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Evaluation of Prognosis and Metastasis by Immunohistochemical Staining of Rab Coupling Protein Expression in Ovarian Cancer

  • 조도연 (Do Yeun Cho, 아주대학교 일반대학원)

초록/요약

Rab coupling protein (RCP) plays physiological roles in the regulation of intracellular transport events through endosomal trafficking, receptor sorting, and recycling. Moreover, RCP has been known to augment tumorigenesis, cancer cell invasion, epithelial to mesenchymal transition, and metastasis by coordinating the activation of the β1 integrin/integrin ligand kinase/EGFR signaling axis with Slug expression. Various cancers have exhibited high levels of RCP expression, which has been correlated with poor prognosis. The purpose of the present study is to determine the role of and underlying mechanism of RCP in the progression and metastasis of ovarian cancer. Immunoblotting of SKOV-3 ovarian cancer cells transfected with or without RCP and immunohistochemical (IHC) staining of paraffin-embedded tumor tissue samples from 82 patients with ovarian cancer who underwent surgical resection with or without chemotherapy were utilized to evaluate the correlation between the expression of RCP and that of p-FAK, p-EGFR, and p-STAT3. Furthermore, the association between the expression of RCP, p-FAK, p-EGFR, and p-STAT3 and clinicopathologic characteristics as well as outcomes of patients with ovarian cancer was investigated. Immunoblotting data showed that cells transfected with RCP had a significantly greater RCP expression compared to those transfected with a control vector. Moreover, IHC staining showed that RCP expression was increased in tumor tissues compared to normal ovarian tissues, with positive staining in 59 (72%) samples. According to the extent and intensity of IHC staining, low and high RCP expression was in 39 (48%) and 43 (52%) samples, respectively. The expression of RCP was associated with that of p-FAK, p-EGFR, and p-STAT3. Moreover, RCP overexpression was significantly associated with a serous tumor subtype, poor histologic grade, advanced FIGO stage, bilateral ovarian cancer site, lymph node metastasis, and peritoneal carcinomatosis. While high RCP expression was correlated with poor progression-free survival (PFS) (p = 0.027) and overall survival (OS) (p = 0.045), the co-expression of RCP with p-FAK, p-EGFR, and p-STAT3 showed significantly poor PFS and OS. Advanced FIGO stage, high neutrophil to lymphocyte ratio, and high expression of p-STAT3 were recognized as independent prognostic factors for poor OS in patients with ovarian cancer, whereas lymph node metastasis and advanced FIGO stage were independently associated with poor PFS. In conclusion, RCP expression was closely associated with the expression of p-FAK, p-EGFR, and p-STAT3, suggesting that RCP induces cancer progression and metastasis by activating STAT3 phosphorylation through the FAK/EGFR axis. Despite having no independent prognostic significance, RCP expression was associated with poor PFS and OS in patients with ovarian cancer. Further clearly understanding of the mechanisms and roles by which signaling factors, such as RCP, p-FAK, p-EGFR, and p-STAT3, affect the metastatic process and outcomes of ovarian cancer would be helpful in establishing effective cancer treatment by predicting patients outcomes and developing new targeted agents.

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목차

I. INTRODUCTION 1
II. MATERIALS AND METHODS 6
1. Ovarian cell culture 6
2. Immunoblotting 6
3. Study populations and tissue samples 7
4. Immunohistochemical staining methods 9
5. Tissue evaluation of immunohistochemical staining 10
6. Statistical analysis 11
III. RESULTS 13
IV. DISCUSSION 48
V. CONCLUSION 60
REFERENCE 61

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