Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder.
Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder.
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DOI：
10.18632/oncotarget.16432
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发表时间：
2017-05-30
期刊：
影响因子：
--
通讯作者：
Fujimoto K
中科院分区：
文献类型：
--
作者：
Miyake M;Hori S;Morizawa Y;Tatsumi Y;Toritsuka M;Ohnishi S;Shimada K;Furuya H;Khadka VS;Deng Y;Ohnishi K;Iida K;Gotoh D;Nakai Y;Inoue T;Anai S;Torimoto K;Aoki K;Tanaka N;Konishi N;Fujimoto K
目前对肿瘤萌发的分子机制的了解还很有限。在这里，我们集中于阐明膀胱尿路上皮癌肿瘤萌芽的详细机制。浸润性尿路上皮癌病理分成三组：结节型、小梁型和浸润型(肿瘤萌芽)。原位肿瘤模型的病理组织学分析显示，人尿路上皮癌细胞系MGH-U3、UM-UC-14和UM-UC-3分别呈现典型的结节状、小梁状和浸润性形态。基于基因芯片(25K人寡核苷酸芯片)的综合基因表达分析结果，我们鉴定了两种胶原，COL4A1和COL13A1，它们可能与浸润性模式的形成有关。蛋白质相互作用网络的可视化显示，与结缔组织疾病、上皮-间充质转化、生长激素和雌激素相关的蛋白质是肿瘤细胞的关键因素。为了评价肿瘤细胞的体外侵袭模式，采用Matrigel软件进行了肿瘤细胞的三维侵袭实验。用明胶明胶诱导法评价异烟肼的形成。用siRNA敲除胶原蛋白导致侵袭模式发生了戏剧性的变化，侵袭能力通过减少侵袭足而降低。在体原位膀胱肿瘤实验模型显示，靶向COL4A1和COL13A1的siRNA膀胱内治疗可抑制浸润性模式的形成。癌细胞产生COL4A1和COL13A1通过诱导肿瘤萌芽在肿瘤侵袭中起关键作用。阻断这些胶原蛋白可能是治疗膀胱尿路上皮癌的一种有吸引力的治疗方法。
Current knowledge of the molecular mechanism driving tumor budding is limited. Here, we focused on elucidating the detailed mechanism underlying tumor budding in urothelial cancer of the bladder. Invasive urothelial cancer was pathologically classified into three groups as follows: nodular, trabecular, and infiltrative (tumor budding). Pathohistological analysis of the orthotopic tumor model revealed that human urothelial cancer cell lines MGH-U3, UM-UC-14, and UM-UC-3 displayed typical nodular, trabecular, and infiltrative patterns, respectively. Based on the results of comprehensive gene expression analysis using microarray (25 K Human Oligo chip), we identified two collagens, COL4A1 and COL13A1, which may contribute to the formation of the infiltrative pattern. Visualization of protein interaction networks revealed that proteins associated with connective tissue disorders, epithelial-mesenchymal transition, growth hormone, and estrogen were pivotal factors in tumor cells. To evaluate the invasion pattern of tumor cells in vitro, 3-D collective cell invasion assay using Matrigel was performed. Invadopodial formation was evaluated using Gelatin Invadopodia Assay. Knockdown of collagens with siRNA led to dramatic changes in invasion patterns and a decrease in invasion capability through decreased invadopodia. The in vivo orthotopic experimental model of bladder tumors showed that intravesical treatment with siRNA targeting COL4A1 and COL13A1 inhibited the formation of the infiltrative pattern. COL4A1 and COL13A1 production by cancer cells plays a pivotal role in tumor invasion through the induction of tumor budding. Blocking of these collagens may be an attractive therapeutic approach for treatment of human urothelial cancer of the bladder.
影响因子：
3.8
作者：
Gieseg MA;Man MZ;Gorski NA;Madore SJ;Kaldjian EP;Leopold WR
通讯作者：
Leopold WR