幹細胞中的訊息路徑和癌細胞有高度相似的特性，SOX2、OCT4、KLF和MYC能調控細胞的幹性(Stemness)及癌症的惡性。首先，我們利用GSE32894資料庫進行大數據庫分析並搭免疫組織染色，結果顯示在部分移型上皮膀胱癌 (Transitional cell carcinoma)中，SOX2轉錄因子會大量表現，且這些SOX2高度表現的腫瘤細胞具有較差的分化程度，且這樣的病人會較快出現癌症復發，並且整體存活率較低。根據Alarmablue及Trypan Blue exclusion assay的結果，在SOX2高表現的5637細胞株中抑制SOX2表現，會抑制其生長增生(proliferation)，並且與上述結果一致地，在SOX2低表現的T24細胞中表現外源性SOX2(ectopic express)會促進細胞生長增生。更進一步發現，在低濃度血清培養下，SOX2能刺激AKT蛋白的磷酸化，並且促進膀胱癌細胞的聚落(colonogenic)和細胞球體(spheroid)形成能力，此結果顯示SOX2能調節膀胱癌細胞的存活能力(survival)，並維持其幹性。我們利用處理MK2206抑制在低濃度血清培養下SOX2所誘導的AKT蛋白磷酸化，膀胱癌細胞的聚落和細胞球體形成能力皆被抑制。基因表現微陣列分析顯示IGF2受SOX2上調，我們也發現到SOX2表現會促進IGF2及IGF1R同時抑制IGFBP1表現，此結果顯示IGF2-IGF1R訊息傳遞路徑受到SOX2的調控。在5637細胞株中分別抑制IGF2和IGF1R表現後，AKT的磷酸化減少，且細胞形成聚落的能力被抑制。我們進一步利用IGF1R抑制劑Linsitinib處理SOX2高表現的T24細胞，結果顯示AKT的磷酸化會受到抑制，且細胞球體形成能力亦被抑制。最後，我們利用TCGA_BLCA數據庫分析，結果指出SOX2或IGF1R高表現的病人都具有較短的無復發存活期(recurrence-free survival)，且同時具有高表現SOX2/IGF1R的病人，其整體存活率更差。研究結果支持SOX2-IGF/IGF1R訊息軸使膀胱癌細胞更為惡性且具有作為膀胱癌生物標記以及治療標靶的潛力。

Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC not only mediates reprogramming of differentiated cells to pluripotency but has also been correlated with tumor malignancy. In this study, we found that SOX2 expression signifies poor recurrence-free survival and correlates with advanced pathological grade in bladder cancer. SOX2 silencing attenuated bladder cancer cell growth, while its expression promoted cancer cell survival and proliferation. Under low serum stress, SOX2 expression promoted AKT phosphorylation and bladder cancer cells’ colony and spheroid forming capability. Furthermore, pharmacological inhibition of AKT phosphorylation, using MK2206, inhibited the SOX2-mediated colony and spheroid formation of bladder cancer cells under low serum stress. Gene expression profiling showed that SOX2 expression, in turn, induced IGF2 expression, while SOX2 silencing inhibited IGF2 expression. Moreover, knocking down IGF2 and IGF1R diminished SOX2-mediated AKT phosphorylation and inhibited bladder cancer cell growth. In addition, pharmacological inhibition of IGF1R, using linsitinib, also inhibited the SOX2-mediated spheroid formation of bladder cancer cells under low-serum stress. Lastly, correlation analysis using TCGA_BLCA cohort showed high expression level of SOX2 and IGF1R correlate with poor recurrence-free survival and patients with SOX2-high/IGF1R-high signature had worse survival outcome. Our findings indicate the SOX2–IGF2/IGF1R signaling affects the aggressiveness of bladder cancer cell growth. This signaling could be a promising biomarker and therapeutic target for bladder cancer intervention.

ABSTRACT..................... i-ii
中文摘要...................... iii
TABLE OF CONTENTS............ v
TABLE OF FIGURES............. vi
LIST OF TABLE................ viii
LIST OF ABBREVIATIONS........ ix
INTRODUCTION................. 1-11
AIMS......................... 12-16
MATERIALS AND METHODS........ 17-23
RESULTS...................... 24-29
DISCUSSION................... 30-34
FIGURES...................... 35-62
TABLES....................... 63-69
REFERENCES................... 70-79

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