![]() ![]() However, the mechanism underlying CAFs activation is still to be clarified in LUAD. Numerous studies have identified that CAFs are prominent in shaping the extracellular matrix (ECM), particularly the α-SMA expression, increasing the synthesis of ECM, and improving the remodeling of ECM, and cancer pathogenesis. Therefore, it is necessary to identify new mechanisms that affect TME to improve therapy and patient survival in lung cancer.Ĭancer-associated fibroblasts (CAFs) are the most abundant stromal components in TME. Genetic studies reveal significant correlationship between the tumor microenvironments (TME) and tumor progression in lung cancer patients. Despite advancements in medical research, this survival rate has remained relatively unchanged over the past three decades. LUAD is one of most common types of lung cancer, with a global 5-year survival rate ranging from 10–20% worldwide. Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death, with an estimated 1.8 million deaths (18%) worldwide. Consequently, this finding suggests a novel strategy for cancer treatment that may tackle tumor progression in the future. Specifically, COX-2/exo-miR-1290/CU元 is suggested as a novel signaling pathway for mediating CAFs activation and tumor progression in LUAD. Our data identify a new CAFs activation mechanism by exosomes derived from cancer cells that overexpress COX-2. Additionally, we identified that Nrf2 is direcctly bound with promoters of FAP-1 and FN1, which enhanced CAFs activation by promoting FAP-1 and FN1 transcription. ![]() CU元 is identified to induce the Nuclear Factor Erythroid 2–Related Factor 2 (NFE2L2, Nrf2) ubiquitination and degradation, while exo-miR-1290 can prevent Nrf2 ubiquitination and increase its protein stability by targeting CU元. Furthermore, Cullin3 (CU元), a potential target of miR-1290, was found to suppress COX-2/exo-miR-1290-mediated CAFs activation and ECM production, consequently impeding tumor progression. COX-2 overexpression increased exo-miR-1290 expression, which promoted CAFs activation. However, PGE2, one of major product of COX-2, did not affect CAFs activation directly. In vivo, a positive correlation was observed between the COX-2 expression levels in parenchyma and α-SMA/FN1 expression levels in mesenchyma in LUAD. Herein, we further elucidated the implicated mechanisms using online prediction software, luciferase reporter assays, co-immunoprecipitation, and experimental animal models. The exosomes were extracted by ultracentrifugation and exo-miRNAs were detected by qRT-PCR. And the expression of Fibronectin (FN1) was used to analyze ECM production by CAFs. MethodsĪs measures of CAFs activation, the expressions of fibroblasts activated protein-1 (FAP-1) and α-smooth muscle actin (α-SMA), the main CAFs markers, were detected by Western blotting and Immunohistochemistry. Therefore, we conducted this study to identify the effects and mechanisms of COX-2 underlying CAFs activation by tumor-derived exosomal miRNAs in lung adenocarcinoma (LUAD) progression. However, the mechanisms of COX-2 mediated CAFs activation have not yet been elucidated. Cyclooxygenase-2 (COX-2) has been proved to promote ECM formation and tumor progression. Cancer-associated fibroblasts (CAFs) are critically involved in tumor progression by maintaining extracellular mesenchyma (ECM) production and improving tumor development.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |