Monteleone Nicholas J, Lutz Carol S
Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA.
Oncotarget. 2020 Dec 22;11(51):4699-4721. doi: 10.18632/oncotarget.27840.
Lung cancer is a collection of aggressive tumors generally not diagnosed until late-stage, resulting in high mortality rates. The vast majority of non-small cell lung cancer (NSCLC) patients undergo combinatory chemotherapeutic treatment, which initially reduces tumor growth, but frequently becomes ineffective due to toxicity and resistance. Researchers have identified multiple signaling pathways involved in lung cancer chemoresistance, including cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1) derived prostaglandin E2 (PGE). While COX-2 inhibitors have shown promise in the clinic, their use is limited due to severe side effects. One novel approach to effectively suppress COX-2 signaling is through microRNA (miRNA). MiRNAs are small-noncoding RNAs commonly misexpressed in cancer. One tumor suppressive miRNA, miR-708-5p, has been shown to repress pro-resistant signaling pathways, including COX-2 and mPGES-1. Here, we demonstrate that chemotherapies reduce COX-2 expression, possibly through induction of miR-708-5p. Moreover, combination treatment of erlotinib (ERL) or paclitaxel (PAC) with miR-708-5p enhances COX-2 and mPGES-1 protein suppression. We also show that combination chemotherapeutic and miR-708-5p treatment intensifies the anti-proliferative and pro-apoptotic effects of ERL and PAC. We also created ERL and PAC resistant lung cancer cell lines, which have increased COX-2 expression and diminished miR-708-5p levels compared to naïve lung cancer cells. While ERL and PAC treatments do not alter resistant cell phenotype alone, combination treatment with miR-708-5p partially restores the chemotherapies' anti-proliferative effects and fully restores their pro-apoptotic qualities. These data suggest miR-708-5p may have potential combinatory therapeutic value to more efficaciously treat lung tumors while overcoming chemoresistance.
肺癌是一组侵袭性肿瘤，通常直到晚期才被诊断出来，导致死亡率很高。绝大多数非小细胞肺癌（NSCLC）患者接受联合化疗，这种治疗最初会减缓肿瘤生长，但由于毒性和耐药性，常常会失效。研究人员已经确定了多个参与肺癌化疗耐药的信号通路，包括环氧化酶-2（COX-2）/微粒体前列腺素E合酶-1（mPGES-1）衍生的前列腺素E2（PGE）。虽然COX-2抑制剂在临床上已显示出前景，但由于严重的副作用，其应用受到限制。一种有效抑制COX-2信号传导的新方法是通过微小RNA（miRNA）。miRNA是通常在癌症中表达失调的小非编码RNA。一种肿瘤抑制性miRNA，即miR-708-5p，已被证明可抑制包括COX-2和mPGES-1在内的促耐药信号通路。在此，我们证明化疗可能通过诱导miR-708-5p来降低COX-2表达。此外，厄洛替尼（ERL）或紫杉醇（PAC）与miR-708-5p联合治疗可增强对COX-2和mPGES-1蛋白的抑制作用。我们还表明，联合化疗和miR-708-5p治疗可增强ERL和PAC的抗增殖和促凋亡作用。我们还创建了ERL和PAC耐药的肺癌细胞系，与未处理的肺癌细胞相比，它们的COX-2表达增加，miR-708-5p水平降低。虽然ERL和PAC单独治疗不会改变耐药细胞表型，但与miR-708-5p联合治疗可部分恢复化疗的抗增殖作用，并完全恢复其促凋亡特性。这些数据表明，miR-708-5p可能具有潜在的联合治疗价值，可更有效地治疗肺肿瘤并克服化疗耐药性。
