Reg IV,a new member of the regenerating gene family,is overexpressed in colorectal carcinomas

A better understanding of the mechanisms by which colon tumor cells are able to survive exposure to drugs would be valuable for the development of new therapeutic strategies. We used differential display-PCR to compare gene expression in the drug-sensitive HT-29 colon cancer cell line and 3 drug-resistant subpopulations derived from this parental cell line. One of the genes identified is a new gene, Regenerating IV gene (Reg IV), and was strongly overexpressed in HT-29 drug-resistant cells. Other drug-resistant cell lines expressed Reg IV at a high level, whereas a low expression was noted in sensitive cell lines. Northern blot and real-time PCR analysis showed that Reg IV is more strongly expressed in 71% of colorectal tumors (in particular in mucinous carcinomas) than in normal colon tissues. The comparison of Reg IV expression with that of other REG genes, Regenerating Ialpha or (Reg Ialpha), Regenerating Ibeta (Reg Ibeta) and Pancreatitis-associated protein (PAP), highlights its predominant expression in colorectal tumors. Reg IV mRNA-positive tumor cells display different phenotypes: mucus-secreting, enterocyte-like or undifferentiated. Interestingly, whereas Reg IV expression is low in normal colon, its level in normal small intestine is similar to that in some colorectal tumors. In normal tissue, Reg IV mRNA-positive cells are mostly enteroendocrine cells and goblet cells. Our results point out the potential role of Reg IV in colorectal tumors and its subsequent interest as a pronostic indicator of tumor survival.     

Usefulness of polysaccharide K (PSK) as postoperative adjuvant immunotherapy in patients with stage IV gastric cancer

Background. We investigated retrospectively the usefulness of polysaccharide K (PSK) administration for prolonging survival after noncurative resection in patients with stage IV gastric cancer who underwent surgery at our department. Methods. 357 patients with gastric cancer evaluated as stage IV according to thegeneral rules for gastric cancer study, 11th edn (1985) of the Japanese Research Society for Gastric Cancer, who were expected to succumb to surgical death or postoperative death within 2 months were studied. The patients were divided into two groups: total PSK dosage greater than or less than 180g. Survival rates were calculated for each group. Results. In these stage-IV gastric cancer patients, the 5-year and 10-year survival rates in the PSK group were both 13.9%. In the non-PSK group, the rates were 8.7% and 7.0%, respectively. The survival rates were significantly higher in the PSK group (p = 0.0001). The survival rate was also calculated with respect to the staging factors. Patients in the PSK group who had H0, P0, se or milder and n3 or n4 showed a significantly higher survival rate than those with these staging factors in the non-PSK group (p = 0.010). Conclusion. PSK administration prolonged survival in stage-IV gastric cancer patients, the effect being marked in patients with severe lymph node metastasis. We suggest that be administered as adjuvant therapy in stage-IV gastric cancer patients with severe lymph node metastasis (n3, n4).     

联合检测术前与术后CEA CA19-9 CA72-4对不同分期胃癌根治术后复发的预测价值

  目的   探讨联合检测术前、术后CEA、CA19-9、CA72-4等肿瘤标志物对不同分期胃癌根治术后复发的预测价值。   方法   回顾性分析北京大学肿瘤医院2002年1月至2007年3月收治的564例胃癌患者的临床资料及血清肿瘤标志物情况。所有患者均未行新辅助治疗,术前、术后均联合检测CEA、CA19-9、CA72-4等肿瘤标志物。分析CEA、CA19-9、CA72-4等肿瘤标志物与胃癌复发的关系。   结果   在Ⅰ、Ⅱ期胃癌患者中,CEA、CA19-9、CA72-4术前阳性的患者术后复发率分别为50.0%、24.1%、22.6%,而术后阳性的患者复发率分别为42.9%、21.7%、14.3%。在Ⅲ期胃癌患者中,CEA、CA19-9、CA72-4术前阳性的患者术后复发率分别为50.0%、55.2%、47.6%,而术后阳性的患者术后复发率分别为75.0%、66.7%、66.7%。多因素分析表明术前CEA增高是Ⅰ、Ⅱ期胃癌复发的独立影响因素,术后CA72-4增高是Ⅲ期胃癌复发的独立影响因素。   结论   对于Ⅰ、Ⅱ期胃癌,术前CEA水平是预测复发较好的因子;对于Ⅲ期胃癌,术后CA72-4水平的预测性较好。      

CPA4 is a promising diagnostic serum biomarker for pancreatic cancer

CPA4 belongs to a member of the metallocarboxypeptidase family, and its expression in pancreatic cancer samples and clinical significance are still not investigated until now. In this study, we aimed to evaluate the level of CPA4 in pancreatic cancer samples and study its clinical implications as a diagnostic marker for pancreatic cancer. The levels of CPA4 in pancreatic cancer tissues and serum samples were measured by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), respectively. Among 150 pancreatic cancer tissues examined, 86.7% (130/150) of cases showed positive staining for CPA4. Clinicopathological relevance analysis showed that CPA4 expression was correlated with advanced clinical stage and lymph node metastasis. Also, we found that the levels of CPA4 in serum samples were significantly high in cases whose expression was also high in paired tissue samples (N=50). In a larger sample set, we found that serum CPA4 in pancreatic cancer patients was significantly higher than for healthy controls (P<0.05). In addition, high serum CPA4 was significantly associated with the TNM stage, Lymph node involvement and distant metastasis. At a cutoff value of 0.3 ng/ml, CPA4 might be a better diagnostic biomarker of pancreatic cancer than CA199. In conclusion, CPA4 overexpression is associated with pancreatic cancer progression, and it might be a potential diagnostic serum marker for pancreatic cancer.     

胃癌患者根治术后腹腔灌洗液中CEA mRNA表达的临床意义

目的：探讨胃癌患者根治术后腹腔冲洗液中CEA mRNA表达情况及其临床意义。方法: 回顾性分析了2013 年1 月至2017 年12 月在南京大学医学院附属鼓楼医院接受胃癌根治切除术后进行腹腔灌洗液CEA mRNA检测的139 名患者的病历资料,并进行术后常规随访。用RT-PCR检测139 胃癌患者根治术后腹腔灌洗液中CEA mRNA表达情况。卡方检验分析腹腔灌洗液中CEA mRNA表达与临床基本特征、组织病理学资料、血液学指标及复发方式之间的关系。采用Logistic 单因素及多因素回归分析筛查影响CEA mRNA表达水平的因素。结果：139 名患者中44 名（31.7%）患者腹腔灌洗液CEA mRNA阳性。分析显示,胃癌患者腹腔灌洗液CEA mRNA阳性表达与性别、年龄、病理分级、Lauren 分型和HER2、EGFR、VEGFR等标记物间均没有明显的关联（均P>0.05）,与病理类型、脉管是否侵犯、局部浸润深度、淋巴结转移程度和临床AJCC 分期有明显的关联（均P<0.05）。CEA mRNA阳性患者腹膜复发率明显高于阴性患者（P=0.012）。Logistic 单因素回归分析显示,印戒细胞癌（P=0.04,HR=2.810,95% CI: 1.050~7.520）、T 分期（P=0.016,HR=6.329,95% CI: 1.417~28.264）、N 分期（P=0.022,HR=3.068,95% CI: 1.172~8.027）、AJCC分期（P=0.016 ,HR=3.971 ,95% CI: 1.295~12.173 ）、神经侵犯（P=0.002 ,HR=6.738,95% CI: 1.995~22.757）、脉管侵犯（P<0.001,HR=16.36,95% CI: 3.85~69.512）为胃癌患者腹腔灌洗液CEA mRNA阳性表达的危险因素。Logistic 多因素回归分析显示,经过对其他因素的校正,脉管侵犯（P<0.001,HR=21.314,95% CI: 4.21~107.907）为胃癌患者腹腔灌洗液CEA mRNA阳性表达的独立危险因素。结论：胃癌腹腔灌洗CEA mRNA阳性的患者腹膜复发转移风险高且预后不良,应考虑包括腹腔局部治疗在内的更加积极的抗肿瘤治疗。     

Serum macrophage migration‐inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer

BACKGROUND:

This study aimed to determine the potential diagnostic value of migration‐inhibitory factor (MIF) for gastric cancer in patients presenting with dyspepsia and its prognostic value for gastric cancer.

METHODS:

A cohort of 97 patients with histologically confirmed gastric adenocarcinoma and 222 patients with dyspepsia were recruited. Enzyme‐linked immunosorbent assay was used to measure serum MIF and carcinoembryonic antigen (CEA).

RESULTS:

The serum MIF concentrations were 6554.0 ± 204.1 pg/mL and 1453.7 ± 79.9 pg/mL, respectively, in gastric cancer patients and dyspeptic patients (P < .001). Serum MIF levels increased with the advancing gastric pathologies (P < .001). With the cutoff value of 3230 pg/mL, serum MIF had sensitivity, specificity, and accuracy of 83.5%, 92.3%, and 89.7%, respectively, in diagnosing gastric cancer, whereas the rates were 60.8%, 83.3%, and 76.5%, respectively, for serum CEA. Gastric cancer patients with serum MIF levels above 6600 pg/mL had a lower 5‐year survival rate than those with serum MIF level below that level (P = .012). Higher serum CEA levels were also associated with poor survival. The prediction for 5‐year survival was even better (P = .0001), using a combination of serum MIF and CEA.

CONCLUSIONS:

Serum MIF level, which correlates with gastric MIF expression, is a better molecular marker than CEA in diagnosing gastric cancer in patients presenting with dyspepsia. A combination of serum MIF and CEA predicts 5‐year survival better than the individual test. Cancer 2009. © 2009 American Cancer Society.     

PFKFB4 as a promising biomarker to predict a poor prognosis in patients with gastric cancer

Gastric cancer (GC) is one of the most common types of cancer worldwide. Previous studies have reported that phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) functions as an oncoprotein in various types of cancer. However, the association between PFKFB4 and GC remains unclear. The present study analyzed the expression levels of PFKFB4 in 148 GC tissue samples, including 46 tumor tissues with matched adjacent normal tissues, using immunohistochemistry, compared the expression levels of PFKFB4 between GC and adjacent normal tissues, and determined the association between PFKFB4 expression levels and patient clinicopathological characteristics. In addition, survival curves were generated using the Kaplan-Meier (KM) plotter database to evaluate the association between PFKFB4 expression and GC prognosis. The results revealed that PFKFB4 expression was upregulated in GC tissues compared with in adjacent normal tissues. PFKFB4 expression was associated with patient age, tumor size, pathological tumor (pT) stage and tumor-node-metastasis (pTNM) stage, and upregulated expression levels of PFKFB4 were observed in tumor tissues from patients <65 years old (compared with that in patients ≥65 years old), as well as patients with a larger tumor size and an advanced stage (pT and pTNM stage) disease. In addition, KM survival analysis demonstrated that patients with low PFKFB4 expression had a significantly improved overall survival (OS), first progression survival and post-progression survival times compared with those with high PFKFB4 expression. Furthermore, PFKFB4 expression was negatively associated with OS time in patients with late pT and pTNM stage disease. In conclusion, the results of the present study indicated that the upregulated PFKFB4 expression in GC tissues may serve as a biomarker for a more advanced disease and a poor prognosis in patients with GC.     

Netrin-4 as a biomarker promotes cell proliferation and invasion in gastric cancer

Gastric cancer (GC) is the second most common cause of cancer-related death with limited serum biomarkers for diagnosis and prognosis. Netrin-4 (Ntn4) is a laminin-related secreted molecule found to regulate tumor progression and metastasis. However, it is completely unknown whether Ntn4 has roles in GC development. Here, we first reported Ntn4 knockdown significantly suppressed cell proliferation and motility, while overexpression or addition of exogenous Ntn4 reversed these effects. In addition, Ntn4 receptor, neogenin (Neo) was also found highly expressed in GC cells and mediated the Ntn4-induced cell proliferation and invasion. Moreover, Ntn4 or Neo silencing decreased the phosphorylation of Stat3, ERK, Akt and p38, indicating multi-oncogenic pathways (Jak/Stat, PI3K/Akt, and ERK/MAPK) were involved in Ntn4-induced effects on the GC cells. Importantly, Ntn4 level was significantly increased in 82 tumor tissues (p = 0.001) and 52 serum samples (p < 0.0001) from GC patients and positively correlated with Neo expression (p = 0.003). Ntn4 expression was negatively correlated with the survival period (p = 0.038), and positively associated with the severity of pathological stages of the tumors (p = 0.008). Taken together, Ntn4 promoted the proliferation and motility of GC cells which was mediated by its receptor Neo and through further activation of multi-oncogenic pathways. Elevated Ntn4 was detected in both tumor tissues and serum samples of GC patients and suggested a relatively poor survival, indicating Ntn4 may be used as a potential non-invasive biomarker for diagnosis and prognosis of GC.     

Olfactomedin 4 downregulation is associated with tumor initiation,growth and progression in human prostate cancer

The olfactomedin 4 (OLFM4) gene has been analyzed as a tumor-suppressor gene and a putative biomarker in many cancers. In our study, we analyzed the relationship of OLFM4 expression with clinicopathological features and with CpG site methylation in the OLFM4 gene promoter region in human primary prostate adenocarcinoma. OLFM4 protein expression was significantly reduced in prostate cancer tissue compared to adjacent normal tissue and was further significantly reduced in more advanced cancers. Bioinformatic studies with clinical datasets revealed that primary prostate adenocarcinoma patients with reduced OLFM4 mRNA expression exhibited higher Gleason scores and higher preoperative serum prostate-specific antigen levels, as well as lower recurrence-free survival. Three of the eight CpG sites in the OLFM4 gene promoter region were hypermethylated in cancerous prostate cells compared to adjacent normal cells, and reduced methylation of eight CpG sites was associated with increased OLFM4 mRNA expression in RWPE1 and PC-3 cells. Furthermore, knockdown of OLFM4 gene expression was associated with enhanced epithelial–mesenchymal transition (EMT)-marker expression in RWPE immortalized normal prostate cells. In contrast, restoration of OLFM4 expression in PC-3 and DU145 prostate cancer cells lacking OLFM4 significantly inhibited both EMT-marker expression and tumor cell growth in in vitro and in vivo models, indicating that OLFM4 may play a tumor-suppressor role in inhibiting the EMT program, as well as tumor initiation and growth, in prostate cells. Taken together, these findings suggest that OLFM4 plays an important tumor-suppressor role in prostate cancer progression and might be useful as a novel candidate biomarker for prostate cancer.     

LGR5 is a promising biomarker for patients with stage Ⅰ and Ⅱ gastric cancer

Objective: To investigate Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) expressions in gastric cancer and to evaluate its clinical significance. Methods: LGR5 expression was assessed by immunohistochemistry in 257 gastric cancer patients after surgery. The relationships between LGR5 expression and clinicopathological features and patients prognosis were statistically analyzed. Results: The expression of LGR5 was significantly higher in gastric cancers as a cancer stem cell marker than in adjacent normal tissues (P<0.001), and more frequently in patients with intestinal type, well-moderate differentiation and stage Ⅰ and Ⅱ (P<0.05). Although we found gastric cancer patients with LGR5 positive expression had a poorer prognosis, it didn’t meet statistical significance (P>0.05). LGR5 negative expression was significantly related to the favorable overall survival in stage Ⅰ and Ⅱ gastric cancer patients (P<0.05). Furthermore, patients with high LGR5 expression tended to be more likely to get progression and have poorer progress-free survival (P<0.05). Multivariate Cox regression analysis revealed that LGR5 expression was an independent factor of overall survival for the patients with stage Ⅰ and Ⅱ gastric cancer (P<0.05). Conclusions: Our results show that LGR5 may play an important role in tumorigenesis and progression and would be a powerful marker to predict the prognosis of patients with stage Ⅰ and Ⅱ gastric cancer.