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|dc.description.abstract||Radiation therapy plays a critical part in cancer therapy for non-small cell lung cancers (NSCLC). However, the population of radioresistant cancer cells can finally cause locoreginal relapse and even fatal metastasis. Radioresistance currently remains a major impediment to effective radiation therapy. Thus, exploring effective radiation sensitizers is needed. Typically, Epithelial-Mesenchymal Transition (EMT) is a transdifferentiation program that is often activated during cancer invasion and metastasis. The EMT process is dysregulated during malignant tumor progression. As a result, EMT of tumor cells also contributes to drug resistance. In addition, EMT is also accompanying with radioresistance, but its linkage between EMT and acquisition of radioresistance remain unexplored. In this research, I aimed to investigate the functional regulation being responsible for radioresistance and radiation-induced EMT progression in non-small cell lung cancers. Here, I found that TWIST1 plays a critical role in regulating the radiation response. Interestingly, the observed TWIST1 upregulation was post-translational regulation. FBXL14 E3 ligase being responsible for TWIST1 protein stability was down-regulated by radiation-induced miR30b microRNA. Of note, irradiation activated JAK1/p-38 MAPK signaling pathway, regulates the miR-30b/FBXL14/TWIST1 axis. Collectivity, radiation treatment may lead to upregulation of TWIST1 and subsequently induced radioresistance in context to existing therapies. Importantly, I found EMT master regulator markers such as CDH2 and VIM were also increased by exposure to radiation. And radiation-induced EMT was regulated by TWIST1 protein stabilization. Here, I also defined fractionated radiation (2 Gy/day for 3 days) exposure induces the secretion of granulocyte colony-stimulating factor (G-CSF) that has been commonly used in cancer therapies to ameliorate neutropenia. However, radiation-induced G-CSF promoted the EMT regulated by radiation increased the stability of β-catenin. Following G-CSF is recognized by G-CSFR and transduced its intracellular signaling JAK/STAT3, thereby triggered EMT program in NSCLCs. These findings suggest that the application of radiation-induced molecular signaling mechanisms, responsible for EMT progression and radioresistance of NSCLCCs. These investigations, may contribute to develop a novel therapeutic molecular target enhancing the efficacy of radiotherapy in lung cancer treatment.||-|
|dc.title||Functional regulation of epithelial to mesenchymal transition in radioresistant human lung cancer cells||-|
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