NPM1/B23於口腔鱗狀細胞癌中之表現

背景 NPM1(nucleophosmin 1)為NPM家族成員之一，在人體正常的生理機能如DNA之複製、轉錄與修復、細胞週期、核醣體合成系統、細胞凋亡、蛋白質之修飾、中心體複製等調控扮演重要角色。NPM1可能促進腫瘤生長(proliferation)及轉移(metastasis)，在人體癌症如大腸癌、膀胱癌及肝癌等的表現量都有提高的情形。本研究欲探討NPM1蛋白於口腔癌病理組織中的表現量及與臨床各參數和存活時間的關係。材料與方法本研究利用免疫組織化學染色方法，探討NPM1於96例口腔鱗狀細胞癌(OSCC)、45例口腔上皮變異(OED)及29例正常口腔黏膜(NOM)中的表現，並以陽性染色指標Labeling index記錄其染色程度。利用卡方檢定(Chi-square test)、Kaplan-Meier 存活率方法及Cox proportional hazard regression model來分析NPM1的表現與口腔鱗狀細胞癌患者臨床病理參數及存活率之相關性，並試圖尋找影響存活時間的獨立預後因子。結果在正常口腔黏膜NPM1的平均陽性標記指數為15% (最低)，口腔上皮變異組的平均陽性標記指數為29%，口腔癌組的平均陽性標記指數為58% (最高)，從正常口腔黏膜、上皮變異至口腔癌的癌化過程，NPM1表現增加之情形已達統計意義(P < 0.001)。NPM1的表現和患者的腫瘤大小(T status)、淋巴結轉移與否(N status)、癌症臨床分期(Stage)有統計上相關。各項臨床參數在Cox proportional hazard regression model分析中，單變數分析後發現，腫瘤大小、淋巴結轉移與否、腫瘤臨床分期及NPM1的陽性染色指標(LI)都與存活率有關；多變數分析腫瘤大小、淋巴結轉移與否及NPM1的陽性染色指標(LI)為影響存活時間的獨立因子(independent factor；p<0.05)；NPM1陽性染色指標若>60%，影響病人存活的危險率(hazard ration)高達4.249倍(p=0.0029)。若以Kaplan-Meier plots來觀察臨床病理各項參數、NPM1的陽性染色指標與病人總存活時間(overall survival)，經Log-Rank Test分析後，腫瘤大小、淋巴結轉移與否、腫瘤臨床分期均影響病人的存活時間，且達統計上之意義(p<0.05)。而本研究探討的NPM1的陽性染色指標(LI)若>60%，則明顯降低了口腔癌病人的存活率(p=0.0017)。結論在本研究中，NPM1的陽性染色指標在口腔癌病理標本中的表現較高且具統計上意義，且與口腔細胞癌患者在臨床參數及存活時間有關。在口腔癌患者而言，NPM1的表現量較高者其存活時間較短；而NPM1在切片組織中的表現程度，或許可以做為口腔癌的預後指標(prognostic marker)。

關鍵字

NPM1 ；口腔鱗狀細胞癌；口腔上皮變異

並列摘要

Background Of the NPM family (nucleophosmin family), NPM1 involves broad physiological functions in the human body, such as DNA replication, transcription and repair, cell cycle control, ribosome biogenesis, apoptosis, protein synthesis and centrosome replication. NPM1 is also known for its effect on tumor cell proliferation and metastasis. Recent cancer research has shown increasingly significant expression of NPM1 in many human cancers, including colon, bladder, and liver. Focused in this research are expression of NPM1 in pathological specimens of oral cancer patients, and the correlation between expression of NPM1 and clinical, pathological parameters, and survival time. Materials and Methods Examined in this study were 96 specimens diagnosed as oral squamous cell carcinoma (OSCC) and 45 specimens of oral epithelial dysplasia (OED). 29 cases of normal oral mucosa (NOM) were also observed for comparison. With a NPM1 monoclonal antibody, immunohistochemistry (IHC) stain was performed for detecting expression of NPM1 in these tissue sections. The degree of positive staining was recorded and graded as labeling index (LI). Finally, the correlations between expression of NPM1, clinical and pathologic parameters, and the overall survival of OSCC patients were analyzed statistically via chi-square test, Cox proportional hazard regression model, and Kaplan-Meier plots. Results The labeling index of NPM1 was significantly higher in OSCC specimens (p<0.001). The average LI of NPM1 in OSCC specimens was 58%. In OED specimens, the average LI was 29%. In NOM, the average LI was only 15%. Meanwhile, higher NPM1 LIs indicated larger tumor size (T3 and T4 status), nodal metastasis and later clinical stage (Stage 3 and stage 4). These results were all revealed with statistical significance (Chi-square test; p<0.05). As Cox proportional hazard regression model, the tumor size (T status), nodal metastasis (N status), clinical stage, and the LIs of NPM1 were statistically significant. Multivariate analysis revealed that tumor size (T status), nodal metastasis (N status) and the LIs of NPM1 were independent factors of patient survival (p<0.05). Kaplan-Meier survival analysis showed that patients had shorter survival time with advanced tumor sizes, nodal metastasis, later clinical staging, and high LIs of NPM1. Conclusions The expression of NPM1 was higher in OSCC specimen. The labeling index of NPM1 has strong correlation with several clinicopathological parameters and survival time. In OSCC patients, higher NPM1 expression seemed to indicate shorter overall survival. Judging from the above analysis, NPM1 is probably a potential prognostic factor of OSCC.

並列關鍵字

NPM1 ； oral squamous cell carcinoma ； oral epithelial dysplasia

參考文獻

1.Neville, et al., Oral and Maxillofacial Pathology. 2 ed2002. 315-76.

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5.Liao, C.T., et al., Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol, 2008. 15(3): p. 915-22.

國際替代計量

NPM1/B23於口腔鱗狀細胞癌中之表現

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