LDR-Induced miR-30a and miR-30b Target the PAI-1 Pathway to Control Adverse Effects of NSCLC Radiotherapy

Abstract

Radiotherapy has been a central part in curing non-small cell lung cancer (NSCLC). However, it is possible that not all of the tumor cells are destroyed by radiation; therefore, it is important to effectively control residual tumor cells that could become aggressive and resistant to radiotherapy. In this study, we aimed to investigate the molecular mechanism of decreased NSCLC radioresistance by low-dose radiation (LDR) pretreatment. The results indicated that miR-30a and miR-30b, which effectively inhibited plasminogen activator inhibitor-1 (PAI-1), were overexpressed by treatment of LDR to NSCLC cells. Phosphorylation of Akt and ERK, the downstream survival signals of PAI-1, was decreased by PAI-1 inhibition. Reduced cell survival and epithelial-mesenchymal transition by PAI-1 inhibition were confirmed in NSCLC cells. Moreover, in vivo orthotopic xenograft mouse models with 7C1 nanoparticles to deliver miRNAs showed that tumor growth and aggressiveness were efficiently decreased by LDR treatment followed by radiotherapy. Taken together, the present study suggested that PAI-1, whose expression is regulated by LDR, was critical for controlling surviving tumor cells after radiotherapy.Recent reports have suggested that increased expression of plasminogen activator inhibitor-1 (PAI-1) indicates poor prognosis of many cancer types, including NSCLC. 12,13 PAI-1 is an inhibitor of fibrinolysis. It is a physiological process that degrades fibrin and the extracellular matrix (ECM) proteins by inhibiting the urokinasetype plasminogen activator (uPA), which cleaves plasminogen to form plasmin. PAI-1, which is associated with the remodeling of the surrounding tissues, is a key factor in cancer proliferation, invasion, dissemination, and release of tumor growth factors and

KCNQ1OT1/miR-217/ZEB1 feedback loop facilitates cell migration and epithelial-mesenchymal transition in colorectal cancer

“…It has been widely reported that miRNAs can participate in the progression of cancers through modulating its downstream target genes [41][42][43] . From this point, we discovered that miR-217 harbored the binding sites for both KCNQ1OT1 and ZEB1.…”

Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

“…Six-week-old male C57BL/6 mice (Orient Bio, Seongnam, Korea) were used for the in vivo experiments following the previous study [ 26 ]. The protocols used were approved by the Institutional Animal Care and Use Committee of Pusan National University (Busan, Korea) and performed in accordance with the provisions of the NIH Guide for the Care and Use of Laboratory Animals.…”

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

“…Radiation therapy combined with chemotherapy can produce a cure only in a small number of NSCLC patients because NSCLC is comparatively less sensitive to chemotherapy or radiation (4,5). Acquired resistance results in local tumor recurrence or failure of radiotherapy (6,7). Increasing evidence has demonstrated that epithelial-to-mesenchymal transition (EMT) mediated tumor metastasis is closely associated with radiation resistance (8,9).…”