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High expression of cAMP-responsive element-binding protein 1 (CREB1) is associated with metastasis, tumor stage and poor outcome in gastric cancer.

Wang YW, Chen X, Gao JW, Zhang H, Ma RR, Gao ZH, Gao P - Oncotarget (2015)

Bottom Line: In the present study, immunohistochemistry was performed to detect the expression of CREB1 protein in 185 primary gastric cancer tissues, 50 secondary lymph node metastatic foci and 50 nontumorous gastric tissues.CREB1 was identified as a direct target of miR-27b and miR-200b, and down-regulated by miR-27b/miR-200b.We conclude that CREB1 is a promising biomarker to predict tumor metastasis and patient outcome in gastric cancer, and the miR-27b/miR-200b-CREB1 pathway may serve as a potential molecular target for the treatment of gastric cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, P.R. China.

ABSTRACT
cAMP responsive element binding protein 1 (CREB1) has been reported to be implicated in tumor development and progression of human cancers. However, the clinical significance and regulatory mechanisms of CREB1 expression in gastric cancer remain largely unknown. In the present study, immunohistochemistry was performed to detect the expression of CREB1 protein in 185 primary gastric cancer tissues, 50 secondary lymph node metastatic foci and 50 nontumorous gastric tissues. A prognostic model combining CREB1 expression with TNM tumor stage was constructed by logistic regression analysis. Regulation of CREB1 by miRNAs was investigated by luciferase reporter assay and Western blot. It was shown that CREB1 was highly expressed and correlated with lymph node metastasis, distant metastasis and tumor stage and poor outcome in gastric cancer. The prognostic model was proven to be an independent prognosis predictor and performed better than CREB1 or tumor stage alone. CREB1 was identified as a direct target of miR-27b and miR-200b, and down-regulated by miR-27b/miR-200b. We conclude that CREB1 is a promising biomarker to predict tumor metastasis and patient outcome in gastric cancer, and the miR-27b/miR-200b-CREB1 pathway may serve as a potential molecular target for the treatment of gastric cancer.

No MeSH data available.


Related in: MedlinePlus

Upregualtion of CREB1 in more aggressive gastric tissues and ROC curves to assess the diagnostic value of CREB1 expression in gastric cancerA. IHC sum scores (0–7) were used to compare CREB1 expression in different gastric tissues. CREB1 was significantly elevated in primary gastric cancer tissues compared to nontumorous gastric mucosa (t-test, P < 0.0001). Further upregualtion of CREB1 was observed in secondary lymph node metastatic foci (t-test, P < 0.0001). B. CREB1 was dramatically overexpressed in primary gastric cancer tissues with lymph node metastasis than those without lymph node metastasis (t-test, P < 0.0001). C. The ROC curves reflected strong separation between gastric cancer tissues and nontumourous tissues, with an area under curve (AUC) of 0.890 (P = 0.000). D. To test the ability of CREB1 as a diagnostic marker for lymph node metastasis, ROC curves were established. Clear separation was observed between the patients with and without lymph node metastasis, with an AUC of 0.680 (P = 0.000).
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Figure 2: Upregualtion of CREB1 in more aggressive gastric tissues and ROC curves to assess the diagnostic value of CREB1 expression in gastric cancerA. IHC sum scores (0–7) were used to compare CREB1 expression in different gastric tissues. CREB1 was significantly elevated in primary gastric cancer tissues compared to nontumorous gastric mucosa (t-test, P < 0.0001). Further upregualtion of CREB1 was observed in secondary lymph node metastatic foci (t-test, P < 0.0001). B. CREB1 was dramatically overexpressed in primary gastric cancer tissues with lymph node metastasis than those without lymph node metastasis (t-test, P < 0.0001). C. The ROC curves reflected strong separation between gastric cancer tissues and nontumourous tissues, with an area under curve (AUC) of 0.890 (P = 0.000). D. To test the ability of CREB1 as a diagnostic marker for lymph node metastasis, ROC curves were established. Clear separation was observed between the patients with and without lymph node metastasis, with an AUC of 0.680 (P = 0.000).

Mentions: Because CREB1 dysregulation in gastric cancer is still not well understood, we firstly investigated the expression of CREB1 protein by immunohistochemistry (IHC) in a total of 285 paraffin-embedded gastric samples including 185 cases of primary gastric cancer tissues, 50 cases of secondary lymph node metastatic foci and 50 cases of nontumorous gastric mucosa. Figure 1 represents the immunostaining profiles of CREB1 in gastric samples, with CREB1 staining predominantly observed in the nuclei of cells. These results provide clues that CREB1 mainly exerts its role as transcription factor in cell nuclei. CREB1 expression was negative or weak in nontumorous gastric tissues (Figure 1A–1C), whereas weak to strong expression was observed in primary gastric cancer tissues (Figure 1D–1I). Furthermore, even stronger expression was seen in secondary lymph node metastatic foci (Figure 1J–1L). In the 50 nontumorous gastric tissues, 31 (62.0%) cases showed negative CREB1 expression, 19 (38.0%) samples had weak expression, and none displayed strong expression (Table 1). In contrast, CREB1 immunoreactivity was predominantly identified as positive in the majority of primary gastric cancer tissues. Among the 185 primary gastric cancer tissues, 100 (54.1%) cases showed weak expression, 75 (40.5%) cases displayed strong expression and only 10 (5.4%) cases were classified as negative. In addition, in the 50 secondary lymph node metastatic foci, 16 (32.0%) cases showed weak expression, 34 (68%) cases displayed strong expression. Our data showed that CREB1 expression exhibited a gradual increase from nontumorous gastric mucosa via primary gastric cancer tissues, to secondary lymph node metastatic foci (Table 1, chi-square test; Figure 2A, t-test; P < 0.05). More interestingly, we found that CREB1 expression in cancerous tissues with lymph node metastasis (LNM) was significantly higher than that in cancerous tissues without LNM (Figure 1D–1I; Figure 2B, t-test; P < 0.05), suggesting that CREB1 may be associated with lymph node metastasis in gastric cancer.


High expression of cAMP-responsive element-binding protein 1 (CREB1) is associated with metastasis, tumor stage and poor outcome in gastric cancer.

Wang YW, Chen X, Gao JW, Zhang H, Ma RR, Gao ZH, Gao P - Oncotarget (2015)

Upregualtion of CREB1 in more aggressive gastric tissues and ROC curves to assess the diagnostic value of CREB1 expression in gastric cancerA. IHC sum scores (0–7) were used to compare CREB1 expression in different gastric tissues. CREB1 was significantly elevated in primary gastric cancer tissues compared to nontumorous gastric mucosa (t-test, P < 0.0001). Further upregualtion of CREB1 was observed in secondary lymph node metastatic foci (t-test, P < 0.0001). B. CREB1 was dramatically overexpressed in primary gastric cancer tissues with lymph node metastasis than those without lymph node metastasis (t-test, P < 0.0001). C. The ROC curves reflected strong separation between gastric cancer tissues and nontumourous tissues, with an area under curve (AUC) of 0.890 (P = 0.000). D. To test the ability of CREB1 as a diagnostic marker for lymph node metastasis, ROC curves were established. Clear separation was observed between the patients with and without lymph node metastasis, with an AUC of 0.680 (P = 0.000).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496382&req=5

Figure 2: Upregualtion of CREB1 in more aggressive gastric tissues and ROC curves to assess the diagnostic value of CREB1 expression in gastric cancerA. IHC sum scores (0–7) were used to compare CREB1 expression in different gastric tissues. CREB1 was significantly elevated in primary gastric cancer tissues compared to nontumorous gastric mucosa (t-test, P < 0.0001). Further upregualtion of CREB1 was observed in secondary lymph node metastatic foci (t-test, P < 0.0001). B. CREB1 was dramatically overexpressed in primary gastric cancer tissues with lymph node metastasis than those without lymph node metastasis (t-test, P < 0.0001). C. The ROC curves reflected strong separation between gastric cancer tissues and nontumourous tissues, with an area under curve (AUC) of 0.890 (P = 0.000). D. To test the ability of CREB1 as a diagnostic marker for lymph node metastasis, ROC curves were established. Clear separation was observed between the patients with and without lymph node metastasis, with an AUC of 0.680 (P = 0.000).
Mentions: Because CREB1 dysregulation in gastric cancer is still not well understood, we firstly investigated the expression of CREB1 protein by immunohistochemistry (IHC) in a total of 285 paraffin-embedded gastric samples including 185 cases of primary gastric cancer tissues, 50 cases of secondary lymph node metastatic foci and 50 cases of nontumorous gastric mucosa. Figure 1 represents the immunostaining profiles of CREB1 in gastric samples, with CREB1 staining predominantly observed in the nuclei of cells. These results provide clues that CREB1 mainly exerts its role as transcription factor in cell nuclei. CREB1 expression was negative or weak in nontumorous gastric tissues (Figure 1A–1C), whereas weak to strong expression was observed in primary gastric cancer tissues (Figure 1D–1I). Furthermore, even stronger expression was seen in secondary lymph node metastatic foci (Figure 1J–1L). In the 50 nontumorous gastric tissues, 31 (62.0%) cases showed negative CREB1 expression, 19 (38.0%) samples had weak expression, and none displayed strong expression (Table 1). In contrast, CREB1 immunoreactivity was predominantly identified as positive in the majority of primary gastric cancer tissues. Among the 185 primary gastric cancer tissues, 100 (54.1%) cases showed weak expression, 75 (40.5%) cases displayed strong expression and only 10 (5.4%) cases were classified as negative. In addition, in the 50 secondary lymph node metastatic foci, 16 (32.0%) cases showed weak expression, 34 (68%) cases displayed strong expression. Our data showed that CREB1 expression exhibited a gradual increase from nontumorous gastric mucosa via primary gastric cancer tissues, to secondary lymph node metastatic foci (Table 1, chi-square test; Figure 2A, t-test; P < 0.05). More interestingly, we found that CREB1 expression in cancerous tissues with lymph node metastasis (LNM) was significantly higher than that in cancerous tissues without LNM (Figure 1D–1I; Figure 2B, t-test; P < 0.05), suggesting that CREB1 may be associated with lymph node metastasis in gastric cancer.

Bottom Line: In the present study, immunohistochemistry was performed to detect the expression of CREB1 protein in 185 primary gastric cancer tissues, 50 secondary lymph node metastatic foci and 50 nontumorous gastric tissues.CREB1 was identified as a direct target of miR-27b and miR-200b, and down-regulated by miR-27b/miR-200b.We conclude that CREB1 is a promising biomarker to predict tumor metastasis and patient outcome in gastric cancer, and the miR-27b/miR-200b-CREB1 pathway may serve as a potential molecular target for the treatment of gastric cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, P.R. China.

ABSTRACT
cAMP responsive element binding protein 1 (CREB1) has been reported to be implicated in tumor development and progression of human cancers. However, the clinical significance and regulatory mechanisms of CREB1 expression in gastric cancer remain largely unknown. In the present study, immunohistochemistry was performed to detect the expression of CREB1 protein in 185 primary gastric cancer tissues, 50 secondary lymph node metastatic foci and 50 nontumorous gastric tissues. A prognostic model combining CREB1 expression with TNM tumor stage was constructed by logistic regression analysis. Regulation of CREB1 by miRNAs was investigated by luciferase reporter assay and Western blot. It was shown that CREB1 was highly expressed and correlated with lymph node metastasis, distant metastasis and tumor stage and poor outcome in gastric cancer. The prognostic model was proven to be an independent prognosis predictor and performed better than CREB1 or tumor stage alone. CREB1 was identified as a direct target of miR-27b and miR-200b, and down-regulated by miR-27b/miR-200b. We conclude that CREB1 is a promising biomarker to predict tumor metastasis and patient outcome in gastric cancer, and the miR-27b/miR-200b-CREB1 pathway may serve as a potential molecular target for the treatment of gastric cancer.

No MeSH data available.


Related in: MedlinePlus