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单细胞 RNA 测序分析揭示了铂耐药基因 COX7B 和替代标志物 CD63。

Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63.

机构信息

Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

出版信息

Cancer Med. 2018 Dec;7(12):6193-6204. doi: 10.1002/cam4.1828. Epub 2018 Oct 26.

DOI:10.1002/cam4.1828
PMID:30367559
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6308066/
Abstract

Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-naïve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum-resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

摘要

癌症通过肿瘤内异质性（ITH）和克隆再增殖获得对基于铂的系统治疗（例如顺铂[CDDP]）的耐药性。然而，对于化疗对单细胞水平 ITH 的影响知之甚少。在这里，我们通过 scRNA-seq 对用 CDDP 治疗的癌症进行转录组图谱分析，发现了一个与铂耐药相关的新基因 COX7B 和替代标志物 CD63。在癌细胞中敲低 COX7B 会降低 CDDP 的敏感性，而过表达则恢复 CDDP 的敏感性。COX7B 水平低与各种类型癌症患者的死亡率较高相关，并且与膀胱癌对化疗反应不良显著相关。接受 CDDP 治疗的患者的肿瘤样本在治疗后 COX7B 蛋白水平降低。对铂-naive 癌细胞的 scRNA-seq 数据进行分析表明，通过检测 CD63，可以从大量癌细胞中分离出 COX7B 低表达的亚克隆。当用 CDDP 对其进行挑战时，这个低 COX7B 亚克隆表现为获得性铂耐药细胞。我们的研究结果提供了铂耐药性的新转录组图谱，为癌症的化疗敏感性和耐药性提供了有价值的见解，并确定了一个新的铂耐药基因 COX7B 和一个替代标志物 CD63。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/0314e0875de5/CAM4-7-6193-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/16fc5cabade0/CAM4-7-6193-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/807322612592/CAM4-7-6193-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/45d29a5e8ca1/CAM4-7-6193-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/6ce9f0440f14/CAM4-7-6193-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/0314e0875de5/CAM4-7-6193-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/16fc5cabade0/CAM4-7-6193-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/807322612592/CAM4-7-6193-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/45d29a5e8ca1/CAM4-7-6193-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/6ce9f0440f14/CAM4-7-6193-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb9/6308066/0314e0875de5/CAM4-7-6193-g005.jpg

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