when compared with low CD10 expression. CD10 expression in the metastases added independent prognostic information for overall survival (p = 0.029) after adjustment for Gleason score of the primary tumor, nodal tumor burden, and resection margins. In conclusion, a high CD10 expression in prostate cancer predicts early death. This information is inherent in the primary tumors and in the lymph node metastases and might help to personalize patient management.     

Effect of Gleason scores of lymph node metastases on prognosis of patients with prostate cancer

The long-term mortality risk from prostate cancer increases in lymph node (LN) positive patients. This study was done to assess the effect of lymph node Gleason score (LNGS) on prognosis in patients with LN-positive prostate cancer. Among the 1,415 patients who received pelvic lymph node dissection (PLND), 117 (8.4%) patients had a positive LN. The PGS of the prostate specimens and the LNGS of the positive LNs were assessed by uropathologists. The median age of patients at surgery was 67 years (interquartile range [IQR], 62-71 years) and the median follow-up duration was 44.3 months (IQR, 27.0-78.5 months). Pathologic Gleason scores (PGS) of 6-9 included one (0.9%), 53 (49.5%), 22 (20.6%), and 31 (29.0%) patients. The median total number of retrieved LNs was 9.0 (IQR, 5.3-12.8). The median number of positive LNs was one (IQR, 1-2). Cancer architecture with a Gleason pattern and score were observed in LNs as in ordinary prostate specimens. LNGS 6-9 included nine (8.1%), 57 (51.4%), 31 (27.9%), and 14 (12.6%) patients. The speaman’s analysis showed the meaningful correlation between PGS and LNGS (P = 0.249, P = 0.011). The univariate analysis showed that the number of positive LNs and LNGS were significantly associated with prostate cancer-specific survival (P = 0.028; P = 0.005). The same architecture that is seen in the prostate was seen in positive LNs, and LNGS may be a significant prognostic factor in patients with LN-positive prostate cancer.     

Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node-positive bladder cancer

Seiler R, von Gunten M, Thalmann G N & Fleischmann A
(2011) Histopathology  58 , 571–578
Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node‐positive bladder cancer Aims: To evaluate risk factors in lymph node‐positive bladder cancer. Methods and results: Lymph node‐positive bladder cancer patients (n = 162), preoperatively staged N0M0, underwent cystectomy and standardized extended lymphadenectomy. Five‐year overall survival of the cohort was 33%. In univariate analysis, tumour stage (P < 0.006), extracapsular extension of lymph node metastases (P < 0.001), total diameter of metastases (P < 0.04) and lymph node stage (P < 0.03) were significantly correlated with overall survival (OS), disease‐specific survival (DSS) and recurrence‐free survival (RFS). On multivariate analysis, only extracapsular extension (OS, P < 0.002; DSS, P < 0.02; RFS, P = 0.058) and primary tumour stage (OS, P = 0.058; DSS, P < 0.02; RFS, P < 0.02) added independent prognostic information. Extracapsular extension of lymph node metastases did not correlate with a specific recurrence pattern; patients with organ‐confined tumours (pT1/2) never had pelvic relapse. Conclusions: Extracapsular extension of lymph node metastases but not lymph node tumour burden adds independent prognostic information in lymph node‐positive bladder cancer. These biological differences in lymph node‐positive bladder cancer are not reflected in the sixth, and challenge future, TNM classification.     

Periprostatic lymph node metastasis in prostate cancer and its clinical significance

Deng F‐M, Mendrinos S E, Das K & Melamed J
(2012) Histopathology  60, 1004–1008
Periprostatic lymph node metastasis in prostate cancer and its clinical significance Aims: To evaluate the potential of periprostatic lymph node (LN) as a staging indicator, particularly with the use of methods for enhanced detection of micrometastasis. Methods and results: We retrieved cases with periprostatic LN from radical prostatectomy specimens accrued between 1997 and 2007 at our institution. Twenty‐one (0.8%) of 2663 radical prostatectomy specimens had periprostatic LNs (total number of LNs = 22). LN size ranged from 0.8 to 4.7 mm. Most of the periprostatic LNs were located close to the posterior base. Seven (32%) of 22 LNs were involved by metastatic prostate cancer (PCa), including five detected on routine haematoxylin and ceosin slides and an additional two detected only by immunohistochemistry. Cases with periprostatic LNs had a significantly higher metastatic rate (29%; six of 21) compared to those with pelvic LNs sampled at radical prostectatomy in our institution (1.9%). When compared to cases with negative periprostatic LNs (n = 15), the tumour characteristics of cases with metastatic periprostatic LNs (n = 6) included higher tumour volume, Gleason score, stage and a greater propensity for prostate‐specific antigen (PSA) recurrence. Conclusions: Despite their infrequent identification, periprostatic LNs if detected in the radical prostatectomy specimen should be evaluated with greater scrutiny (step sections and/or immunohistochemical studies) to evaluate their prognostic potential.     

L-CAM expression in lymph node and liver metastases of colorectal carcinomas

L-CAM, also known as E-cadherin, is a cell adhesion molecule expressed on the plasma membranes of epithelial cells at the intercellular interface. From in vitro gene transfection experiments the idea has been conceived that loss of L-CAM expression might be related to the invasive capacity as well as metastatic potential of tumour cells. In several tumours a relation between the grade of differentiation and L-CAM expression has been noticed: loss of differentiation appears to be associated with loss of L-CAM immunoreactivity. Also, in lymph node metastases of poorly differentiated carcinomas loss of L-CAM expression was demonstrated. In this study we describe L-CAM expression in lymphogenous and haematogenous metastases of large bowel adenocarcinomas, using an indirect immunoperoxidase method with the monoclonal anti-L-CAM antibody 6F9. All the metastases studied—lymphogenous as well as haematogenous—demonstrated L-CAM immunoreactivity in a pattern comparable to that of primary tumours. Intratumour heterogeneity in expression was noted, with normal intercellular, apical (non-functional), and focally negative areas in the same tumour. The data indicate that primary tumours and their metastases do not differ strikingly in their pattern of L-CAM expression. This would be consistent with transient rather than constitutive down-regulation of L-CAM in invasive and metastatic cancer cells.     

Abnormal expression of pRb, p16, and cyclin D1 in gastric adenocarcinoma and its lymph node metastases: relationship with pathological features and survival

The retinoblastoma (Rb) pathway controls the G1-S checkpoint of the cell cycle. Inactivating mutations and deletions of p16 and Rb and up-regulation of cyclin D1 disrupt this pathway and occur in many cancers. However, the concurrent expression of these genes in primary and metastatic gastric cancer is unknown, and the prognostic value of their expression is unclear. In this study, the expression of cyclin D1, retinoblastoma protein (pRb), and p16 in 67 resected gastric adenocarcinomas, and of pRb and p16 in 40 associated lymph node metastases, was determined using a streptavidin-biotin-peroxidase immunohistochemical method. Relationships with clinical and pathological features were analyzed. Cyclin D1 overexpression (>/=5% expression) was seen in 55% of cancers; pRb loss (<20% expression), in 33%; p16 loss (<10% expression), in 49%; and at least 1 of these abnormalities, in 92.5%. Cyclin D1 overexpression was associated with poor differentiation (P = 0.027) and signet ring cell type (P = 0.029). pRb expression was lower in lymph node metastases than in the corresponding primary tumors (P <0.001). Univariate and multivariate survival analysis (minimum follow-up 72 months or until death) revealed that <20% pRb expression, <30% pRb expression, and International Union Against Cancer stage >2 were associated with worse overall survival. The results suggest that Rb pathway disturbances play an important role in gastric carcinogenesis. The poor prognosis of cancers with low pRb expression and the reduced pRb expression in lymph node metastases raise the possibility that Rb and related genes also influence progression.     

Comparison of molecular determinants of angiogenesis and lymphangiogenesis in lymph node metastases and in primary tumours of patients with breast cancer

Angiogenesis and lymphangiogenesis are complex processes, driven by multiple factors. In primary breast tumours (PTs), VEGFA, -C and -D are the most important (lymph)angiogenic factors. The induction of lymphangiogenesis in axillary lymph node (LN) metastases of patients with breast cancer was described recently. To compare the molecular determinants of (lymph)angiogenesis in LN metastases and PTs of breast cancer patients, RNA was isolated from formalin-fixed, paraffin-embedded tissue sections of a metastatically involved and uninvolved LN and the PT from 26 lymph node-positive patients. The expression of 12 (lymph)angiogenic markers was measured by qRT-PCR. Expression was correlated with tumour cell proliferation, angiogenesis and lymphangiogenesis, quantified by tumour cell proliferation fraction (TCP%) and (lymphatic) endothelial cell proliferation fraction [(L)ECP%]. TCP%, ECP% and LECP% were assessed on immunohistochemical double stains for CD34/Ki-67 and D2-40/Ki-67, respectively. In involved LNs, the relative gene expression levels of PROX1 (p < 0.001) and FGF2 (p = 0.008) were decreased and the expression levels of VEGFA (p = 0.01) and PDGFB (p = 0.002) were increased compared to uninvolved LNs. The expression of most markers was increased in PTs compared to involved LNs. In metastatically involved LNs, the expression of VEGFA correlated with ECP% (r = 0.54, p = 0.009) and LECP% (r = 0.76, p < 0.001). In PTs, VEGFA correlated only with ECP% (r = 0.74, p < 0.001). VEGFD correlated with peritumoural LECP% (r = 0.61, p = 0.001) and with VEGFC (r = 0.78, p < 0.001). Linear regression analysis confirmed the expression of VEGFA as an independent predictor of ECP% in both PTs and LN metastases and of LECP% in LN metastases. The expression of VEGFD, but not of VEGFA, independently predicted peritumoural LECP% in PTs. Our results confirm existing data that, in PTs, angiogenesis and lymphangiogenesis are respectively driven by VEGFA and VEGFD. In contrast, in LN metastases, both processes seem to be driven by VEGFA. Lymphangiogenesis in PTs and in LN metastases might thus be driven by different factors.     

乳腺癌组织蛋白酶D和PSA表达与同侧腋淋巴结转移的关系

目的：探讨乳腺癌中组织蛋白酶Ｄ（ｃａｔｈｅｐｓｉｎＤ，ＣＤ）和前列腺特异性抗原（ＰＳＡ）的表达与同侧腋淋巴结转移的关系。方法：应用ＬＳＡＢ免疫组化法检测ＣＤ和ＰＳＡ在７８例乳腺癌中的表达，其中伴同侧腋淋巴结转移者３６例。结果：（１）７８例乳腺癌ＣＤ阳性表达率４１．０３％（３２／７８），ＰＳＡ阳性表达率４３．５％（３４／７８）；（２）同侧腋淋巴结转移组ＣＤ阳性表达率６９．４４％（２５／３６），无同侧腋淋巴结转移组ＣＤ阳性表达率１６．６７％（７／４２），差异有高度显著性（Ｐ＜０．０１）；（３）同侧腋淋巴结转移组ＰＳＡ阳性表达率２５．０％（９／３６），无同侧腋淋巴结转移组ＰＳＡ阳性表达率５９．５２％（２５／４２），差异有高度显著性（Ｐ＜０．０１）。结论：ＣＤ和ＰＳＡ的表达可作为乳腺癌预后检测的参考指标。ＣＤ表达阳性率与同侧腋淋巴结转移呈正相关，与预后负相关；而ＰＳＡ表达阳性率与同侧腋淋巴结转移呈负相关，与预后正相关     

Membrane-type 1 matrix metalloproteinase enhances lymph node metastasis of gastric cancer

The mechanisms of the lymph node metastasis remain unclear. We demonstrate the role of MT1-MMP on the lymph node metastasis using in vivo experimental model of lymph node metastasis by orthotopic implantation of MT1-MMP transfected gastric cancer cell line in the stomach of nude rats. TMK-1 cell line without expression of MT1-MMP was transfected with the pcDNA3 plasmid containing a 3.4-kb MT1-MMP cDNA fragment by calcium phosphate method, and the transfected cell line was designated as TMK-MT. Western blot and RT-PCR analyses showed the specific bands corresponding to MT1-MMP in the TMK-MT cells. By gelatin zymography, the activated form (62-kDa) of MMP-2 was identified in the medium of TMK-MT cell line, but was not detected in TMK-1 cells. Six weeks after orthotopic implantation of TMK-1 and TMK-MT xenografts of nude mouse-subcutaneus tumor into the stomach of nude rats, gastric tumors were found in all the animals. Histologically, the lymphatic invasion was found in the submucosa of the TMK-MT gastric tumors. Lymph node metastasis was not detected in nude rats bearing TMK-1 gastric tumor (0/8). In contrast, lymph node metastasis was detected in five out of 8 rats, bearing TMK-MT gastric tumor. MT1-MMP immunoreactivity was found on the cell membrane and cytoplasm of TMK-MT cells not only in the lymph node metastasis but also in the stomach tumor. These results suggest that MT1-MMP overexpression induced by transfection of its gene may promote lymph node metastasis of transformed cells. This revised version was published online in July 2006 with corrections to the Cover Date.     

Benign glandular inclusion in obturator lymph node of a man treated for prostate carcinoma

Benign glandular inclusions in lymph nodes are extremely rare in men. Their identification is essential because it changes dramatically the prognosis and therapy of neoplasms. Described herein is the first case of benign glandular inclusion in an obturator lymph node dissected during a radical prostatectomy for treatment of prostate adenocarcinoma. A 60-year-old man underwent radical prostatectomy and obturator-hypogastric lymph node dissection for treatment of prostate adenocarcinoma. Benign glandular inclusion was found in microscopic examination. The lesion was characterized by two glandular spaces lined by a single, cuboid, benign epithelium localized in the sinus of one of four dissected lymph nodes. Immunohistochemistry showed mesothelial differentiation. Pathologists should be aware of benign glandular inclusion in obturator lymph nodes dissected during a radical prostatectomy for treatment of prostate cancer in order to avoid the incorrect diagnosis of metastatic disease.     

The expression of aldehyde dehydrogenase 1 in invasive primary breast tumors and axillary lymph node metastases is associated with poor clinical prognosis

The enzyme aldehyde dehydrogenase 1 (ALDH1) has been reported as a biomarker for identifying cancer stem cells. Previous studies have shown that ALDH1 expression in primary breast cancers was associated with poor clinical prognosis. In this study, we aimed to determine whether ALDH1 expression in axillary lymph node metastases (ALNM) of breast cancer patients was also associated with poor prognosis. Expression of ALDH1, ER, PgR, HER2 and KI-67 was examined in primary tumors and ALNM of 161 patients with invasive breast cancer. Survival analysis and multivariate analysis were used to determine the relationship between ALDH1 expression and clinical prognosis. Patients with positive ALDH1 expression in primary tumors and in ALNM had significantly shorter relapse-free survival (RFS) times and overall survival (OS) times compared to those whose tissues were ALDH1 negative. ALDH1-positivity in primary tumors was significant both in univariate and multivariate analyses of RFS and OS. ALDH1 expression in ALNM was significant in a univariate analysis of RFS and OS but not in a multivariate analysis of RFS and OS. We conclude that the expression of ALDH1 in primary breast tumors or ALNM may be one potential risk factor for poor, long-term outcomes.     

乳腺癌cyclin D1、Rb蛋白表达的意义

目的：探讨cyclin D1蛋白和Rb蛋白的表达状况与乳腺癌发生发展的关系。方法：采用S-P免疫组化法检测52例乳腺癌和20例良性乳腺病变组织中cyclin D1蛋白和Rb蛋白的表达。结果：乳腺癌中cyclin D1过表达率为34．60％（18／52），显著高于良性乳腺病变组织的10．00％（2／20），P〈0．05，cyclin D1过表达出现于导管内癌中并持续于浸润、转移等进展过程中，与患者年龄、肿瘤大小、腋窝淋巴结转移及组织学分级均无相关性。乳腺癌中Rb蛋白阴性表达率为76．91％（40／52），显著高于良性乳腺病变组织的15．00％，P〈0．05；Rb蛋白阴性表达与乳腺癌临床病理特征间无相关性，Rb蛋白表达阴性者中，cyclin D1过表达率为20．00％，而Rb蛋白表达阳性者中，其cyclin D1过表达率为83．33％，两者比较有显著差异（P〈0．05）。结论：cyclin D1蛋白和Rb蛋白与乳腺癌发生、发 展密切相关；cyclin D1、P16及Rb通路失活可能与乳腺癌的发生密切相关。     

Lymphangiogenesis in breast cancer is associated with non-sentinel lymph node metastases in sentinel node positive patients

Axillary lymph node dissection (ALND) is not suggested in breast cancer patients with negative sentinel lymph node (SLN) biopsies, and SLN is the only positive node in 40-70% of the remaining cases. To distinguish a subgroup in which ALND would be omitted, we investigated the role of lymphangiogenesis in primary breast cancer as a risk factor for distal lymph node involvements in patients with positive SLNs. 86 patients were included in this study. The frequency of proliferative lymphatic endothelial cells (LECP%) was evaluated in each specimen after immunohistochemical double staining for D2-40 and Ki-67. Larger primary tumor size, increased number of positive SLNs, lymphatic vessel invasion and LECP% were significantly associated with non-SLN metastases in the univariate analysis, but only LECP% retained significance in the multivariate model. A positive correlation between LECP% and lymphatic vessel invasion was also revealed. Our study confirmed the important role of lymphangiogenesis in tumor spread, and suggested that LECP% is a promising predictor for additional axillary lymph node involvements.     

Prognostic factors in lymph node metastases of prostatic cancer patients: the size of the metastases but not extranodal extension independently predicts survival

Aims: To analyse tumour characteristics and the prognostic significance of prostatic cancers with extranodal extension of lymph node metastases (ENE) in 102 node‐positive, hormone treatment‐naive patients undergoing radical prostatectomy and extended lymphadenectomy. Methods and results: The median number of nodes examined per patient was 21 (range 9–68), and the median follow‐up time was 92 months (range 12–191). ENE was observed in 71 patients (70%). They had significantly more, larger and less differentiated nodal metastases, paralleled by significantly larger primary tumours at more advanced stages and with higher Gleason scores than patients without ENE. ENE defined a subgroup with significantly decreased biochemical recurrence‐free (P = 0.038) and overall survival (P = 0.037). In multivariate analyses the diameter of the largest metastasis and Gleason score of the primary tumour were independent predictors of survival. Conclusions: ENE in prostatic cancer is an indicator lesion for advanced/aggressive tumours with poor outcome. However, the strong correlation with larger metastases suggests that ENE may result from their size, which was the only independent risk factor in the metastasizing component. Consequently, histopathological reports should specify the true indicator of poor survival in the lymphadenectomy specimens, which is the size of the largest metastasis in each patient.     

IMP3 expression in biopsy specimens of colorectal cancer predicts lymph node metastasis and TNM stage

IMP3 is associated with lymph node metastasis and TNM stage and is a good independent prognostic biomarker for colorectal cancer (CRC). However, the expression status and clinical implication of IMP3 in biopsy specimens have not yet been studied. We aim to address whether the presence of IMP3 expression in preoperative biopsies of CRC could predict lymph node metastasis and TNM stage. In this study, we examined IMP3 expression in paired biopsy and resection specimens of 71 CRC and analyzed the correlation of IMP3 expression with clinicopathological parameters. In the biopsy specimens, IMP3 positive expression was observed in 56 of 71 cases (78.9%) whereas negative expression was observed in 15 of 71 cases (21.1%). In the resection specimens, IMP3 positive expression was detected in 83.1% cases (59/71) whereas negative expression was detected in 16.9% cases (12/71). The absolute concordance rate between biopsy and resection specimens was 90.1% (64/71). The Spearman correlation test documented the existence of a strong linear correlation between the percentage of IMP3-positive cells in the biopsy and resection specimen (r = 0.629; P < 0.001). IMP3 expression in resection specimens was significantly related to histological grade (P = 0.043), T classification (P = 0.035), lymph node metastasis (P = 0.023), TNM stage (P = 0.007), tumor border (P = 0.049) and tumor budding (P = 0.012). IMP3 expression in biopsy specimens was significantly related to lymph node metastasis (P = 0.004), TNM stage (P = 0.005) and tumor budding (P = 0.001). In conclusion, IMP3 expression in biopsy specimens could be used to predict lymph node metastasis and TNM stage in CRC patients.     

VEGF-C在卵巢癌局部淋巴结内淋巴管生成中的作用

目的观察血管内皮生长因子-C(VEGF-C)在卵巢癌组织内的表达,分析其与卵巢癌局部淋巴结内淋巴管生成之间的关系。方法取卵巢癌64例,其中,有淋巴结转移40例,无淋巴结转移24例。应用免疫组化法和Western blot技术观察VEGF-C在卵巢癌组织内的表达。以D2-40作为淋巴管内皮特异性标记物,检测卵巢癌局部淋巴结内淋巴管生成情况。结果 VEGF-C主要表达于卵巢癌细胞浆和胞膜以及癌组织周围浸润的炎性细胞,在有淋巴结转移组的表达率明显高于其在无淋巴结转移组的表达率。Western blot检测结果表明,VEGF-C蛋白在有淋巴结转移的卵巢癌组织中的表达量高于其在无淋巴结转移的卵巢癌组织内的表达量。D2-40表达于卵巢癌局部淋巴结内的淋巴管内皮细胞,在有转移的淋巴结内可见大量新生的淋巴管,淋巴管腔内存在入侵的肿瘤细胞,在无转移的淋巴结内观察到新生的淋巴管。在无淋巴结转移组病例中,卵巢癌组织VEGF-C阳性者局部淋巴结内淋巴管密度明显高于VEGF-C阴性者淋巴结内的淋巴管密度。结论 VEGF-C的表达与卵巢癌淋巴结转移密切相关,卵巢癌在发生局部淋巴结转移之前存在淋巴结内淋巴管生成的现象,卵巢癌组织内VEGF-C的表达在卵巢癌局部淋巴结内的淋巴管生成中可能发挥重要作用。     

FAS and FAS-L expression by tumor cells and lymphocytes in breast carcinomas and their lymph node metastases

FAS receptor (FAS, CD95) and FAS ligand (FAS-L, CD95-L) are complementary members of a particular apoptotic pathway that plays a major role in immune regulation. The activation of FAS-L may trigger cytotoxic mechanisms leading to the death of FAS-expressing cells. Tumor cells and tumor-infiltrating lymphocytes (TIL) may express FAS and FAS-L in various proportions, and their interplay may affect tumor behavior. In the present study, we explored the expression of FAS and FAS-L in 28 mammary carcinomas (19 ductal and 9 lobular) and in their lymph node metastases. The expression of these mediators in immunostained sections was graded and evaluated comparatively between normal and neoplastic mammary epithelium, between tumor cells and TILs, and between mammary carcinoma cells and their lymph node metastases. We demonstrated the coexpression of FAS and FAS-L by breast carcinoma cells and TIL, with FAS expressed more strongly by normal epithelial cells and TIL than tumor cells. FAS-L was better stained on tumor cells than on TIL. There was equal or greater expression of FAS and FAS-L in the primary tumors and their TIL than in the metastatic counterparts. Comparing the expression of FAS with that of FAS-L, we recorded FAS equal or stronger than FAS-L in the primary mammary tumors and the reversal of their expression, FAS-L greater than FAS in the lymph node metastases. These results are consistent with reports of studies with other tumors, suggesting that the upregulated FAS-L indicates an increased ability of tumor cells to induce apoptosis in TIL and in the normal tissues invaded. However, it is understood that the FAS/FAS-L system, although essential for apoptosis, is only a contributing factor to the complex process of tumor invasion and antitumor defense.     

Correlation of RKIP,STAT3 and cyclin D1 expression in pathogenesis of gastric cancer

RKIP is proposed as a new metastasis suppressor. Our recent study showed that RKIP inhibits malignant phenotypes of gastric cancer cells. However, the underlying mechanism of RKIP function in gastric cancer is unclear. This study aimed to investigate the correlation of RKIP, STAT3 and cyclin D1 expression in the tumorigenesis of gastric cancer. RKIP, STAT3 and cyclin D1 proteins were detected by immunohistochemistry in tissues of gastric ulcer (n = 27), gastric adenomatous polyp (n = 7), intestinal metaplasia (n = 26), dysplasia (n = 40), gastric carcinoma (n = 169) and metastatic lymph node (n = 36). RKIP, STAT3 and cyclin D1 mRNA levels were analyzed by RT-PCR in SGC7901 cells. We found that RKIP protein expression was significantly decreased in advanced gastric cancer and metastatic lymph node tissues while cyclin D1 and STAT3 protein expression was markedly increased in severe dysplasia, gastric cancer and metastatic lymph node tissue (P < 0.01). RKIP expression in gastric cancer was negatively correlated with the invasion, TNM stage and lymphoid node metastasis (P < 0.01), while cyclin D1 and STAT3 expression was positively correlated with histological differentiation and lymphoid node metastasis (P < 0.01). RKIP protein level was negatively correlated with cyclin D1 and STAT3 protein level, while cyclin D1 protein level was positively correlated with STAT3 protein level in gastric cancer samples. Moreover, reconstitution of RKIP in SGC7901 gastric cancer cells led to reduced cyclin D1 and STAT3 mRNA levels. In conclusion, these data suggest that RKIP inhibits gastric cancer metastasis via the downregulation of its downstream target genes STAT3 and cyclin D1.     

肝细胞癌细胞周期蛋白D1基因的扩增和表达

目的　探讨细胞周期蛋白 (cyclin)D1基因 (CCND1)扩增和cyclinD1在肝细胞癌 (HCC)中的表达情况及其与HCC发生发展的关系。方法　分别应用差异聚合酶链反应 (DPCR)、逆转录(RT) PCR和免疫组织化学法检测 2 0例HCC中cyclinD1基因扩增率、mRNA和蛋白表达状况 ,并分析其与HCC组织学分级的关系。结果　cyclinD1基因扩增结果为 6/ 2 0 ,其mRNA和蛋白过表达分别为9/ 2 0和 14 / 2 0。cyclinD1mRNA表达与基因扩增相关 (P <0 .0 5) ,也和蛋白表达水平相关 (P <0 .0 5)。cyclinD1蛋白表达与HCC组织学分级具有相关性 (P <0 .0 5)。结论　cyclinD1基因扩增在HCC中较常见 ,是引起cyclinD1mRNA和蛋白过表达的主要原因之一。cyclinD1蛋白过表达与HCC的组织学分级相关。cyclinD1基因扩增及过表达可能在肝癌的演进和分化中起重要作用