Exosomal miR-106b serves as a novel marker for lung cancer and promotes cancer metastasis via targeting PTEN.
- 作者列表："Sun S","Chen H","Xu C","Zhang Y","Zhang Q","Chen L","Ding Q","Deng Z
:As novel non-invasive tumor diagnostic biomarkers, exosomal bioactive miRNAs have received increasing attention. Herein, the aim of this study is to explore the clinical values and roles of exosomal miR106b in lung cancer. The exosomal miR-106b level was much higher in the serum of patients with lung cancer than that in healthy volunteers. Also, the exosomal miR-106b level in the lung cancer patient serum was associated with TNM stages and lymph node metastasis. Furthermore, exosomal miR-106b enhanced the migrated and invasive ability of lung cancer cells and increased the MMP-2 and MMP-9 expression. Mechanistically, exosomal miR-106b could target PTEN, and promote lung cancer cell migration and invasion. More importantly, PTEN overexpression reversed the effect of exosomal miR-106b on lung cancer cell migration and invasion. Taken together, these findings indicate that exosomal miR-106b may be a promising diagnostic biomarker and drug target for patients with lung cancer.
: 外泌体生物活性mirna作为新型非侵入性肿瘤诊断生物标志物日益受到关注。本研究的目的是探讨外泌体miR106b在肺癌中的临床价值和作用。肺癌患者血清外泌体miR-106b水平明显高于健康志愿者。此外，肺癌患者血清中的外泌体miR-106b水平与TNM分期和淋巴结转移相关。此外，外泌体miR-106b增强了肺癌细胞的迁移和侵袭能力，并增加了MMP-2 和MMP-9 的表达。在机理上，外泌体miR-106b可以靶向PTEN，并促进肺癌细胞迁移和侵袭。更重要的是，PTEN过表达逆转了外泌体miR-106b对肺癌细胞迁移和侵袭的影响。总之，这些发现表明外泌体miR-106b可能是肺癌患者的有希望的诊断生物标志物和药物靶标。
METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.
METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.
METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.