MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis

Abstract

Background Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. Methods To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. Results A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. Conclusions Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. Graphical Abstract MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.

RRM2‑mediated Wnt/β‑catenin signaling pathway activation in lung adenocarcinoma: A potential prognostic biomarker

“…However, in cancer cells, DNA damage repair processes, such as nucleotide excision repair, post-replication repair and homologous recombination repair, may counteract the effects of cisplatin, resulting in cisplatin resistance (28). Recent studies have indicated that RRM2, an oncogene, plays a critical role in the proliferation, migration, invasion, and drug resistance of breast cancer cells, small cell lung cancer cells, renal clear cell carcinoma cells, and pancreatic cancer cells (29)(30)(31)(32). In lung adenocarcinoma, suppression of RRM2 also inhibits the proliferation, migration and invasive ability of lung adenocarcinoma cells (33)(34)(35)(36).…”

Non-Coding RNAs as Key Regulators in Lung Cancer

“…Numerous studies have shown the involvement of miRNAs in the regulation of cell proliferation [ 28 , 29 , 30 ]. One of them revealed increased expression of 16 miRNAs and insufficient expression of eight miRNAs in SCLC cell lines and in primary SCLC tumour cells compared to normal lung tissue [ 30 ].…”

Nucleic acid-sensing-related gene signature in predicting prognosis and treatment efficiency of small cell lung cancer patients

“…Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, comprises about 15% of bronchogenic carcinomas (1)(2)(3). It is known for its swift progression, propensity for widespread metastasis, and overall dismal prognosis (4,5). Platinumbased chemotherapy combined with etoposide remains the cornerstone of SCLC treatment, delivering an initially favorable response in patients (6,7).…”