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標題: | RBMY基因的表現在人類肝細胞癌之預後所扮演的角色 The role of RNA binding motif on Y Chromosome (RBMY) expression in the outcome of human hepatocellular carcinoma |
作者: | Pei-chi Kao 高佩琪 |
指導教授: | 張美惠(Mei-Hwei Chang) |
關鍵字: | 肝細胞癌,RBMY,預後, RBMY,hepatocellular carcinoma,outcome, |
出版年 : | 2014 |
學位: | 碩士 |
摘要: | 〔研究背景及目的〕
肝臟惡性腫瘤是人類最好發的癌症之一,其中肝細胞癌與肝母細胞癌是最主要的兩種類型。研究顯示B型肝炎帶原是導致肝細胞癌的重要危險因子之一,台灣的研究顯示大約百分之八十的成人肝細胞癌和幾乎百分之百的孩童肝細胞癌與B型肝炎帶原有密切的關係。肝母細胞癌佔了小於五歲的孩童之原發肝腫瘤的百分之九十。肝癌好發於男性,在青春期之前的男童亦然,尤其是B型肝炎相關之肝癌男女比例特高,男女比介於二比一與七比一之間;而肝母細胞癌發生於男性的比例也是較高,其原因仍待研究。 RBMY基因位於所有哺乳類動物的Y染色體上,與男性精子發育有關。過去的研究發現,在一位患有肝細胞癌的孩童基因體中,RBMY基因被B型肝炎DNA所嵌入。後續研究也顯示利用基因反轉錄方法,在九十名罹患肝細胞癌的男性病患中,有三十二名(36%)患者的肝癌細胞組織,以及在六名罹患肝母細胞癌的男孩童中,有四名(67%)孩童的肝母細胞癌內,偵測到RBMY轉錄體的表現,但在同一病人的非癌性肝組織中則無。另外,也在活體小鼠的實驗中,發現到RBMY基因具有癌前病變及致癌性。本研究目的在於釐清RBMY基因的表現與人類肝細胞癌之預後,是否有相關聯存在。 〔研究方法〕 本研究收案197個患有肝細胞癌且在台大醫院接受開刀之男性病患當作基本研究組,他們的肝組織會藉由手術中而取得,並以冷凍方式包埋切片。另外也找來75位患有肝細胞癌且在台大醫院開刀之男性病患當作驗證組,他們的肝組織檢體是以福馬林固定的方式。所有個案的病歷記載皆詳細回顧並整理,包括病人的臨床表徵,腫瘤的美國癌症聯合委員會分期、病理組織分級,與病人存活情況。再利用免疫組織化學染色法的方法來偵測病人肝腫瘤細胞中,RBMY蛋白質的表現情況,並且與他們的臨床及存活情況相互比較。 〔結果〕 共計有143位基本研究組的病人,藉由免疫組織化學染色法,可以在肝細胞癌細胞內檢測出RBMY的表現(72.6%),包含了RBMY蛋白質表現在細胞核與細胞質兩個地方。RBMY的表現與美國癌症聯合委員會分期 (AJCC) 較高,有顯著相關性(p= 0.034),且有較低的存活率,尤其是細胞質內帶有RBMY表現的病人,其五年存活率較其他病患為最差(p= 0.0027)。而在驗證組也同樣證實了這樣的結果。 〔結論〕 肝細胞癌病人身上RBMY的表現,與美國癌症聯合委員會腫瘤分期較高有顯著的相關聯。另外,RBMY也是個肝細胞癌的重要預後因子。 Background and aim: Liver cancer remains one of the commonest cancers worldwide. Hepatocellular carcinoma (HCC) and hepatoblastoma (HB) are two major types of human liver cancer. Chronic infection with hepatitis B virus (HBV) has been closely associated with the development of HCC, which was found in around 80% of adult HCC and nearly 100% of childhood HCC. HB accounted for 90% of primary malignant liver tumor in children less than 5 years of age in Taiwan. Male predominance had been observed in both adult and childhood HCC, especially HBV-related HCC, with man to woman sex ratio ranging from 2:1 to 7:1. HB occurs in males significantly more frequently than it does in females and the reason remains obscure. The RNA-binding motif gene on Y chromosome ( RBMY gene), encoding a male germ cell-specific RNA binding protein associated with spermatogenesis, was found integrated by HBV DNA in a childhood HCC tissue. The RBMY transcripts, expressed exclusively in the testis of normal people, were detected by reverse transcription – polymerase chain reaction in 32 (36%) out of 90 male HCCs and in 4 (67%) of 6 male HB in a previous study. Nontumor liver counter parts were all negative for RBMY transcripts. Besides, previous study also revealed liver-specific RBMY transgenic mice developed hepatic pre-cancerous lesions, adenoma, and HCC. This study was aimed to evaluate the expression of RBMY in HCC patients to determine if a correlation between RBMY expression and the survival outcome existed. Methods: We enrolled total 197 male patients of hepatocellular carcinoma, from National Taiwan University Hospital as the baseline-study group. The HCC liver tissues were collected from the surgery and they were dealt with frozen embedded. To elaborate our model further, an additional cohort of 75 male patients of hepatocellular carcinoma, from the same hospital was enrolled as the validation group. Their liver tissues were collected from the surgery and dealt with paraffin embedded. Clinical data and pathologic findings were obtained from the medical records, including clinical presentation, American joint committee on cancer (AJCC) pathologic staging system, tumor grading, and survival condition. We checked the RBMY protein expression status by immunohistochemistry assessment. We evaluated the correlation between the clinical presentation and survival condition with RBMY protein expression. Results: RBMY protein was expressed in 143 (72.6%) of baseline-study group, including two patterns of RBMY protein distribution within HCC hepatocytes, including nucleus and cytoplasm. RBMY protein expression correlated with high grade AJCC staging (p= 0.034) and also contributed to poor prognosis trend, especially those with RBMY protein expression within the cytoplasm of hepatocytes (p= 0.0027). We confirmed the similar results in the validation group. Conclusions: RBMY protein expression correlated with higher AJCC tumor stage and was a significant prognostic factor for human hepatocellular carcinoma. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/5098 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 臨床醫學研究所 |
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