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Expression of phospho-ERK1/2 and PI3-K in benign and malignant gallbladder lesions and its clinical and pathological correlations.

Li Q, Yang Z - J. Exp. Clin. Cancer Res. (2009)

Bottom Line: Moreover, the frequency of p-ERK1/2 expression in gallbladder adenocarcinomas without gallstone was significantly lower than those with gallstones.Increased expression of p-ERK1/2 (P < 0.05) and PI3K (P = 0.062) was associated with decreased overall survival.Multivariate Cox regression analysis showed that increased p-ERK1/2 expression was an independent prognostic predictor in gallbladder carcinoma (P = 0.028).

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Laboratory of Hepatobiliary Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China. liqinglonga@sina.com

ABSTRACT

Background: An increasing number of studies have shown that ERK and PI3-K/AKT signaling pathways are involved in various human cancers including hepatocellular carcinoma and cholangiocarcinoma. However, few studies have examined gallbladder cancer specimens, and little is known about the clinical and pathological significance of ERK1/2 and PI3-K/AKT signaling changes in gallbladder adenocarcinoma. In this study, we examined phospho-ERK1/2 (p-ERK1/2) and PI3K expression and analyzed its clinicopathological impact in gallbladder adenocarcinoma.

Methods: Immunohistochemistry was used to detect and compare the frequency of p-ERK1/2 and PI3-K expression in gallbladder adenocarcinoma, peri-tumor tissues, adenomatous polyps, and chronic cholecystitis specimens.

Results: The positive staining for p-EKR1/2 and PI3-K were 63/108 (58.3%) and 55/108 (50.9%) in gallbladder adenocarcinoma; 14/46 (30.4%) and 5/46 (10.1%) in peri-tumor tissues; 3/15 (20%) and 3/15 (20%) in adenomatous polyps; and 4/35 (11.4%) and 3/35 (8.6%) in chronic cholecystitis. The positive rate of p-ERK1/2 or PI3-K in gallbladder adenocarcinoma was significantly higher than that in peri-tumor tissue (both, P < 0.01), adenomatous polyps (p-ERK1/2, P < 0.01; PI3-K, P < 0.05), and chronic cholecystitis (both, P < 0.01). The positive staining for p-ERK1/2 or PI3-K was significantly lower in well/highly-differentiated adenocarcinomas with maximal diameter < 2.0 cm, no metastasis to lymph node, and no infiltration of regional tissues or organs compared to poorly-differentiated adenocarcinomas which are characterized by a maximal diameter >or= 2.0 cm, with metastasis to lymph node and infiltration of regional tissues or organs (P < 0.05 or P < 0.01). Moreover, the frequency of p-ERK1/2 expression in gallbladder adenocarcinomas without gallstone was significantly lower than those with gallstones. Increased expression of p-ERK1/2 (P < 0.05) and PI3K (P = 0.062) was associated with decreased overall survival. Multivariate Cox regression analysis showed that increased p-ERK1/2 expression was an independent prognostic predictor in gallbladder carcinoma (P = 0.028).

Conclusion: Increased expression of p-ERK1/2 and PI3K might contribute to gallbladder carcinogenesis. p-ERK1/2 over-expression is correlated with decreased survival and therefore may serve as an important biological marker in development of gallbladder adenocarcinoma.

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Immunohistochemical staining of p-ERK1/2 and PI3-K (original magnification 200×). p-ERK1/2 expression in peri-tumor tissues with severe atypical proliferation of gallbladder adenocarcinoma (a), in gallbladder adenoma polyps with moderate atypical proliferation (b), in chronic cholecystitis with moderate atypical proliferation (c). PI3-K staining in surrounding tissues with severe atypical proliferation of gallbladder adenocarcinoma (d), in gallbladder adenoma polyps with severe atypical proliferation pericancerous tissues (e), and in chronic cholecystitis with mild (f).
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Figure 2: Immunohistochemical staining of p-ERK1/2 and PI3-K (original magnification 200×). p-ERK1/2 expression in peri-tumor tissues with severe atypical proliferation of gallbladder adenocarcinoma (a), in gallbladder adenoma polyps with moderate atypical proliferation (b), in chronic cholecystitis with moderate atypical proliferation (c). PI3-K staining in surrounding tissues with severe atypical proliferation of gallbladder adenocarcinoma (d), in gallbladder adenoma polyps with severe atypical proliferation pericancerous tissues (e), and in chronic cholecystitis with mild (f).

Mentions: Immunohistochemistry for p-ERK1/2 and PI3-K were conducted with 108 gallbladder adenocarcinomas, 46 surrounding tissues of gallbladder adenocarcinoma, 15 adenoma polyps, and 35 chronic cholecystitis samples. Positive staining for p-ERK1/2 was observed in the cytoplasm and/or nucleus (Figure 1 and 2a–c). PI3-K staining was mostly seen in the cytoplasm as expected (Figure 1 and 2d–f). As shown in Table 1, of the 108 gallbladder adenocarcinomas, expression of p-ERK1/2 and PI3-K was detected in 63 (58.3%) and 55 cases (50.9%), respectively. In the 46 surrounding tissues of gallbladder adenocarcinoma, p-ERK1/2 and PI3-K were positive in 14 (30.4%) and 5 (10.1%) cases, respectively. Moderate to severe atypical hyperplasia were observed in all gallbladder mucous epithelium in p-ERK1/2 positive cases. In PI3-K positive samples, however, gallbladder mucous epithelium was normal in one case, mild atypical hyperplasia in one case, while moderate and severe atypical hyperplasia were seen in one and 2 cases, respectively. Positive staining for p-ERK1/2 and PI3-K was both observed in 3 out of 15 adenoma polyps which all showed moderate to severe atypical hyperplasia. In the chronic cholecystitis group, p-ERK1/2 and PI3-K staining was positive in 4 (11.4%) and 3 (8.6%) of the 35 cases, respectively. Gallbladder mucous epithelium in positive specimens showed moderate to severe atypical hyperplasia. Overall, the frequency of samples positive for p-ERK1/2 and PI3-K in gallbladder adenocarcinomas was significantly higher than that in surrounding tissues (χ2pERK = 10.04, P < 0.01; χ2PI3-K = 21.77, P < 0.01), in adenoma polyps (χ2pERK = 7.78, P < 0.01; χ2PI3-K = 5.06, P < 0.01), and in chronic cholecystitis (χ2pERK = 23.35, P < 0.01; χ2PI3-K = 19.67, P < 0.01).


Expression of phospho-ERK1/2 and PI3-K in benign and malignant gallbladder lesions and its clinical and pathological correlations.

Li Q, Yang Z - J. Exp. Clin. Cancer Res. (2009)

Immunohistochemical staining of p-ERK1/2 and PI3-K (original magnification 200×). p-ERK1/2 expression in peri-tumor tissues with severe atypical proliferation of gallbladder adenocarcinoma (a), in gallbladder adenoma polyps with moderate atypical proliferation (b), in chronic cholecystitis with moderate atypical proliferation (c). PI3-K staining in surrounding tissues with severe atypical proliferation of gallbladder adenocarcinoma (d), in gallbladder adenoma polyps with severe atypical proliferation pericancerous tissues (e), and in chronic cholecystitis with mild (f).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691734&req=5

Figure 2: Immunohistochemical staining of p-ERK1/2 and PI3-K (original magnification 200×). p-ERK1/2 expression in peri-tumor tissues with severe atypical proliferation of gallbladder adenocarcinoma (a), in gallbladder adenoma polyps with moderate atypical proliferation (b), in chronic cholecystitis with moderate atypical proliferation (c). PI3-K staining in surrounding tissues with severe atypical proliferation of gallbladder adenocarcinoma (d), in gallbladder adenoma polyps with severe atypical proliferation pericancerous tissues (e), and in chronic cholecystitis with mild (f).
Mentions: Immunohistochemistry for p-ERK1/2 and PI3-K were conducted with 108 gallbladder adenocarcinomas, 46 surrounding tissues of gallbladder adenocarcinoma, 15 adenoma polyps, and 35 chronic cholecystitis samples. Positive staining for p-ERK1/2 was observed in the cytoplasm and/or nucleus (Figure 1 and 2a–c). PI3-K staining was mostly seen in the cytoplasm as expected (Figure 1 and 2d–f). As shown in Table 1, of the 108 gallbladder adenocarcinomas, expression of p-ERK1/2 and PI3-K was detected in 63 (58.3%) and 55 cases (50.9%), respectively. In the 46 surrounding tissues of gallbladder adenocarcinoma, p-ERK1/2 and PI3-K were positive in 14 (30.4%) and 5 (10.1%) cases, respectively. Moderate to severe atypical hyperplasia were observed in all gallbladder mucous epithelium in p-ERK1/2 positive cases. In PI3-K positive samples, however, gallbladder mucous epithelium was normal in one case, mild atypical hyperplasia in one case, while moderate and severe atypical hyperplasia were seen in one and 2 cases, respectively. Positive staining for p-ERK1/2 and PI3-K was both observed in 3 out of 15 adenoma polyps which all showed moderate to severe atypical hyperplasia. In the chronic cholecystitis group, p-ERK1/2 and PI3-K staining was positive in 4 (11.4%) and 3 (8.6%) of the 35 cases, respectively. Gallbladder mucous epithelium in positive specimens showed moderate to severe atypical hyperplasia. Overall, the frequency of samples positive for p-ERK1/2 and PI3-K in gallbladder adenocarcinomas was significantly higher than that in surrounding tissues (χ2pERK = 10.04, P < 0.01; χ2PI3-K = 21.77, P < 0.01), in adenoma polyps (χ2pERK = 7.78, P < 0.01; χ2PI3-K = 5.06, P < 0.01), and in chronic cholecystitis (χ2pERK = 23.35, P < 0.01; χ2PI3-K = 19.67, P < 0.01).

Bottom Line: Moreover, the frequency of p-ERK1/2 expression in gallbladder adenocarcinomas without gallstone was significantly lower than those with gallstones.Increased expression of p-ERK1/2 (P < 0.05) and PI3K (P = 0.062) was associated with decreased overall survival.Multivariate Cox regression analysis showed that increased p-ERK1/2 expression was an independent prognostic predictor in gallbladder carcinoma (P = 0.028).

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Laboratory of Hepatobiliary Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China. liqinglonga@sina.com

ABSTRACT

Background: An increasing number of studies have shown that ERK and PI3-K/AKT signaling pathways are involved in various human cancers including hepatocellular carcinoma and cholangiocarcinoma. However, few studies have examined gallbladder cancer specimens, and little is known about the clinical and pathological significance of ERK1/2 and PI3-K/AKT signaling changes in gallbladder adenocarcinoma. In this study, we examined phospho-ERK1/2 (p-ERK1/2) and PI3K expression and analyzed its clinicopathological impact in gallbladder adenocarcinoma.

Methods: Immunohistochemistry was used to detect and compare the frequency of p-ERK1/2 and PI3-K expression in gallbladder adenocarcinoma, peri-tumor tissues, adenomatous polyps, and chronic cholecystitis specimens.

Results: The positive staining for p-EKR1/2 and PI3-K were 63/108 (58.3%) and 55/108 (50.9%) in gallbladder adenocarcinoma; 14/46 (30.4%) and 5/46 (10.1%) in peri-tumor tissues; 3/15 (20%) and 3/15 (20%) in adenomatous polyps; and 4/35 (11.4%) and 3/35 (8.6%) in chronic cholecystitis. The positive rate of p-ERK1/2 or PI3-K in gallbladder adenocarcinoma was significantly higher than that in peri-tumor tissue (both, P < 0.01), adenomatous polyps (p-ERK1/2, P < 0.01; PI3-K, P < 0.05), and chronic cholecystitis (both, P < 0.01). The positive staining for p-ERK1/2 or PI3-K was significantly lower in well/highly-differentiated adenocarcinomas with maximal diameter < 2.0 cm, no metastasis to lymph node, and no infiltration of regional tissues or organs compared to poorly-differentiated adenocarcinomas which are characterized by a maximal diameter >or= 2.0 cm, with metastasis to lymph node and infiltration of regional tissues or organs (P < 0.05 or P < 0.01). Moreover, the frequency of p-ERK1/2 expression in gallbladder adenocarcinomas without gallstone was significantly lower than those with gallstones. Increased expression of p-ERK1/2 (P < 0.05) and PI3K (P = 0.062) was associated with decreased overall survival. Multivariate Cox regression analysis showed that increased p-ERK1/2 expression was an independent prognostic predictor in gallbladder carcinoma (P = 0.028).

Conclusion: Increased expression of p-ERK1/2 and PI3K might contribute to gallbladder carcinogenesis. p-ERK1/2 over-expression is correlated with decreased survival and therefore may serve as an important biological marker in development of gallbladder adenocarcinoma.

Show MeSH
Related in: MedlinePlus