结合多组学的单细胞 RNA-seq 揭示 SERPINE2 作为晚期肾细胞癌转移的靶标,Cell Death & Disease

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结合多组学的单细胞 RNA-seq 揭示 SERPINE2 作为晚期肾细胞癌转移的靶标
Cell Death & Disease ( IF 8.1 ) Pub Date : 2023-01-16 , DOI: 10.1038/s41419-023-05566-w
Wen-Jin Chen _{1,

2} , Ke-Qin Dong ₃ , Xiu-Wu Pan ₁ , Si-Shun Gan ₂ , Da Xu ₂ , Jia-Xin Chen ₂ , Wei-Jie Chen ₂ , Wen-Yan Li ₁ , Yu-Qi Wang ₁ , Wang Zhou ₁ , Brian Rini ₄ , Xin-Gang Cui _{1,

2}

Affiliation

肿瘤生长、转移和治疗反应被认为受晚期肾细胞癌 (RCC) 中肿瘤及其微环境 (TME) 的调节。然而，RCC 进展中基因组、转录组和表观遗传学改变的潜在机制尚未完全确定。在这项研究中，单细胞 RNA 测序 (scRNA-seq) 数据是从 RCC 患者的八个组织样本中获得的，包括两对匹配的原发性和转移性部位（淋巴结），以及 Hi-C，可转座的染色质RCC (Caki-1) 和人肾小管上皮细胞系 (HK-2) 之间的高通量 (ATAC-seq) 和 RNA 测序 (RNA-seq)。确定的目标在临床组织样本（407 名 RCC 患者的微阵列，TMA-30 和 TMA-2020）中得到验证，其功能通过击倒或过表达的体外和体内实验得到进一步验证。我们分析了 30514 个恶性细胞和 14762 个非恶性细胞的转录组。综合多组学分析显示恶性细胞和 TME 在 RCC 中起关键作用。基质细胞和免疫细胞的表达程序在样本中是一致的，而恶性细胞表达与缺氧、细胞周期、上皮分化和两种不同转移模式相关的不同程序。层次结构的比较表明，SERPINE2 与这些 NNMF 表达程序相关，同时针对切换的隔室。SERPINE2 在 RCC 组织中高表达，在癌旁组织或 HK-2 细胞系中低表达。SERPINE2 敲低显着抑制 RCC 细胞生长和侵袭，而 SERPINE2 过表达显着促进 RCC 细胞在体外和体内的转移。此外，SERPINE2 可以激活上皮-间质转化途径。上述发现表明，恶性细胞和 TME 的不同表达模式在 RCC 进展中发挥了独特的作用。SERPINE2 被确定为抑制晚期 RCC 转移的潜在治疗靶点。

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Single-cell RNA-seq integrated with multi-omics reveals SERPINE2 as a target for metastasis in advanced renal cell carcinoma

Tumor growth, metastasis and therapeutic response are believed to be regulated by the tumor and its microenvironment (TME) in advanced renal cell carcinoma (RCC). However, the mechanisms underlying genomic, transcriptomic and epigenetic alternations in RCC progression have not been completely defined. In this study, single-cell RNA-sequencing (scRNA-seq) data were obtained from eight tissue samples of RCC patients, including two matched pairs of primary and metastatic sites (lymph nodes), along with Hi-C, transposable accessible chromatin by high-throughput (ATAC-seq) and RNA-sequencing (RNA-seq) between RCC (Caki-1) and human renal tubular epithelial cell line (HK-2). The identified target was verified in clinical tissue samples (microarray of 407 RCC patients, TMA-30 and TMA-2020), whose function was further validated by in vitro and in vivo experiments through knockdown or overexpression. We profiled transcriptomes of 30514 malignant cells, and 14762 non-malignant cells. Comprehensive multi-omics analysis revealed that malignant cells and TME played a key role in RCC. The expression programs of stromal cells and immune cells were consistent among the samples, whereas malignant cells expressed distinct programs associated with hypoxia, cell cycle, epithelial differentiation, and two different metastasis patterns. Comparison of the hierarchical structure showed that SERPINE2 was related to these NNMF expression programs, and at the same time targeted the switched compartment. SERPINE2 was highly expressed in RCC tissues and lowly expressed in para-tumor tissues or HK-2 cell line. SERPINE2 knockdown markedly suppressed RCC cell growth and invasion, while SERPINE2 overexpression dramatically promoted RCC cell metastasis both in vitro and in vivo. In addition, SERPINE2 could activate the epithelial-mesenchymal transition pathway. The above findings demonstrated that the role of distinct expression patterns of malignant cells and TME played a distinct role in RCC progression. SERPINE2 was identified as a potential therapeutic target for inhibiting metastasis in advanced RCC.

更新日期：2023-01-18

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