Liu Mingxin, Hu Peihong, Tang Bo, Yang Qi, Xiang Run, Liu Yiqiang, Li Juan, Wu Binghuo, Wu Hong, Tian Bo, Xu Chuan, Li Qiang
Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
J Thorac Dis. 2024 Dec 31;16(12):8363-8378. doi: 10.21037/jtd-24-1477. Epub 2024 Dec 28.
Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and presents early metastasis and poor prognosis. Chemotherapy with cisplatin (CDDP) remains one of the standards of care in first-line treatment. However, the emergence of acquired resistance to CDDP causes disease progression and cancer recurrence. A comprehensive understanding of the CDDP-resistant mechanisms aids in defining accurate biomarkers and developing potential strategies.
The liquid chromatograph mass spectrometer (LC-MS/MS) was conducted to analyze the differential exosomal proteins from plasma samples of SCLC patients with non-treatment or resistance to CDDP. The online RNA-seq data with clinicopathological information on SCLC patients were downloaded from the Gene Expression Omnibus (GEO) database for further prognostic analysis. The SCLC cell line model of acquired CDDP resistance was established to investigate the role of platelet protein multimerin-1 (MMRN1) in CDDP resistance.
MMRN1 was increased in CDDP-resistant SCLC patients and cell line models. Reduction of MMRN1 recovered the sensitivity to CDDP while overexpression of MMRN1 conferred CDDP resistance. The CDDP-resistant SCLC cells disseminated resistant to the CDDP-sensitive SCLC cells via the exosomal MMRN1. Additionally, CDDP treatment induces endoplasmic reticulum (ER) stress and subsequent upregulation of MMRN1. Increasing MMRN1 interacted with binding immunoglobulin protein (BiP) in the ER, maintaining the ER stress in SCLC cells.
The present study identified exosomal MMRN1 as a potential biomarker for CDDP resistance in SCLC. MMRN1 sustains ER stress via interaction with BiP and subsequently facilitates CDDP resistance, which might be a promising therapeutic target to overcome CDDP resistance.
小细胞肺癌（SCLC）占所有肺癌的15%，具有早期转移和预后不良的特点。顺铂（CDDP）化疗仍是一线治疗的标准方案之一。然而，对CDDP获得性耐药的出现会导致疾病进展和癌症复发。全面了解CDDP耐药机制有助于确定准确的生物标志物并制定潜在的治疗策略。
采用液相色谱-质谱联用仪（LC-MS/MS）分析未接受治疗或对CDDP耐药的SCLC患者血浆样本中差异外泌体蛋白。从基因表达综合数据库（GEO）下载具有SCLC患者临床病理信息的在线RNA测序数据，进行进一步的预后分析。建立获得性CDDP耐药的SCLC细胞系模型，以研究血小板蛋白多聚蛋白-1（MMRN1）在CDDP耐药中的作用。
MMRN1在CDDP耐药的SCLC患者和细胞系模型中升高。MMRN1的降低恢复了对CDDP的敏感性，而MMRN1的过表达则赋予了CDDP耐药性。CDDP耐药的SCLC细胞通过外泌体MMRN1将耐药性传递给CDDP敏感的SCLC细胞。此外，CDDP治疗诱导内质网（ER）应激并随后上调MMRN1。增加的MMRN1与ER中的结合免疫球蛋白蛋白（BiP）相互作用，维持SCLC细胞中的ER应激。
本研究确定外泌体MMRN1是SCLC中CDDP耐药的潜在生物标志物。MMRN1通过与BiP相互作用维持ER应激，随后促进CDDP耐药，这可能是克服CDDP耐药的一个有前景的治疗靶点。
