臺灣博碩士論文加值系統

中文摘要
研究背景與目標:
以全球癌症流行病學而言，頭頸部鱗狀上皮細胞癌的盛行率占所有癌症的第六位，且許多患者會因這個疾病而死亡。在台灣，60-70% 的頭頸部鱗狀上皮細胞癌其原發部位來自口腔，又稱口腔癌。即使接受了合併手術、放射線治療以及化學治療，約只有一半的病患能達到長期存活。當口腔癌處於復發或轉移階段，存活時間中位數約只有7-10個月。因此，在口腔癌治療上仍有很大的進步空間。
蟲草素 (Cordycepin)是一種可以由中草藥”冬蟲夏草”提取出來的純化合物。在已知的研究結果中，蟲草素表現出包含了抗腫瘤在內的作用。本研究的目標分兩點:(一) 蟲草素能對口腔癌細胞有細胞毒殺及抑制生長的效果，並抑制癌症的上皮間質轉化(epithelial mesenchymal transition, EMT)特性。(二) 蟲草素能做為放射線增敏劑，加強放射線治療對口腔癌細胞毒殺作用。

研究材料與方法:
實驗中所使用口腔癌細胞株為SAS、OEC-M1、OC-3，正常組織對照細胞為人類纖維母細胞(HFW cell)及角質形成細胞(HaCaT cell)。
MTT 試驗用於測定蟲草素對細胞活性的影響，而colony formation試驗則是檢測加強放射線毒殺作用的效果。流式細胞儀用於確認細胞週期分布的比例。傷口癒合試驗(wound healing assay)用於評估細胞移動侵犯的能力。細胞凋亡則是由caspase-3 活性來測定。我們同時使用免疫螢光染色以及流式細胞儀來偵測γ-H2AX的存在，是一個DNA 雙股斷裂的指標。上皮間質轉化以及放射線治療後的DNA修補反應在分子層面的變化與探究則是藉由西方墨點法。蟲草素單獨使用或合併放射線對口腔癌細胞的治療效果，都再經由動物實驗驗證。

結果:
MTT試驗顯示，蟲草素可以抑制口腔癌細胞活性，並有隨劑量與時間增加而遞增的效應。形態學的評估以及caspase-3 活性增加，支持了蟲草素使口腔癌細胞進入細胞凋亡。單獨蟲草素的治療使得癌細胞細胞週期增加停留在 G2/M phase的比例，這個現象在合併放射線治療時更為顯著。蟲草素也減緩口腔癌細胞移動與侵犯的能力，而這個現象可由上皮指標E-cadherin表現量增加，間質指標N-cadherin表現量減少，所代表上皮間質轉化被抑制來解釋。上述現象也在動物實驗中腫瘤的免疫染色被驗證。而當蟲草素合併放射線治療時，可更抑制口腔癌細胞形成聚落能力。蟲草素也使得放射線治療所造成癌細胞DNA 雙股斷裂的時間延長，意即癌細胞修補DNA缺陷的能力下降。上述現象，與西方墨點法顯示共濟失調毛細血管擴張症突變激酶(ataxia-telangiectasia mutated, ATM)和檢查點激酶2 (checkpoint kinase 2, Chk2)的表現量下降相關。同時，蟲草素也增加了檢查點激酶1 (checkpoint kinase 1, Chk1)的表現，此現象可能會弱化蟲草素促進放射線毒性的能力。當以siRNA方法將癌細胞Chk1蛋白表現阻斷後，可再加強放射線毒殺細胞的效果而間接驗證上述推論。蟲草素無論是單獨給予或合併放射線治療，都能有效抑制口腔癌腫瘤在小鼠模式下的生長。同時在實驗中低劑量長時間給予的投藥方式，並無顯著的毒性產生。

結論:
由研究結果，蟲草素確實能藉由抑制上皮間質轉化現象，而破壞口腔癌細胞的活性及生長能力。蟲草素同時也經由對DNA損害反應路徑(DNA damage response pathway)的調控，來加強放射線治療對癌細胞的毒殺效果。以上蟲草素對於口腔癌抗癌效果，都在細胞及動物實驗中獲得驗證。

ABSTRACT
Study background and aim
Squamous cell carcinoma of the head and neck (SCCHN) is the 6th most common cancer and causes a major cancer-related mortality. In Taiwan, sixty-to-seventy percent of SCCHN arises from oral cavity, namely oral squamous cell carcinoma (OSCC). Despite combination treatments with surgery, radiotherapy (RT) and chemotherapy, the long term survival remains approximately 50%. Patients with recurrent or refractory diseases have even dismal prognosis with a median overall survival 7 to 10 months. There are great unmet medical needs in the OSCC treatment.
Cordycepin, one of the important pure compounds purified from the fungal medicinal herb Cordyceps sinensis, possesses anticancer activity through a variety of mechanisms. The aim of our study was to investigate if cordycepin exerts anti-cancer effect against oral cancer through inhibiting the epithelial mesenchymal transition (EMT) and enhancing the radiation response of OSCC cells.

Materials and Methods:
OSCC cell lines, include SAS, OEC-M1 and OC-3 were used in the study. We performed MTT and colony formation assay to test the cytotoxicity and radiosensitizing effects of cordycepin. The cell cycle analysis was performed by flow cytometry. The apoptotic effect was measured by caspase 3 activity assay. The migration inhibition was demonstrated by wound healing assay. Hallmark of RT induced DNA double strand break (DSB), γ-H2AX, was testified by immunofluorescence and flow cytometry. The molecular modulation of EMT process and DNA damage response were evaluated by Western blotting. Lastly, the anticancer effect was examined in the OSCC-bearing mice model.

Results:
Cordycepin inhibited the OSCC cell viability in a dose and time dependent manner. Morphological characteristics of apoptosis and increased caspase 3 activity were observed. Cell cycle arrested on G2/M phase by treating with cordycepin alone. Combination of cordycepin and RT further prolonged G2/M arrest. Delayed tumor cell migration and inhibited EMT process were demonstrated by decreased E-cadherin and increased N-cadherin expression. This EMT inhibition was further examined by the immunohistochemical stain of the xenograft tumors. Colony formation assay revealed that cordycepin potentiated the RT cytotoxic effects. The combination treatment also prolonged the DNA DSB repair. We found that cordycepin decreased expression of ataxia telangiectasia-mutated kinase and checkpoint kinase 2 protein to prevent appropriate DNA repair and cell cycle arrest. Reciprocal upregulation in the expression of checkpoint kinase 1(Chk1) might suggest a compensatory cell protection mechanism. Furthermore, we demonstrated the enhanced radiosensitizing effect through siRNA knockdown of the Chk1 protein. Metronomic administration of cordycepin inhibited the OSCC-bearing mice tumor growth. Cordycepin combination treatment further augmented the growth inhibitory activity of RT. No major toxicities of the metronomic dosing were observed.

Conclusion:
In our study, we concluded that cordycepin possesses anticancer effects against OSCC cells through EMT inhibition and DNA damage response modulation. Development of cordycepin into a novel metronomic therapeutic agent as well as a radiosensitizer against OSCC needs further investigation.

Contents
致謝------------------------------------------------i
Contents ------------------------------------------iii
List of Figures -----------------------------------vi
Abstract ------------------------------------------viii
中文摘要 -------------------------------------------xi
1. Introduction ----------------------------------1
1.1 Head and neck cancer: epidemiology ------------1
1.2 Head and neck cancer: treatments and unmet
medical needs ---------------------------------1
1.3 Hallmarks of cancer ---------------------------2
1.3.1 Programmed cell death (PCD) and apoptosis
-------------------------------------------3
1.3.2 Sustained proliferation and cell cycle
regulation --------------------------------5
1.3.3 Epithelial-mesenchymal transition and
metastasis --------------------------------7
1.4 Radiotherapy ----------------------------------9
1.4.1 Radiation biology and radioresistance -----9
1.4.2 DNA damage response -----------------------10
1.5 Concept of metronomic therapy -----------------12
1.6 Traditional Chinese medicine (TCM) with
anticancer effects ----------------------------13
1.6.1 Cordyceps Sinensis and cordycepin ---------13
1.7 Hypothesis and aim of the study ---------------14

2.Materials and methods ---------------------------15
2.1. Chemicals and reagents -----------------------15
2.2. Cell lines and cell culture ------------------16
2.3. Cell viability measurement: MTT assay --------17
2.4. Cell morphology: Liu`s stain -----------------17
2.5. Apoptosis cell death : Caspase 3 activity assay
----------------------------------------------17
2.6. Cell Cycle Analysis --------------------------18
2.7. Cell migration: wound healing assay ----------19
2.8. Colony formation assay -----------------------19
2.9. Immunofluorescence analysis of γH2AX ---------20
2.10. Flow cytometric analysis of γH2AX -----------20
2.11. Western blot analysis -----------------------21
2.12. Chk1 siRNA knockdown and colony formation
assay ---------------------------------------22
2.13. Animals and in vivo experiments -------------22
2.14. Immunohistochemistry staining of xenograft
tumor ---------------------------------------24
2.15. Statistical analysis ------------------------25

3.Results -----------------------------------------25
3.1. Cordycepin exerted growth inhibition on OSCC -25
3.2. Cordycepin induced OSCC apoptosis ------------26
3.3. Cordycepin resulted in G2/M arrest -----------26
3.4. Combined cordycepin and radiotherapy treatment
further prolonged the G2/M phase arrest ------27
3.5. Cordycepin delayed wound closure by inhibiting
EMT process ----------------------------------27
3.6. Cordycepin inhibited xenograft tumor growth and
prolonged survival ---------------------------28
3.7. Validation of EMT inhibition by Cordycepin in
xenograft tumor ------------------------------28
3.8. Cordycepin enhanced radiosensitivity of OSCC
cells ----------------------------------------29
3.9. Cordycepin protracted radiotherapy-induced DNA
double stand break ---------------------------29
3.10.Cordycepin enhanced radiotherapy effects
through the DNA damage repair machinery ------30
3.11.Knockdown of Chk1 sensitized the OSCC cells to
combined radiation and cordycepin treatment---30
3.12.Combined radiotherapy and cordycepin treatment
improved OSCC xenograft tumor control --------31
3.13.Cordycepin plus irradiation promoted apoptosis
of the OSCC tumor cells ----------------------32

4.Discussion --------------------------------------32
4.1. Pro-apoptotic effects of cordycepin ----------32
4.2. Anti-EMT effects of cordycepin ---------------33
4.3. Cell cycle and DNA damage response modulation
by cordycepin --------------------------------35
4.4. Metronomic schedule of cordycepin in xenograft
model ----------------------------------------38
4.5. Anti-cancer development of cordycepin and its
derivatives ----------------------------------39

5. Conclusion -------------------------------------40
Reference -----------------------------------------41

List of Figures
Figure 1 Cordycepin inhibited oral cancer cell
proliferation ---------------------------71
Figure 2 Cordycepin triggered apoptosis in two
OSCC cell lines, but not human fibroblasts
-----------------------------------------72
Figure 3 Cordycepin resulted in OSCC cell cycle
arrest at G2/M phase --------------------74
Figure 4 Combined cordycepin and RT treatment
prolonged G2/M phase arrest of OSCC cells
-----------------------------------------76
Figure 5 Cordycepin inhibited the migration ability
of OSCC cells through EMT prohibition ---77
Figure 6 Cordycepin treatment inhibited tumor
growth, prolonged survival time and
maintained organ functions --------------80
Figure 7 Cordycepin prohibited EMT in xenograft
tumors ----------------------------------82
Figure 8 Cordycepin enhanced the radiosensitivity
of the OSCC cells -----------------------83
Figure 9 Combined cordycepin and RT treatment
prolonged the presence of γ-H2AX, a
biomarker of double strand breaks -------84
Figure 10 Cordycepin enhanced radiation toxicity
through the regulation of DNA damage
response proteins -----------------------86
Figure 11 Chk1 protein knockdown sensitized the OSCC
cells to cordycepin and RT treatment ----87
Figure 12 Cordycepin in combination with RT delayed
the OSCC tumor growth in the xenograft
model -----------------------------------89
Figure 13 Cordycepin plus radiotherapy increased
apoptosis in OSCC tumor cells -----------91
Figure 14 Anticancer mechanisms of cordycepin
against oral cancer ---------------------93

Appendix
1. Metronomic cordycepin therapy prolongs survival of
oral cancer-bearing mice and inhibits epithelial-
mesenchymal transition. Molecules. 2017 Apr. 13;
22(4). Pii: E629. doi: 10.3390/molecules22040629.

2. Cordycepin, isolated from medicinal fungus Cordyceps
sinensis, enhances radiosensitivity of oral cancer
associated with modulation of DNA damage repair. Food
Chem Toxicol. 2019 Feb; 124:400-410.
doi: 10.1016/j.fct.2018.12.025.

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