YWHAZ 基因增殖與過度表現在膀胱癌抗藥性與抗輻射性發展中所扮演的角色

先前實驗室利用 DNA 微陣列技術 ( microarray ) 發現後期膀胱癌組織在八號染色體中有異常的基因放大，從基因庫比對後發現其中多個基因有異常放大現象，其中包括了 YWHAZ 基因。現有的研究顯示 YWHAZ 被認為和癌症的發生有直接的關係，且近期也有研究提出 YWHAZ 與癌症治療後的復發與較差的預後有相關性。但 YWHAZ 的表達量對於膀胱癌治療上的影響卻未被探討，於是我們想探討不同嚴重程度的膀胱癌移行細胞株是否 YWHAZ 的表達量會有所不同，接著探討 YWHAZ 表達量不同的膀胱癌細胞株對於不同的化療藥物濃度與輻射劑量是否有抵抗性。膀胱癌在泌尿道系統癌症中死亡率位於第一，其原因是約有 90% 為移形上皮細胞癌 ( Ttransitional Cell Carcinoma ; TCC ) 。致癌因素則因為正常膀胱尿路上皮受到了環境、職業、吸菸等種種因素發生增生性變化，進而癌化。因環境風險因素的影響，在台灣西南沿海一帶，烏腳病流行區膀胱癌發生率更高，且隨著台灣工業化所造成的汙染更為嚴重，膀胱癌是近年來新興的癌症。臨床上治療膀胱癌常規的治療是手術輔助使用化學治療或是放射治療。然而治療上的難處在於膀胱癌的高復發率 ( 50% - 70% ) 和侵犯性/轉移強 ( 10%-20% ) 。有癌轉移的患者通常有較短的存活，這是膀胱癌治療失敗的主要原因。實驗結果顯示，屬於第一期的膀胱癌細胞 RT4 ， YWHAZ 的表達量較為低落，而屬於第三期的 T24 ， YWHAZ 的表達量為最高。在不同的化療藥物濃度及輻射劑量照射下， T24 對於化療藥物及輻射的治療效果不佳，相較之下 RT4 對於化療藥物及輻射的治療效果較為好。而 YWHAZ 表達量亦會影響癌細胞的凋亡，抑制了 YWHAZ 基因的 T24 細胞與控制組的 T24 細胞，加入相同濃度的化療藥物後，其抑制了 YWHAZ 基因的 T24 細胞凋亡的現象遠高於控制組；同樣的結果也在擴增了 YWHAZ 基因的 RT4 中驗證。最後我們初步的結論是 YWHAZ 的表達量對於膀胱癌在化學治療及放射治療上會有抵抗作用。並且 YWHAZ 的表達量亦會影響膀胱癌細胞的細胞凋亡。而這樣的現象，也許可以推從使用 YWHAZ 來當作膀胱癌治療的生物標誌，進而使膀胱癌的治療可以有更進步的發展。

Previously we used DNA microarray to identify the abnormal gene amplification at the 8th chromosome in late stage bladder cancer, which multiple genes have abnormal amplification are comparison from the gene bank, including the YWHAZ gene.The literature shows YWHAZ has been most directly linked to cancer and YWHAZ was associated with poor tumor response and poor prognosis to treatment with chemotherapy. The impact of YWHAZ expression on bladder cancer has not been discussed, so we would like to discuss whether different stages of bladder transitional cell carcinoma cell lines expression results in the different amount of YWHAZ. Secondly, we would like to investigate whether different amount of YWHAZ in bladder cancer cell lines influence resistant to different concentration of chemotherapy drug and radiation dose.Bladder cancer is the most common tumor of the urinary collecting system and it is the first most common cause of death in urinary tract malignancies. Transitional cell carcinoma ( urothelial cancer) accounts for over 90% of malignant tumors of the bladder. Risk factors causally related to the development of bladder cancer include cigarette smoking; occupational exposure to chemicals, and leaded to normal bladder urothelium proliferative and then change into bladder cancer. Notably, a higher incidence rate was found in the coastal area of South-Western Taiwan, and also the epidemic area for black-foot disease, suggesting the potent effects of environmental risk factors. With more pollution caused by industrialization in Taiwan, bladder cancer is an emerging cancer in recent years.Clinical limitations of treating bladder cancer are high recurrence rate ( 50% - 70% of patients ) and invasion/metastasis ( 10% - 20% ). Patients with metastasis usually have a shorter survival, which is the main cause of treatment failure for bladder cancer.The experimental results show that the YWHAZ expression level is relatively low in the first stage of bladder cancer cell of RT4, and it is highest in the third stage. In different concentrations of chemotherapy drugs and radiation dose exposure, T24 is ineffective to chemotherapy drugs and radiation therapy in comparison with RT4. The amount of YWHAZ expression will also affect apoptosis in bladder cancer cells. After treated with the same concentration of chemotherapy drugs, the group with inhibited YWHAZ gene of T24 cells shows much higher apoptosis phenomenon than the control group. The finding is also validated in RT4 which amplified YWHAZ gene.Finally, we found YWHAZ overexpression is associated with therapeutic resistance in bladder cancer, and also affects the apoptosis of bladder cancer cell lines.