DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells.
DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells.
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膀胱癌在男性最常见的癌症中排名第四，并且是每个患者治疗费用最高的癌症。膀胱癌的肌肉浸润形式是最致命的癌症之一，具有远处转移的患者的5年存活率仅为6%。有效的治疗选择仍然很少。SNHG 1是一种长的非编码RNA，在95%的肌肉浸润性膀胱癌中过度表达。然而，关于SNHG 1在膀胱肿瘤形成和进展中的作用和机制的信息很少。在这里，我们提供了实验证据，证明SNHG 1通过特定的信号通路驱动膀胱癌细胞侵袭和干细胞样行为。我们的研究结果揭示了预测肌层浸润性膀胱癌进展的新生物标志物和潜在的治疗干预新靶点。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，并与耐药性和不利的临床结果密切相关。然而，癌细胞干细胞性的分子基础仍然没有完全确定。在这里，我们发现SNHG 1是一种长的非编码RNA，在约95%的人肌肉浸润性膀胱癌（MIBC）中过表达，通过上调Rho GT3，Rac 1诱导干细胞样球体形成和培养的膀胱癌细胞的侵袭。我们进一步表明SNHG 1与DNA甲基化转移酶3A蛋白（DNMT 3A）结合，并将DNMT 3A与miR-129-2的启动子连接，从而过度甲基化并抑制miR-129-2- 5 p转录。miR-129-2与Rac 1 mRNA的3′-UTR结合减少，导致Rac 1 mRNA稳定和Rac 1蛋白水平增加，从而刺激MIBC细胞球形成和侵袭。对人类蛋白质图谱的分析表明，Rac 1的高表达与MIBC患者的生存率低密切相关。我们的数据强烈表明SNHG 1/DNMT 3A/miR-129-2- 5 p/Rac 1效应通路驱动MIBC（一种致命的膀胱癌）中的干细胞样和侵袭性行为。靶向这一途径，单独或与铂类药物联合治疗，可能会降低MIBC患者的耐药性并改善长期结局。
Bladder cancer ranks fourth among the most prevalent cancers in men and is the most expensive cancer to treat on a per-patient basis. The muscle-invasive form of bladder cancer is one of the deadliest cancers, with a 5-year survival rate of only 6% in patients with distant metastasis. Effective therapeutic options remain few and far between. SNHG1 is a long non-coding RNA that is over-expressed in 95% of muscle-invasive bladder cancers. However, very little information is available about the role and mechanisms of SNHG1 in bladder tumor formation and progression. Here, we provide experimental evidence establishing that SNHG1 drives bladder cancer cell invasion and stem-cell-like behaviors through a specific signaling pathway. Our results reveal novel biomarkers predictive of the progression of muscle-invasive bladder cancer and potential new targets for therapeutic intervention. 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 SNHG1, 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 SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3′-UTR of Rac1 mRNA leads to the stabilization of Rac1 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 SNHG1/DNMT3A/miR-129-2-5p/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.
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