Correlation of REG1A, Claudin 7 and Ki67 expressions with tumor recurrence and prognostic factors in superficial urothelial urinary bladder carcinomas

A?m: Superficial urothelial urinary bladder tumors are neoplasms that frequently recur and have a potential for invasion and metastasis. REG gene family is composed of various acute phase reactants, lectins, antiapoptotic factors, and growth factors that are effective on pancreatic island cells, neural cells, and epithelial cells. REG1A and REG1B are two forms of the human REG1 gene. It is reported that they are expressed in several cancers and are correlated with the prognosis of the patient. Claudins are integral transmembrane proteins that interconnect cells. However, their role in human tumorigenesis is extremely controversial. The aim of this study is to evaluate the relationship of REG1A, claudin 7 protein expressions, and Ki67 proliferation index in superficial urothelial urinary bladder tumors with well-known parameters of prognosis and tumor recurrence, and also to clarify whether these parameters are independent prognostic factors or not. Materials and Methods: A hundred and eleven patients diagnosed with superficial urothelial carcinoma between 2011 and 2016 years in our hospital and followed up in our urology clinic were included in this study. The slides prepared from paraffin blocks were immunohistochemically stained with REG1A, claudin 7, and Ki67 antibodies. Results: REG1A showed positive staining in 37 (33%) and negative staining in 74 (67%) of urothelial tumors. Claudin 7 was positive in 24 (22%) and negative in 87 (78%) cases. REG1A expression showed a positive correlation with tumor stage and tumor recurrence; a high Ki67 proliferation index was positively correlated with tumor stage and grade. The loss of claudin 7 expression was related to tumor recurrence. Besides, tumors with REG1A expression and claudin 7 loss had a shorter survival independent of recurrence. Conclus?on: In urothelial tumors, REG1A expression and loss of claudin 7 might be significant markers of prognosis that predict tumor recurrence.

Expression and clinical significance of CLDN-7 in pancreatic cancer / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression of tight junction protein claudin-7 (CLDN-7) in pancreatic cancer and its correlation with the clinicopathological features and prognosis of pancreatic cancer patients. Methods: Oncomine, GEPIA and GEO databases were used to comprehensively analyze the mRNA expression level of CLDN-7 in pancreatic cancer, and Kaplan-Meier Plotter database was used to analyze the relationship between the expression of CLDN-7 and the survival prognosis of pancreatic cancer patients. Immunohistochemical staining was used to detect the protein level of CLDN-7 in 44 cases of pancreatic cancer tissues and 31 cases of para-cancerous tissues resected in the Department of General Surgery of the Second Hospital of Lanzhou University from 2015 to 2018, and the relationship between CLDN-7 expression and clinicopathological characteristics and prognosis of patients was also analyzed. GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis were conducted to analyze the possible signaling pathways that CLDN-7 may involve in and their main functions, which were further verified in TCGA and GEPIA databases. Results: Analysis of both the databases and the clinical samples showed that CLDN-7 was significantly over-expressed in pancreatic cancer tissues, and its high expression was correlated with clinical prognosis of pancreatic cancer patients; moreover, CLDN-7 expression was an independent factor affecting the overall survival time of pancreatic cancer patients (all P<0.05). GO analysis and KEGG pathway enrichment analysis confirmed that CLDN-7 was involved in DNA damage repair and glucose metabolism in pancreatic cancer patients. TCGA and GEPIA database validation showed that CLDN-7 expression in pancreatic cancer was significantly and positively correlated with the expression of DNA damage repair related genes (POLD4, SMUG1, NTHL1) and glucose metabolism related genes (ALDOA, TALDO1, PGLS) (all P<0.01). Conclusion: CLDN-7 is highly expressed in pancreatic cancer and indicates a worse clinical prognosis; moreover, CLDN-7 is associated with DNA damage repair and intratumoral glucose metabolism in pancreatic cancer.

Value of combined detection of Cyclin D1 and claudin7 in differential diagnosis of renal epithelial tumors / 临床与实验病理学杂志

Purpose To investigate the value of Cyclin D1 and claudin 7 expression in the differential diagnosis of renal epithelial tumors.Methods The expression of Cyclin D1 and claudin7 was detected by immunohistochemical staining with tissue microarray.Totally 309 cases of renal epithelial tumors and 20 cases of normal renal tissues were collected for immunohistochemical staining.Comparative analysis for the values of Cyclin D1 and claudin 7 was performed on the diagnosis and differential diagnosis of renal tumors.Results The positive rates of Cyclin D1 in renal oncocytoma (RO),chromophobe renal cell carcinoma (ChRCC),clear cell renal cell carcinoma (CCRCC),papillary renal cell carcinoma (PRCC),Xp11.2 translocation/TFE3 gene fusion associated renal cell carcinoma (Xp11.2/TFE3) and clear cell tubulopapillary renal cell carcinoma (CCTPRCC) were 86.2％ (50/58),8.2％ (4/49),70.0％ (98/140),8.8％ (3/34),42.9％ (6/14),and 71.4％ (10/14),respectively.The positive rates of RO were significantly different from those of ChRCC and PRCC (x2 =64.72,52.56,P ＜0.000 1).Significant differences in positive rates of CCRCC and ChRCC (x2 =55.87,P ＜ 0.000 1),PRCC and Xp11.2/TFE3 (X2 =4.28,P=0.039),CCTPRCC and ChRCC (x2 =21.69,P ＜0.000 1)were also observed.The positive rates of claudin 7 in RO,ChRCC,CCRCC,PRCC,Xp11.2/TFE3 and CCTPRCC were 20.7％ (12/58),87.8％ (43/49),8.6％ (12/140),50％(17/34),14.3％ (2/14),and 57.1％ (8/14),respectively.There were significant differences in positive ratios of RO and ChRCC (x2 =47.82,P ＜ 0.000 1),CCRCC and CCTPRCC(x2 =26.57,P ＜0.000 1),PRCC and Xp11.2/TFE3 (x2 =5.29,P ＜ 0.05).The sensitivity and specificity of Cyclin D1 +/claudin 7-immunophenotype for RO were 69％ and 95.9％ respectively.The diagnostic sensitivity and specificity of Cyclin D1-/claudin 7 + for ChRCC were 83.7％ and 96.6％.In the identification of CCRCC and CCTPRCC,the sensitivity and specificity of Cyclin D1 +/claudin 7-for CCRCC were 65.7％ and 71.4％,and the diagnostic sensitivity and specificity of Cyelin D1 +/claudin7 + for CCTPRCC were 42.9％ and 95％.Conclusion The differential expression of Cyclin D1 and claudin7 in RO and ChRCC,CCRCC and ChRCC,PRCC and Xp11.2/TFE3 suggests that combined detection of two proteins provides an important assistance for the identification of these renal epithelial tumors.

Expression of Claudin-1 and -7 in Clear Cell Renal Cell Carcinoma and Its Clinical Significance

PURPOSE: We investigated the correlations between the expression of claudin-1 and claudin-7 in clear cell renal cell carcinoma (clear cell RCC) and clinical parameters. MATERIALS AND METHODS: The subjects of this study were 119 patients with confirmed clear cell RCC between January 2000 and December 2007. Their RCC tissues were immunohistochemically stained for claudin-1 and claudin-7. The correlations between the expression of claudin and parameters such as sex, age, body mass index (BMI), tumor size, TNM stage, Furhman nuclear grade, postoperative distant metastasis, and cancer-specific survival were analyzed. RESULTS: Among the total 119 subjects, claudin-1 was expressed in 18 (15.1%) and claudin- 7 in 31 (26.1%). Claudin-1 was expressed in patients who were older (p=0.007), who had a greater tumor size (p=0.001), who had a higher pathologic T stage (p=0.009), who had preoperative distant metastasis (p=0.035), and who had a higher Furhman nuclear grade (p=0.004). Claudin-7 was expressed only in patients who had a higher Furhman nuclear grade (p=0.031). The risk of postoperative distant metastasis was associated with the expression of claudin-1 (p0.05). CONCLUSIONS: In clear cell RCC, claudin-1 was expressed in patients who were older and who had a greater tumor size, who had higher T or M stages, and who had a higher Furhman nuclear grade. The expression of claudin-1 was associated with a higher risk of postoperative distant metastasis.

Diagnostic Utility of AMACR and Claudin-7 for the Classification of Renal Cell Carcinoma

BACKGROUND: The histologic classification of renal cell carcinoma (RCC) is based on the cytoarchitectural features, yet sometimes this requires correlation with the immunophenotype. Alpha-methylacyl-CoA racemase (AMACR) and claudin-7 have recently been introduced as useful markers that are frequently expressed in papillary RCC (PRCC) and chromophobe RCC (ChRCC), respectively. The aims of this study are to evaluate the expressions of AMACR and claudin-7 in RCCs and to investigate whether they are helpful for making the histological classification of RCCs. METHODS: Immunohistochemistry for CD10, RCC marker, cytokeratin (CK)7, CD117, AMACR and claudin-7 was performed for 104 RCCs, and these consisted of 54 clear cell RCCs (CCRCC), 26 PRCCs and 24 ChRCCs. RESULTS: For diagnosing PRCC, the sensitivity and specificity of AMACR were 92.3% and 71.8%, respectively, and using AMACR(+)/CK7(+), the specificity was increased by 23.1% to 94.9%. For diagnosing ChRCC, the sensitivity and specificity of claudin-7 were 91.7% and 78.8%, respectively, and using claudin-7(+)/AMACR(-), the specificity was significantly improved (to 96.3%). For diagnosing CCRCC, CK7(-)/claudin-7(-)/CD117(-) was the most useful immunohistochemical panel (sensitivity, 96.3%; specificity, 98%). CONCLUSIONS: AMACR and claudin-7 are helpful markers for the histologic classification of RCCs, and their diagnostic utility is strengthened when they are used as an immunohistochemical panel, AMACR(+)/CK7(+) for PRCC, claudin-7(+)/AMACR(-) for ChRCC and CK7(-)/claudin-7(-)/CD117(-) for CCRCC.

Reduced Expression of Claudin-7 Correlates with Invasiveness and Nuclear Grade of Breast Carcinomas

Background : Claudins are important components of the tight junctions in the intercellular barriers and cell polarity. Among them, claudin-7 is down-regulated in breast cancers compared with the normal breast epithelium. The aim of this study was to determine the expression pattern and prognostic value of claudin-7 in breast carcinomas. Methods : Claudin-7 expression was evaluated immunohistochemically in 42 cases of ductal carcinoma in situ (DCIS) and in 142 cases of invasive breast carcinoma (IBC) using a tissue microarray (TMA). Results : Claudin- 7 was strongly expressed in the normal luminal epithelial cells in the breast lobule. The level of claudin-7 expression was significantly lower or absent in 45.2% (19/42) of DCIS and 72.5% (103/142) of IBC. A loss or reduced expression of claudin-7 correlated with the invasiveness (p=0.001) of breast carcinomas and a high nuclear grade (p=0.013) in IBC. Conclusion: Claudin-7 is an important tight junction protein in the breast and a loss of expression may assist in the dissociation and invasion of tumor cells.

Claudin-7 is Highly Expressed in Chromophobe Renal Cell Carcinoma and Renal Oncocytoma

Claudin-7 has recently been suggested to be a distal nephron marker. We tested the possibility that expression of claudin-7 could be used as a marker of renal tumors originating from the distal nephron. We examined the immunohistochemical expression of claudin-7 and parvalbumin in 239 renal tumors, including 179 clear cell renal cell carcinoma (RCC)s, 29 papillary RCCs, 20 chromophobe RCCs, and 11 renal oncocytomas. In addition, the methylation specific-PCR (MSP) of claudin-7 was performed. Claudin-7 and parvalbumin immunostains were positive in 3.4%, 7.8% of clear cell RCCs, 34.5%, 31.0% of papillary RCCs, 95.0%, 80.0% of chromophobe RCCs, and 72.7%, 81.8% of renal oncocytomas, respectively. The sensitivity and specificity of claudin-7 in diagnosing chromophobe RCC among subtypes of RCC were 95.0% and 92.3%. Those of parvalbumin were 80.0% and 88.9%. The expression pattern of claudin-7 was mostly diffuse in chromophobe RCC and was either focal or diffuse in oncocytoma. All of the cases examined in the MSP revealed the presence of unmethylated promoter of claudin-7 without regard to claudin-7 immunoreactivity. Hypermethylation of the promoter might not be the underlying mechanism for loss of its expression in RCC. Claudin-7 can be used as a useful diagnostic marker in diagnosing chromophobe RCC and oncocytoma.

Increased expressions of claudin-1 and claudin-7 in cervical squamous intraepithelial neoplasias and invasive squamous cell carcinomas / 대한산부인과학회지

OBJECTIVE: The change of claudin expressions, integral transmembrane proteins for tight junction, might be related to progression of cervical premalignancy or malignancy. The aim of this study was to verify the tendency of expressions of claudin-1 and -7 according to the progression of cervical pathology of uterus. METHODS: There were 162 tissues obtained at AA institute. 25 tissues were normal, 26 were cervical intraepithelial neoplasia (CIN) 1, 30 were CIN2, 44 were CIN3, 25 were microinvasive cervical carcinomas, and 12 were invasive squamous cervical carcinomas (ISCC). H and E and immunohistochemical staining were done. RESULTS: Among normal tissues, 52% showed no expression, 48% weak expressions at claudin-1, and 28% no expression, 56% weak expressions at claudin-7. Among CIN3, 20% showed weak expressions, 41% showed moderate expressions at claudin-1, and 14% weak expressions, 52% moderate expressions at claudin-7. Among ISCC, 42% showed moderate expressions, 50% strong expressions at claudin-1, and 33% moderate expressions, and 33% strong expressions at claudin-7. These data shows the increasing tendency of claudin-1 and claudin-7 expressions according to the severity of lesions (p<0.01). CONCLUSION: The expressions of claudin-1 and claudin-7 were increased more according to the progression of cervical lesions.

Increased expressions of claudin-1 and claudin-7 in cervical squamous intraepithelial neoplasias and invasive squamous cell carcinomas / 대한산부인과학회지

OBJECTIVE: The change of claudin expressions, integral transmembrane proteins for tight junction, might be related to progression of cervical premalignancy or malignancy. The aim of this study was to verify the tendency of expressions of claudin-1 and -7 according to the progression of cervical pathology of uterus. METHODS: There were 162 tissues obtained at AA institute. 25 tissues were normal, 26 were cervical intraepithelial neoplasia (CIN) 1, 30 were CIN2, 44 were CIN3, 25 were microinvasive cervical carcinomas, and 12 were invasive squamous cervical carcinomas (ISCC). H and E and immunohistochemical staining were done. RESULTS: Among normal tissues, 52% showed no expression, 48% weak expressions at claudin-1, and 28% no expression, 56% weak expressions at claudin-7. Among CIN3, 20% showed weak expressions, 41% showed moderate expressions at claudin-1, and 14% weak expressions, 52% moderate expressions at claudin-7. Among ISCC, 42% showed moderate expressions, 50% strong expressions at claudin-1, and 33% moderate expressions, and 33% strong expressions at claudin-7. These data shows the increasing tendency of claudin-1 and claudin-7 expressions according to the severity of lesions (p<0.01). CONCLUSION: The expressions of claudin-1 and claudin-7 were increased more according to the progression of cervical lesions.