富含絲氨酸/精氨酸接合因子–1調控大腸直腸癌的上皮– 間質轉化與侵襲能力

大腸直腸癌是常見的惡性腫瘤，惡性度取決於腫瘤細胞的侵襲能力和是否已轉移至淋巴結、肝臟、肺臟等周圍組織器官，也影響到治療的成效與預後的情形。轉移是大腸直腸癌造成死亡的主要原因。腫瘤的轉移是一連串複雜過程，包含脫離細胞間的黏附、穿透基底膜、分解細胞間質、移動性和侵襲能力等，目前的研究尚未釐清大腸直腸癌轉移的機制。我們透過生物資訊分析，分析發表在公領域(public domain) 的生物晶片數據，找到數個可能與細胞轉移相關的基因。經RT-PCR分析後發現–富含絲氨酸/精氨酸接合因子-1 (Serine/arginine-rich splicing factor-1, ASF/SF2, SFRS1) 在轉移淋巴結的大腸直腸癌細胞株SW620表現高於原位大腸直腸癌細胞株SW480。為了進一步探討SFRS1基因是否會調控大腸直腸癌的轉移。首先利用惡性度高的SW620細胞，減幅 (knockdown) 其SFRS1基因，發現SW620/shSFRS1細胞在細胞增生 (proliferation) 與腫瘤生成(tumorigenesis) 的能力都減低；上皮細胞標誌鈣黏著素E (E-cadherin) 的蛋白表現量增加，間質細胞標誌波形蛋白 (Vimentin) 的蛋白表現量減少，且控制其上皮–間質轉化的轉錄因子Snail蛋白表現量亦呈現減少。此外，SW620/shSFRS1細胞移動性和侵襲能力都降低，且骨橋素 (Osteopontin, OPN)、膠質水解酶 (Matrix-Metalloproteinases-2, MMP-2) 和缺氧誘發因子-1α (Hypoxia-inducible factor–1α﹐HIF-1α)的蛋白表現量也都減少。上皮–間質轉化(Epithelial-Mesenchymal-Transition, EMT) 是癌細胞由原位轉移至遠端的機制； SW620/shSFRS1細胞的骨橋素、膠質水解酶、缺氧誘發因子-1α蛋白表現量皆減少，象徵細胞癌化能力趨緩，也顯示SFRS1基因在大腸直腸癌細胞中具有調控癌細胞轉移能力，且可能作為大腸直腸癌治療的分子標靶。

關鍵字

富含絲氨酸/精氨酸接合因子–1

並列摘要

Colorectal carcinoma is one of the most malignant cancers. Metastasis is a major cause of mortality in patients with malignant colorectal cancers. The criteria of colon cancer stages classification are based on the invasiveness of the cancer cells,frequency of tumor metastasis into local lymph node, liver and lung organ, and the effect of therapy and outcome. Tumor metastasis is a complex and multistage process involving the degradation of extracellular matrix, and gain of cell mobility and invasiveness. In this study, we first used bioinformatics to retrieve relevant data from public data bank, and identified several genes that are candidates for metastasis-related genes. We verified that the expression level of serine/arginine-rich splicing factor-1 (ASF/SF2, SFRS1) was much higher in SW620 cells that were isolated from lymph node metastasis colorectal carcinoma cells, as compared to the syngeneic SW480 cell line, which was isolated from in situ colorectal carcinoma . Transfection of SFRS1 specific shRNA into SW620 cells decreased cell proliferation, tumorigenesis and the protein expression levels of vimentin, and the transcription factor, Snail. On the other hand, knock down of SFRS1 increased the protein expression levels of E-cadherin. Because transcription factor Snails and the intermediate microtubule, vimentin have been linked to epithelial mesenchymal transition (EMT), these data suggest that SFRS1 may regulate the EMT. In agreement, knockdown of SFRS1 in SW620 cells decreased cell migration, invasiveness, and the protein expression level of osteopontin (OPN), matrix-metalloproteinases-2 (MMP-2), and hypoxia-inducible factor–1α (HIF-1α). These data suggest that SFRS-1 might regulate the metastasis and be used as therapeutic target for colorectal cancer therapy.

並列關鍵字

Serine/arginine-rich splicing factor-1

參考文獻

1. Orlowska, J., Hyperplastic polyposis syndrome and the risk of colorectal cancer. Gut, 2011.

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5. Li, X., et al., Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition. Cancer Sci, 2011. 102(6): p. 1151-7.

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富含絲氨酸/精氨酸接合因子–1調控大腸直腸癌的上皮– 間質轉化與侵襲能力

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