Xu Jiheng, Yang Rui, Li Jingxia, Wang Lidong, Cohen Mitchell, Simeone Diane M, Costa Max, Wu Xue-Ru
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
Cancers (Basel). 2022 Aug 27;14(17):4159. doi: 10.3390/cancers14174159.
The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that , a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of , thus hyper-methylating and repressing transcription. The reduced binding of to the 3'-UTR of mRNA leads to the stabilization of mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the /DNMT3A//Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients.
癌细胞的干细胞样行为在肿瘤异质性和侵袭中起着核心作用，并且与耐药性及不良临床结果密切相关。然而，癌细胞干性的分子基础仍未完全明确。在此，我们表明，一种在约95%的人类肌肉浸润性膀胱癌（MIBC）中过表达的长链非编码RNA，通过上调Rho GTP酶Rac1诱导培养的膀胱癌细胞形成干细胞样球体并发生侵袭。我们进一步表明，该RNA与DNA甲基转移酶3A蛋白（DNMT3A）结合，并将DNMT3A tether到该RNA的启动子上，从而使其发生高甲基化并抑制其转录。该RNA与该RNA mRNA的3'-UTR结合减少导致该RNA mRNA稳定以及Rac1蛋白水平升高，进而刺激MIBC细胞球体形成和侵袭。对人类蛋白质图谱的分析表明，Rac1的高表达与MIBC患者的不良生存密切相关。我们的数据强烈表明，该RNA/DNMT3A/该RNA/Rac1效应通路驱动MIBC（一种致命的膀胱癌形式）中的干细胞样和侵袭行为。单独或与铂类疗法联合靶向该通路，可能会降低MIBC患者的化疗耐药性并改善长期预后。 （注：原文中部分“该RNA”指代不明，翻译时保留原文表述）
