Hao Zhexue, Feng Fenlan, Wang Qi, Wang Yucong, Li Jin, Huang Jinkun
Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
The Key Laboratory of Advanced Interdisciplinary Studies, The State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
J Thorac Dis. 2024 Dec 31;16(12):8754-8770. doi: 10.21037/jtd-2024-2144. Epub 2024 Dec 28.
Tyrosine kinase inhibitors (TKIs) are the first-line therapy for patients with non-small cell lung cancer (NSCLC) with sensitized mutations in the epidermal growth factor receptor (). However, resistance to TKIs is a major clinical issue that affects the survival and prognosis of the patients, with the mechanisms underlying this resistance remaining elusive. Circular RNAs (circRNAs) are a class of single-stranded, covalently closed RNA molecules, which are generated from pre-messenger RNAs (mRNAs) through back splicing. The aim of this study was to investigate the role of cRNA SPECC1 in promoting resistance to TKIs in NSCLC and to explore its potential involvement in tumorigenesis and metastasis of lung adenocarcinoma (LUAD).
In this study, we identified differentially expressed genes through RNA sequencing from three tumor samples obtained from patients with poor postoperative TKI treatment outcomes. Validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and cell function experiments. We further constructed a competing endogenous RNA (ceRNA) network and performed Gene Ontology (GO) analysis to explore the underlying mechanisms of circRNA.
circular RNA (circ) was found to be significantly upregulated in tumors as compared to adjacent tissues. Knockdown of circ in NSCLC cell lines resulted in decreased proliferation, migration, and invasion. Additionally, apoptosis was increased in cell lines with TKI-sensitive mutations when treated with osimertinib.
circ may promote TKI resistance and contribute to the tumorigenesis and metastasis of NSCLC. This study offers a novel perspective on TKI resistance research at the RNA level.
酪氨酸激酶抑制剂（TKIs）是表皮生长因子受体（EGFR）敏感突变的非小细胞肺癌（NSCLC）患者的一线治疗方法。然而，对TKIs的耐药性是一个影响患者生存和预后的主要临床问题，其耐药机制仍不清楚。环状RNA（circRNAs）是一类单链、共价闭合的RNA分子，由前体信使RNA（mRNAs）通过反向剪接产生。本研究的目的是探讨环状RNA SPECC1在促进NSCLC对TKIs耐药中的作用，并探讨其在肺腺癌（LUAD）发生和转移中的潜在作用。
在本研究中，我们通过对3例术后TKI治疗效果不佳患者的肿瘤样本进行RNA测序，鉴定出差异表达基因。使用定量实时聚合酶链反应（qRT-PCR）和细胞功能实验进行验证。我们进一步构建了竞争性内源RNA（ceRNA）网络，并进行基因本体（GO）分析，以探索环状RNA的潜在机制。
与相邻组织相比，发现环状RNA（circ）在肿瘤中显著上调。敲低NSCLC细胞系中的circ导致增殖、迁移和侵袭减少。此外，在用奥希替尼治疗时，具有EGFR敏感突变的细胞系中凋亡增加。
circ可能促进TKI耐药，并有助于NSCLC的发生和转移。本研究为RNA水平上的TKI耐药研究提供了新的视角。
