碩士 / 高雄醫學大學 / 醫學研究所碩士班 / 106 / Cancer has now taken the lead among the ten leading causes of death in Taiwan. The two most common ones are lung cancer and hepatoma. Though renal cell carcinoma is not so prevalent as these two malignancies, the response to medical treatment is very poor.
Therefore, the new effective drugs development for renal cell cancer treatment become very important. Recent advances in the clinical new target drugs use for cancer treatment is much more progress, the side effects may cause secondary injuries to the patients. It is more safte to obtain effective anti-cancer compound from daily edible natural products .
Fucoidan (Fu), is a sulfated polysaccharide and the polysaccharide backbone is mainly composed of fucopyranose. They are mainly distributed as a mucovesicuous fluid on the surface of brown algae.
In addition, the sea echinoderm also contains this component. According to different extraction methods, the molecular weight of fucoidan products can range from 200,000 to 2,000,000 (large) 20,000 to 200,000 (middle) or 400 to 5,000 (small) daltons, which is called low-molecular-weight fucoidan (LMF), soluble in water and acidic solutions.
The anti-cancer activity of fucoidan on cancer cells has caused worldwide attention such as in breast cancer cell (MCF and MDA-MB-231 cells), human bladder cancer cells (5637 and T-24 cells) and human prostate cancer cell (PC-3 cell).
We have previously reported fucoidan on the proliferation of cytotoxic activity in different cancer cells. Present study we continued to explore the molecular related pharmacological mechanism and its anti-cancer epigenetic regulation on gene expression.
We conducted the anti-cancer cytotoxicity of Fucoidan (Fu) with XTT and methylene blue methods at different concentrations (0,20,40,60,80,100 μg/ml) in human lung adenocarcinoma cells (A549) , humans hepatoma cells (HepG2) , humans breast cancer cells (MCF7) , human clear cell renal cell carcinoma (786-O) and renal cell carcinoma (A498).
Fu possessed cytotoxicity to five cancer cell lines . It have demonstrated as a dose-dependent response phenomenon. Since cell cycle and apoptosis modulation are necessary to regulate cell life and death, we examined the cell cycle regulation role of fucoidan.
It is shown that Fu cause cell cycle arrest in G1 phase and cycle-associated regulatory proteins such as cyclins (Cyclin D1/E) and its associated cyclin-dependent kinases (CDK; CDK2/4/6) were all observed have significant changes. Western blotting (WB) analysis also confirmed the the promote expression of G1 phase inhibitory P21 protein expression .
In the intrinsic pathway proapoptotic anti-apoptotic Bcl-2 proteins and extrinsic pathways signal proteins Fas, Fas ligand these death related signals and caspases were modulated by fucoidan and lead to cells apoptosis. Our results demonstrate that anti-cancer activity of fucoidan be attributed to cytotoxic effect, cell cycle G1 arrest and apoptosis induction and inhibition of metastasis.
To study the epigenetic regulation of cancer cell genes expression, we analyzed the signal transducer and activator of transcription 3 (STAT3) , nuclear factor-κB (NFκB) and HDAC (Histone deacetylase) which are involved in the processes of carcinogenesis.
The STAT family is responsible for conducting cell membrane signals to the nucleus. In particular, STAT3 causes the tumor cell to proliferate and malignancy progresses to be in an inflammatoary microenvironment where it develops and progresses.
NFκB is also an important transcription factor. It controls oncogene expression in proliferation, invasion, angiogenesis, and metastasis. NFκB and STAT3 synergistically promote cancer development through the induction of the oncogenes.
HDAC cause post-translational histone acetylation by removing
acetyl group of chromatin and diversify the transcription of oncogenes and tumor suppressor genes.
In this study, we investigate and compare anti-cancer activity of fucoidan with its cell cycle regulation, apoptosis-inducing effects, and nucleus transcription factors STAT3, NFκB and HDAC in human renal cancer cells to elucidate the molecular modulation of fucoidan in gene expression of anti-cancer modulation.
It is the first report of fucoidan on human renal cell carcinoma, our data have demonstrated that fucoidan may be a potential novel anti-cancer compound for renal cell carcinoma.
| Identifer | oai:union.ndltd.org:TW/106KMC05534031 |
| Date | January 2018 |
| Creators | Wei-Tung Lin, 林暐棟 |
| Contributors | Hui-Fen Chiu, 邱慧芬 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 92 |
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