- 學位論文
肝癌病人 XBP1的表現與臨床關係
X-box binding protein-1 expression in hepatocellular carcinoma patients and its clinicopathologic correlation
摘要
肝癌為最常見的原發性肝臟腫瘤，其癌症致死率全球排名第三，主要原因為肝癌不容易早期診斷且其對放射線治療或化學治療反應有限，另外致肝癌的原因很多且繁複，目前仍還不是很清楚。人類X-box結合蛋-1 (X-box binding protein-1, XBP1)是未折疊蛋白反應(Unfold protein response, UPR)的重要調節因子，也被確定為多種人類癌症的存活因子，越來越多的證據支持XBP1在腫瘤進展和侵襲中的作用，但XBP1與肝癌預後之間的關聯尚未完全闡明。本實驗收集267個肝癌組織標本，使用免疫組織化學染色測量XBP1蛋白在肝癌細胞的表達，計算肝癌細胞XBP1的表現與臨床病理因子和存活結果之間的關聯；並使用肝癌病人的追蹤資料進行存活分析來評估肝癌細胞XBP1蛋白表現對肝癌病人的預後價值。結果發現免疫組織化學染色顯示XBP1蛋白表現在肝癌組織腫瘤細胞的細胞質上。低細胞質XBP1表現與肝癌血管侵襲以及較差的5年總存活率、長期疾病特異性存活率(disease-specific survival, DSS) 和無疾病存活率(disease-free survival, DFS)有顯著的相關性。Kaplan-Meier 存活曲線證實了低肝癌腫瘤細胞細胞質XBP1蛋白表現與較差的長期疾病特異性存活率和無疾病存活率之間的顯著關聯。單變量和多變量存活分析顯示肝癌細胞細胞質XBP1的表現、腫瘤分化、血管侵犯、腫瘤分期和肝癌復發與長期疾病特異性存活率有關，且進一步證實低細胞質XBP1表現是較差的長期疾病特異性存活率的獨立預測因子。我們的分析還顯示肝癌細胞細胞質的XBP1表現、腫瘤分化、血管侵犯和T分類與無疾病存活率有關，且進一步認證低細胞質XBP1表現是較差的無疾病存活率的獨立預測因子。我們的結果證明肝癌細胞細胞質中XBP1蛋白的低表現可能在肝癌的發病機制中發揮重要作用，這表明XBP1可能成為肝癌治療策略之一。
並列摘要
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and the third leading cause of cancer death in the world. In most patients, HCC has been diagnosed at advanced stages, and at this point the disease is largely incurable. Besides, HCC is less responsive to radiotherapy and chemotherapy. Hepatocarcinogenesis is highly complex and presents extraordinary molecular heterogeneity. Till now, X-box binding protein 1 (XBP1) is known to be involved in the unfolded protein response (UPR) pathway and tissue-specific transcriptional networks of many types of cancer. It is shown that XBP1 could be a survival factor of cancer cells and plays an important role in tumor progression or invasion. However, the link between XBP1 and HCC prognosis has yet to be fully elucidated. The expression of XBP1 protein in 267 HCC tissue specimens was measured using immunohistochemistry in order to characterize the associations among XBP1 expression, clinicopathological factors and survival outcomes. Survival analysis using follow-up data was used to assess the prognostic value of XBP1 in cases of HCC. Immunohistochemical results showed that low cytoplasmic XBP1 expression was significantly associated with vascular invasion, as well as poor 5-year overall survival and long-term disease-specific (DSS) and disease-free survival (DFS). Kaplan-Meier survival curves further confirmed a significant association between low cytoplasmic XBP1 protein expression and poor DSS as well as poor DFS. Univariate and multivariate analyses revealed that XBP1 expression, tumor differentiation grade, vascular invasion, tumor stage, and the rate of recurrence were linked to DSS, while low cytoplasmic XBP1 expression remained an independent predictor of poor DSS. Our analysis also revealed that XBP1 expression, tumor differentiation grade, vascular invasion, and T classification were linked to DFS, while low cytoplasmic XBP1 expression remained an independent predictor of poor DFS. In conclusion, low cytoplasmic XBP1 protein expression may play an important role in the pathogenesis of HCC, which suggests that XBP1 could potentially be targeted to benefit therapeutic strategies for HCC.