Heterogeneous expression and role of receptor tyrosine kinase-like orphan receptor 2 (ROR2) in small cell lung cancer
Heterogeneous expression and role of receptor tyrosine kinase-like orphan receptor 2 (ROR2) in small cell lung cancer
复制标题
DOI：
10.1007/s13577-022-00830-1
复制
发表时间：
2022-12
期刊：
影响因子：
4.3
通讯作者：
M. Sanada;Masaya Yamazaki;T. Yamada;K. Fujino;S. Kudoh;Yuki Tenjin;Haruki Saito;Noritaka Kudo;Younosuke Sato;Akira Matsuo;Makoto Suzuki;Takaaki Ito
中科院分区：
文献类型：
--
作者：
M. Sanada;Masaya Yamazaki;T. Yamada;K. Fujino;S. Kudoh;Yuki Tenjin;Haruki Saito;Noritaka Kudo;Younosuke Sato;Akira Matsuo;Makoto Suzuki;Takaaki Ito
本研究探讨了ROR2在小细胞肺癌（SCLC）中的表达及其作用。为了检测ROR2的表达，对27例手术切除的SCLC组织样本进行了ROR2免疫染色。16个组织样本呈阳性，部分组织在染色强度上呈肿瘤内异质性。在SCLC PDX模型的肿瘤组织中也观察到ROR2表达的异质性，其中存在ROR2高表达的细胞（ROR2highcells）和不表达的细胞（ROR2lowcells）。对这些细胞进行RNA序列分析。我们进行了GSEA，结果显示在ror2high细胞中G2M检查点、有丝分裂纺锤体和E2F靶点等分子富集。在PDX模型和SCLC细胞系的ror2高细胞中，EdU的掺入率明显高于ror2低细胞。体外和体内实验均可抑制ror2ko SBC3细胞的增殖。将ror2ko SBC3细胞中下调的差异表达基因与PDX模型中ROR2highcells中DEG上调的差异表达基因进行比较，发现135个共同基因。在对这些基因进行meta分析后，我们将重点放在了极光激酶上。在SCLC细胞系中，ROR2的下调抑制了Aurora激酶。因此，ROR2似乎通过Aurora激酶调节细胞周期。本研究结果揭示了ROR2在SCLC中的作用，并提供了SCLC中伴随肿瘤异质性的候选系统（ROR2-极光激酶）。
The present study investigated the expression and role of ROR2 in small cell lung cancer (SCLC). To examine the expression of ROR2, 27 surgically resected SCLC tissue samples were immunostained for ROR2. Sixteen tissue samples were positive and some showed intratumor heterogeneity in staining intensity. The heterogeneity of ROR2 expression was also observed in tumor tissues from a PDX model of SCLC, in which there were cells with high ROR2 expression (ROR2highcells) and without its expression (ROR2lowcells). These cells were subjected to a RNA sequence analysis. GSEA was performed and the results obtained revealed the enrichment of molecules such as G2M checkpoint, mitotic spindle, and E2F targets in ROR2highcells. The rate of EdU incorporation was significantly higher in ROR2highcells than ROR2lowcells from the PDX model and the SCLC cell lines. Cell proliferation was suppressed inROR2KO SBC3 cells in vitro and in vivo. Comparisons of down-regulated differentially expressed genes inROR2KO SBC3 cells with up-regulated DEG in ROR2highcells from the PDX model revealed 135 common genes. After a Metascape analysis of these genes, we focused on Aurora kinases. In SCLC cell lines, the knockdown of ROR2 suppressed Aurora kinases. Therefore, ROR2 appears to regulate the cell cycle through Aurora kinases. The present results reveal a role for ROR2 in SCLC and afford a candidate system (ROR2-Aurora kinase) accompanying tumor heterogeneity in SCLC.