Background Gallbladder cancer (GBC) is usually detected in advanced stages with a low 5-year survival rate. Delta-like ligand 4 (DLL4), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-2alpha (HIF2α) have been studied for their role in tumorigenesis and potential for therapeutic target, and multiple clinical trials of the agents targeting them are ongoing. We investigated the expression of these markers in surgically resected GBC and tried to reveal their association with the clinicopathologic features, mutual correlation of their expression, and prognosis of the GBC patients by their expression.
Methods We constructed the tissue microarray blocks of 99 surgically resected GBC specimens and performed immunohistochemistry of DLL4, VEGF, and HIF2α. We used the quantitative digital image analysis to evaluate DLL4 and VEGF expression, while the expression of HIF2α was scored manually.
Results The expression of VEGF and HIF2α showed a significant trend with tumor differentiation (p= .028 and p= .006, respectively). We found that the high DLL4 and VEGF expression were significantly correlated with lymph node metastasis (p= .047, both). The expression of VEGF and HIF2α were significantly correlated (p < .001). The GBC patients with low HIF2α expression showed shorter recurrence-free survival than those with high HIF2α expression.
Conclusions This study suggested the possibility of the usage of DLL4 and VEGF to predict the lymph node metastasis and the possibility of VEGF and HIF2α to predict the expression level mutually. Further studies may be needed to validate our study results and eventually accelerate the introduction of the targeted therapy in GBC.
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BACKGROUND Cyclooxygenase-2 (COX-2) is an enzyme that promotes proliferation of tumor cells. HuR is a member of the family of embryonic lethal abnormal vision-like proteins. Recent studies show that cytoplasmic HuR stabilizes the mRNA of COX-2 and regulates the expression of COX-2. Moreover, cytoplasmic HuR expression is associated with a poorer prognosis for patients with some cancers. The aim of this study was to investigate the expression patterns of and the relationship between COX-2 and HuR in gallbladder carcinoma. METHODS We analyzed COX-2 and HuR expression by immunohistochemical staining of 108 gallbladder carcinomas. RESULTS COX-2 expression and nuclear and cytoplasmic HuR expression were seen in, respectively, 61 (56.5%), 77 (71.3%), and 4 (3.7%) cases. COX-2 and nuclear HuR were simultaneously expressed in 44 of the 108 samples without any quantitative association between the levels of each.
COX-2 expression correlated with tumor stage, differentiation (based on histology), lymph node metastasis, perineural invasion, and survival. Nuclear and cytological expression of HuR did not correlate with any clinical parameters. CONCLUSIONS COX-2 expression but not HuR may play an important role in the prognosis of patients with gallbladder carcinoma.
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BACKGROUND Matrix metalloproteinase (MMP)-2 and MMP-9 degrade type IV collagen and are antagonized by the tissue inhibitors of metalloproteinase (TIMP)-2 and TIMP-1, respectively. METHODS We studied by immunohistochemistry the expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 in 72 cases of adenocarcinoma of the gallbladder. RESULTS The MMP-2, MMP-9 and TIMP-1 expressions were significantly higher in well/moderately differentiated adenocarcinomas than in poorly differentiated adenocarcinomas, in adenocarcinomas that had invaded the lamina propria/proper muscle than in those that had invaded the perimuscular connective tissue or beyond the serosa, and in adenocarcinomas with fungating growth than in those with infiltrative growth. The TIMP-2 expression showed a similar pattern without statistical significance. Regarding the status of lymph node metastasis, the MMP-2 expression was significantly higher in cases without lymph node metastasis.
The MMP-2 and MMP-9 expressions were significantly related to those of TIMP-2 and TIMP-1, respectively, with regard to depth of invasion, differentiation, and growth patterns of the adenocarcinomas. CONCLUSIONS MMP-2, MMP-9, TIMP-1 and TIMP-2 are suggested to play important roles in the progression to early invasion of adenocarcinomas, in which the function of MMP-2 is inhibited by TIMP-2.
BACKGROUND It has been well demonstrated that the overexpression of epidermal growth factor receptor (EGFR) is associated with numerous gastrointestinal malignancies, including gallbladder carcinoma. However, the cellular events that regulate EGFR in cancer cells have not been fully elucidated. A novel negative regulator of EGFR that is referred to as EGFR related protein (ERRP) has recently been identified. The aim of this study was to investigate the expression and localization of ERRP in gallbladder carcinoma and to examine a possible role for ERRP. METHODS We examined the immunohistochemical expressions of ERRP, p53 and proliferating cell nuclear antigen labeling index (PCNA-LI) in formalin-fixed, paraffinembedded specimens of 43 cases of gallbladder carcinoma, 7 cases of adenoma and 3 cases of dysplasia. RESULTS In the normal mucosa, ERRP immunoreactivity was positive in over 64% of specimens. In contrast, the ERRP staining was positive in only 46% of the cancer specimens.
The expression of ERRP in cancer cells was inversely correlated with tumor cell proliferation. The loss of ERRP expression correlated with the p53 overexpression. CONCLUSIONS Our data indicate that the down-regulation or loss of ERRP could play an important role in the progression of gallbladder carcinoma. The inverse relationship between the ERRP expression and PCNA-LI suggests that ERRP may play a role in the inhibition of tumor cell proliferation in gallbladder cancer.
BACKGROUND There are evidences that uPA and its inhibitor play a key role in tumor spread. We studied whether uPA and PAI-1 expressions could serve as prognostic parameters along with clinical, gross and microscopic findings in gallbladder carcinomas. METHODS We analyzed 42 cases of gallbladder carcinomas by immunohistochemical staining and clinicopathologic parameters. RESULTS uPA and PAI-1 were more frequently expressed in the adenocarcinoma than in the normal or benign gallbladder tissue. The uPA expression in the glands of low grade adenocarcinoma was significantly correlated with both distant and lymph node metastases. The uPA expression in the stroma around the low grade adenocarcinoma was significantly correlated with either distant or lymph node metastasis. The PAI-1 expression was significantly correlated with lymph node metastasis only for both distant and lymph node metastases. In multivariate analysis, the lymphatic invasion was significantly related to poor survival (p= 0.0115). In univariate analysis, the cases without lymphatic invasion had prolonged survival. Positive expression of uPA in the glands of low-grade adenocarcinoma was significantly correlated with poor survival (p=0.0391). CONCLUSION In conjunction with clinicopathologic findings, expressions of uPA and PAI-1 may be useful prognostic markers in gallbladder carcinomas.