Shao Yebo, Lian Shixian, Zheng Jiajia, Tong Hanxing, Wang Jiongyuan, Xu Jing, Liu Wenshuai, Hu Guoxiang, Zhang Yong, He Junyi
Department of General Surgery, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen 361015, China.
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Mol Ther Nucleic Acids. 2021 May 29;25:264-276. doi: 10.1016/j.omtn.2021.05.017. eCollection 2021 Sep 3.
Emerging evidence has shown that long non-coding RNAs (lncRNAs) play crucial roles in human cancers. However, systematic characterization of lncRNAs and their roles in gastrointestinal stromal tumor (GIST) therapy have been lacking. We performed high-throughput RNA sequencing (RNA-seq) of 20 GIST and paired adjacent normal samples. We characterized the transcriptional landscape and dysregulation of lncRNAs in GIST. We identified 866 upregulated and 1,268 downregulated lncRNAs in GIST samples, the majority of which were GIST-specific over other cancer types. Most hallmarks were found to be dysregulated in GIST samples, and lncRNAs were highly associated with cancer-related hallmarks. RP11-616M22.7 was identified to increase in imatinib-resistant samples compared to those in non-resistant samples. Further analysis revealed that RP11-616M22.7 was closely associated with the Hippo signaling pathway. By treating GIST cells with different doses of imatinib, we verified that RP11-616M22.7 knockdown promotes the sensitivity of tumor cells, whereas RP11-616M22.7 overexpression induces resistance to imatinib. We further confirmed reducing of resistance to imatinib by knocking down RP11-616M22.7 . Additionally, RP11-616M22.7 was observed to interact with RASSF1 protein. Our study revealed that deficiency of RP11-616M22.7 was able to reduce resistance of the GIST cell response to imatinib treatment both and .
新出现的证据表明，长链非编码RNA（lncRNAs）在人类癌症中发挥着关键作用。然而，lncRNAs及其在胃肠道间质瘤（GIST）治疗中的作用尚未得到系统的表征。我们对20例GIST及其配对的相邻正常样本进行了高通量RNA测序（RNA-seq）。我们表征了GIST中lncRNAs的转录图谱和失调情况。我们在GIST样本中鉴定出866个上调的lncRNAs和1268个下调的lncRNAs，其中大多数在其他癌症类型中是GIST特异性的。发现大多数特征在GIST样本中失调，并且lncRNAs与癌症相关特征高度相关。与非耐药样本相比，RP11-616M22.7在伊马替尼耐药样本中被鉴定为增加。进一步分析表明，RP11-616M22.7与Hippo信号通路密切相关。通过用不同剂量的伊马替尼处理GIST细胞，我们验证了敲低RP11-616M22.7可促进肿瘤细胞的敏感性，而RP11-616M22.7的过表达诱导对伊马替尼的耐药性。我们进一步证实通过敲低RP11-616M22.7可降低对伊马替尼的耐药性。此外，观察到RP11-616M22.7与RASSF1蛋白相互作用。我们的研究表明，RP11-616M22.7的缺失能够降低GIST细胞对伊马替尼治疗的耐药反应。
