| Summary: | 博士 === 中國醫藥大學 === 臨床醫學研究所博士班 === 100 === Treatment of lung cancer has been toward more refined and personalized. Target therapy developed in recent years indeed brings hope to patients, also encourages clinical research. Even so, patients benefit from that is still a minority compared to overall lung cancer population. More input requires searching more potential therapy. Metastasis is the most terrible aspect for cancer disease. The characteristics of cancer cell migration are the common cause of death for various cancer diseases. Lung cancer is the leading cause of cancer death in the world, including this country, and the incidence ranks top also. It then becomes urgent for us to explore the mechanism regarding metastasis of lung cancer, and the potential therapeutic compounds. Traditional herbal medicine has inherited thousands of years of clinical experience. Learning from which to aggressively search for possible anti-cancer drugs will become an important direction of cancer research in modern medicine, and some results shed. Ganoderma is known as the reputation of the top grade, several studies show their anti-cancer effects. Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. We therefore interested in exploring the potential of Ganoderma and resveratrol on the treatment for lung cancer. Ganoderma tsugae was obtained from an improved strain in Taiwan. The quality control of Ganoderma tsugae extracts (GTE) was assured using HPLC, ESI-MS, and bio-response platform (PhytomicsQC) to confirm chemical and bio-response fingerprints. Through the experiments of cell and animal model, the inhibition effects of GTE on lung cancers in vitro and in vivo were shown. Combination of GTE with doxorubicine increased chemo-sensitivity of doxorubicine-resistant lung adenocarcinoma cell line (H23/0.3). Our results indicated that GTE may down regulate AKT signaling to induce cell cycle arrest (S-arrest) and promote apotosis through intrinsic mitochondria pathway. Moreover, through various techniques which included cell culture, direct observation via microscopy, genetic transfer, animal study, and immunohistochemstry stain for clinical lung cancer tissues, to explore the inhibition effects for resveratrol on metastasis of lung cancer and explore the underlying mechanisms. We found that treatment with resveratrol inhibited cell mobility through induction of the Mesenchymal-Epithelial Transition (MET) in lung cancer cells. Besides, downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol enhanced activity of PP2A/C through down regulated miRNA-520h, then the enhanced PP2A/C further inhibited AKT signaling pathway “AKT ?_NF-κB ?_FOXC2”, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provides the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression. In terms of the results, we believe it is possible to develop new therapeutic model on cancer management using Traditional Chinese Medicine.
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