Leping Yang

Positive ALDH1A3 and Negative GPX3 Expressions Are Biomarkers for Poor Prognosis of Gallbladder Cancer

Background. Gallbladder cancers (GBCs) are highly aggressive cancers with high mortality. However, biological markers for the progression and prognosis of GBC are currently unavailable in the clinic. Objective. To identify biomarkers for predicting GBC metastasis and prognosis. Methods. We examined ALDH1A3 and GPX3 expressions in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) by using immunohistochemistry. Results. Positive ALDH1A3 and negative GPX3 expressions were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either positive ALDH1A3 (P < 0.001) or negative GPX3 (P < 0.001) expression significantly correlated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive ALDH1A3 expression or negative GPX3 expression was an independent poor-prognostic predictor in both SC/ASC and AC patients. Conclusions. Our study suggested that positive ALDH1A3 and negative GPX3 expressions are closely associated with clinical pathological behaviors and poor prognosis of gallbladder cancer.

Expressive levels of MUC1 and MUC5AC and their clinicopathologic significances in the benign and malignant lesions of gallbladder

This article is intended to make a study on the expressive levels of mucin core proteins (MUC1 and MUC5AC) and detect their clinicopathologic significances in the benign and malignant lesions of gallbladder.

PSCA and Oct-4 Expression in the Benign and Malignant Lesions of Gallbladder: Implication for Carcinogenesis, Progression, and Prognosis of Gallbladder Adenocarcinoma

PSCA and Oct-4 have been thought as markers of cancer stem cells. Although overexpression of PSCA and Oct-4 in cancer has been reported, little is known about the clinical and pathological significance with PSCA and Oct-4 expression in gallbladder adenocarcinoma. In this study, overexpression of PSCA and Oct-4 was detected in gallbladder adenocarcinoma (54.6% and 55.6%). Less expression of PSCA and Oct-4 was detected in the pericancerous tissues (19.6% and 21.7%), gallbladder polyps (13.3% and 13.3%), and gallbladder epithelium with chronic cholecystitis (14.3% and 14.3%). The overexpression of PSCA and Oct-4 was significantly associated with differentiation, tumor mass, lymph node metastasis, invasion of gallbladder adenocarcinoma, and decreased overall survival. Our study suggested that overexpression of PSCA and Oct-4 might be closely related to the carcinogenesis, progression, metastasis, or invasive potential and prognosis of gallbladder carcinoma.

Expression levels of HMGA2 and CD9 and its clinicopathological significances in the benign and malignant lesions of the gallbladder

BackgroundThe objective of this study was to investigate CD9 and HMGA2 expression and its clinicopathological significance in benign and malignant lesion tissues of the gallbladder.MethodsThe resected specimens of 108 cases of gallbladder adenocarcinoma, 46 cases of adjacent tissue, 15 cases of polyps and 35 cases of chronic cholecystitis were made into conventional paraffin-embedded sections, using the method of EnVision immunohistochemistry to stain HMGA2 and CD9.ResultsHMGA2 expression of gallbladder adenocarcinoma was significantly higher than that of adenocarcinoma adjacent tissues (= 16.13, P <0.01), polyps (= 8.19, P <0.01) and chronic cholecystitis (= 21.41, P <0.01); but CD9 expression was the opposite (P <0.05 or P <0.01). The positive rate of HMGA2 expression from the cases that had well-differentiated adenocarcinoma, with the largest tumor diameter <2 cm, and without lymph node metastasis, and that did not invade the surrounding tissue was significantly lower than that of HMGA2 expression from the cases that had poorly differentiated adenocarcinoma, with the largest tumor diameter ≥2 cm, lymph node metastasis, and that invaded the surrounding tissues (P <0.05 or P <0.01). The positive rate of CD9 expression from the cases that had well-differentiated adenocarcinoma, with the largest tumor diameter <2 cm, and without lymph node metastasis, and that did not invade the surrounding tissue was significantly higher than that of CD9 expression from the cases that had poorly differentiated adenocarcinoma, with the largest tumor diameter ≥2 cm, lymph node metastasis, and which invaded the surrounding tissues (P <0.05 or P <0.01). The Kaplan-Meier survival analysis showed that after surgery, the survival period of HMGA2 expression-positive cases was significantly lower than that of HMGA2 expression- negative cases (P = 0.020), but the survival period of CD9 expression-positive cases was significantly higher than that of cases with CD9 expression-negative (P = 0.019). Cox multivariate regression analysis showed that the HMGA2 positive expression and/or CD9 negative expression was an important indicator reflecting the poor prognosis of gallbladder cancer.ConclusionThe expression of HMGA2 and/or CD9 might be closely related to the carcinogenesis, clinical biological behaviors and prognosis of gallbladder adenocarcinoma.

Expression of VHL and HIF-1α and Their Clinicopathologic Significance in Benign and Malignant Lesions of the Gallbladder.

BackgroundThe Von Hippel-Lindau (VHL) gene is a tumor-suppressor gene. Recent studies have shown that low expression of VHL has a close relationship with tumor formation, progression, and prognosis. Hypoxia-inducible factor (HIF)-1&agr; is a transcription factor, which exists universally in mammals including humans under states of hypoxia. Some studies have also shown that expression of HIF-1&agr; closely correlates with tumor progression, angiogenesis, metastasis, and invasion. This molecule is also an important cytokine, which may be used to evaluate the prognosis of some malignant tumors. In this study, we studied the expression of VHL and HIF-1&agr; and evaluated their clinicopathologic significance and relationship in benign and malignant lesions of the gallbladder. MethodsEnVision immunohistochemistry was used for detecting the expression level of VHL and HIF-1&agr; in routinely paraffin-embedded sections from specimens of gallbladder adenocarcinoma (n=108), peritumoral tissues (n=46), adenomatous polyps (n=15), and chronic cholecystitis (n=35). ResultsThe frequency of positive VHL expression was significantly lower in adenocarcinoma of gallbladder (48.1%) than that in peritumoral tissues (80.4%), adenomatous polyps (80.0%), and chronic cholecystitis (88.6%) (P<0.05 or P<0.01). In contrast, the positive HIF-1&agr; expression was significantly higher in adenocarcinoma (53.7%) than that in peritumoral tissues (34.8%), adenomatous polyps (26.7%), and chronic cholecystitis (14.3%) (P<0.05 or P<0.01). The benign lesions with positive VHL and/or negative HIF-1&agr; expression showed atypical hyperplasia in gallbladder epithelium. The positive expression of VHL and negative expression of HIF-1&agr; were significantly associated with differentiation, tumor mass, lymph node metastasis, and invasion of adenocarcinoma (P<0.05 or P<0.01). The highly inconsistent expression of VHL and HIF-1&agr; in gallbladder adenocarcinoma was found (P<0.01). Univariate Kaplan-Meier analysis showed that elevated expression of VHL (P=0.023) or lowered expression of HIF-1&agr; (P=0.020) was closely associated with decreased overall survival. Multivariate Cox regression analysis showed that positive expression of VHL (P=0.013) and/or negative expression of HIF-1&agr; (P=0.005) was an independent poor-prognostic predictor in gallbladder adenocarcinoma. ConclusionsThe lowered expression of HIF-1&agr; and elevated expression of VHL in gallbladder adenocarcinoma are important markers for the progression, clinical biological behavior, and prognosis. Measurement of VHL and HIF-1&agr; expression could be a tool for early detection of gallbladder cancer in benign lesions and in population screening. The highly inconsistent expression of VHL and HIF-1&agr; in gallbladder may require further study to see whether they are intrinsically related.

Expression of ezrin, HGF and c-met and its clinicopathological significance in the benign and malignant lesions of the gallbladder.

BACKGROUND/AIMS To investigate the expression of ezrin, HGF and c-met in the benign and malignant lesions of the gallbladder. METHODOLOGY Ezrin, HGF and c-met expression was detected by immunohistochemistry. RESULTS The positive ezrin, HGF and c-met expression was significantly higher in gallbladder adenocarcinoma than in benign lesions. The benign lesions with positive ezrin, HGF and/or c-met expression showed moderately- or severely-atypical hyperplastic epithelium. The positive expression of ezrin, HGF and c-met was significantly associated with differentiation, tumor mass, lymph node metastasis and invasion of adenocarcinoma. Univariate Kaplan-Meier analysis showed that increased expression of ezrin, HGF and c-met was associated with decreased overall survival. Multivariate Cox regression analysis showed that increased expression of ezrin, HGF or c-met was an independent bad-prognostic predictor in gallbladder adenocarcinoma. CONCLUSIONS The expression of ezrin, HGF and/or c-met might be closely related to the carcinogenesis, progression, clinical biological behaviors and prognosis of gallbladder adenocarcinoma.

Glypican-3 and KRT19 are markers associating with metastasis and poor prognosis of pancreatic ductal adenocarcinoma

OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with metastasis in most patients at diagnosis. The molecular mechanisms associated with its high malignancy have not been fully elucidated. This study investigated the clinicopathological significances of GPC3 and KRT19 expression in PDAC. METHODS GPC3, KRT19, and CA19-9 protein expression were measured by immunohistochemistry. RESULTS GPC3 and KRT19 protein levels were overexpressed in PDAC tumors compared to normal pancreatic tissues, benign pancreatic tissues, and peritumoral tissues (P< 0.01). The percentage of positive GPC3 and KRT19 expression were significantly higher in PDAC patients with larger tumor size, poorly differentiated tumor, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with small tumor size, well-differentiated tumor, no lymph node metastasis and invasion, as well as TNM stage I/II stage disease (P< 0.05 or P< 0.01). Benign pancreatic lesions with positive GPC3 and KRT19 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive GPC3 and KRT19 expression survived significantly shorter than patients with negative GPC3 and KRT19 expression (P < 0.05 or P< 0.001). Cox multivariate analysis revealed that positive GPC3 and KRT19 expression were independent poor prognosis factors in PDAC patients. CONCLUSIONS GPC3 and KRT19 overexpression are associated with carcinogenesis, progression, and poor prognosis in patients with PDAC and a valuable biomarker for diagnosis of PDAC.

Expression of DNA-repair proteins and their significance in pancreatic cancer and non-cancerous pancreatic tissues of Sprague-Dawley rats

BackgroundTo establish a model of pancreatic cancer induced by 7,12-dimethylbenzantracene (DMBA) in Sprague–Dawley (SD) rats, and detect the expression of DNA-repair proteins (MGMT, ERCC1, hMSH2, and hMLH1) and their significance in pancreatic cancer and non-cancerous pancreatic tissues of SD rats.MethodsDMBA was directly implanted into the parenchyma of rat pancreas (group A and group B), and group B rats were then treated with trichostatin A (TSA). The rats in both groups were executed within 3 to 5 months, and their pancreatic tissues were observed by macrography and under microscopy. Meanwhile, the rats in the control group (group C) were executed at 5 months. Immunohistochemistry was used to assay the expression of MGMT, ERCC1, hMSH2, and hMLH1.ResultsThe incidence of pancreatic cancer in group A within 3 to 5 months was 48.7% (18/37), including 1 case of fibrosarcoma. The incidence of pancreatic cancer in group B was 33.3% (12/36), including 1 case of fibrosarcoma. The mean of maximal diameters of tumors in group A was higher than that in group B (P <0.05). No pathological changes were found in pancreas of group C and other main organs (except pancreas) of group A and group B. No statistical differences were found among the positive rates of MGMT, ERCC1, hMSH2, and hMLH1 in ductal adenocarcinoma and non-cancerous pancreatic tissues of group A (P >0.05). The positive rates of MGMT, ERCC1, hMSH2, and hMLH1 were significantly lower in ductal adenocarcinoma than those in non-cancerous tissues of group B (P ≤0.05). All pancreas of group C had positive expression of MGMT, ERCC1, hMSH2, and hMLH1 and two cases of fibrosarcoma showed a negative expression.ConclusionsDMBA, directly implanted into the parenchyma of pancreas, creates an ideal pancreatic cancer model within a short time. TSA might restrain DNA damage related to the genesis and growth of pancreatic cancer in rats. The DNA-repair proteins, including MGMT, ERCC1, hMSH2, and hMLH1, might play an important role in the genesis of pancreatic cancer induced by DMBA in rats.

BIRC7 and KLF4 expression in benign and malignant lesions of pancreas and their clinicopathological significance

This study investigated the KLF4 and BIRC7 protein expression in malignant and benign pancreatic tissues by immunohistochemical staining and the clinical and pathological significance of KLF4 and BIRC7 expression in PDAC. KLF4 expression was significantly lower, whereas BIRC7 expression was significantly higher in PDAC than that in peritumoral tissue, benign pancreatic lesions, and normal pancreatic tissue (P < 0.01). The percentage of positive BIRC7 and negative KLF4 expression was significantly lower in PDAC patients with well differentiated tumors, maximum tumor size < 3 cm, no lymph node metastasis, no invasion to the surrounding tissues and organs, and TNM stage I/II stage disease than in patients with poorly differentiated tumor, maximum tumor size > 5 cm, lymph node metastasis, invasion to surrounding tissues and organs, and TNM stage III/IV disease (P < 0.05 or P < 0.01). Kaplan-Meier survival analysis showed that the differentiation, maximum tumor size, TNM stage, lymph node metastasis, invasion, negative KLF4 expression, and positive BIRC7 expression were significantly associated with the short survival of patients with PDAC (P < 0.05 or P < 0.01). Cox multivariate analysis revealed that positive BIRC7 expression and negative KLF4 expression were independent poor prognosis factors in PDAC patients. In conclusions, positive BIRC7 expression and negative KLF4 expression are associated with the progression of PDAC and poor prognosis in patients with PDAC.

The Clinical and Pathological Significance of Nectin-2 and DDX3 Expression in Pancreatic Ductal Adenocarcinomas

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, but the genetic basis of PDAC is still unclear. In this study, Nectin-2 and DDX3 expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic lesions, and 13 normal pancreatic tissues were measured by immunohistochemical methods. Results showed that the percentage of positive Nectin-2 and DDX3 expression was significantly higher in PDAC tumors than in peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P < 0.01). The percentage of cases with positive Nectin-2 and DDX3 expression was significantly lower in PDAC patients without lymph node metastasis and invasion and having TNM stage I/II disease than in patients with lymph node metastasis, invasion, and TNM stage III/IV disease (P < 0.05 or P < 0.01). Positive DDX3 expression is associated with poor differentiation of PDAC. Kaplan-Meier survival analysis showed that positive Nectin-2 and DDX3 expression were significantly associated with survival in PDAC patients (P < 0.001). Cox multivariate analysis revealed that positive Nectin-2 and DDX3 expression were independent poor prognosis factors in PDAC patients. In conclusion, positive Nectin-2 and DDX3 expression are associated with the progression and poor prognosis in PDAC patients.