microRNAs作為放射治療預後之生物標誌物與miR-148a-3p於頭頸癌放射敏感度之研究

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姓名

李安倫(An-Lun Li) 查詢紙本館藏

畢業系所

系統生物與生物資訊研究所

論文名稱

microRNAs作為放射治療預後之生物標誌物與miR-148a-3p於頭頸癌放射敏感度之研究
(The study of the microRNAs as the prognostic biomarkers for the radiotherapy and the radiation effects of miR-148a-3p in head and neck cancer)

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至系統瀏覽論文 (2027-2-21以後開放)

摘要(中)

放射線治療為頭頸癌及直腸癌常用的治療方法，腫瘤復發仍是導致預後不佳的主要原因，且目前臨床上欠缺有效的方法評估病人的預後。微型RNA（microRNA）被發現參與在基因轉錄後的調控，此外微型RNA被包裹於胞外小體（Extracellular Vesicles）釋放至體液中，藉此扮演訊息傳遞的角色，因而成為液態切片（Liquid Biopsy）重要的一環。文獻中尚無完整的報導關於血液微型RNA的表現量用來評斷放射線治療預後，並近一步探討微型RNA於細胞內的功能與機制。所以我們探尋血液中的微型RNA的表現量，嘗試以量化方法開發血液生物標記，同時也藉由細胞實驗暸解微型RNA參與在放射線抗性的功能與角色。
在此研究中，先透過高通量的方法先篩選出22個表現量可能與預後不良有關的血液微型RNA，其中有9個微型RNA的表現量在治療後有顯著改變，我們也發現發現3個微型RNA的表現量與4種微型RNA比值和預後不良有顯著關係。透過公開數據庫調查頭頸癌組織中微型RNA的表現量，結果發現miR-519d-3p的表現量與癌症的五年存活率有顯著相關。最後利用血液中的微型RNA比值、腫瘤期別等資料，以邏輯式回歸（logistic regression）建立2種預測模型，用來預測治療6個月的預後狀態。
放射線治療主要的機制是讓細胞中DNA斷裂，進一步激活DNA損傷反應（DNA damage response）促使細胞凋亡或細胞週期停滯。在我們發現的微型RNA中， miR-342-5p、miR-148a-3p、miR-323a-3p等3個微型RNA先前並無調控放射線抗性、DNA損傷反應及其下游的訊息傳遞之相關研究。我們針對miR-148a-3p深入探討如何在頭頸癌中調控放射線抗性，以及可能的機制。結果發現細胞照射放射線後miR-148a-3p表現量顯著降低。相反的，過度表現miR-148a-3p並照射放射線可以抑制癌細胞增殖、遷移能力，另外也觀察到細胞中DNA損傷及基因組不穩定性增加。我們發現miR-148a-3p可能藉由調控ITGA5、14-3-3或釋放至培養基中（Conditional media）與其他細胞進行訊息傳遞，最終改變腫瘤放射線抗性。有趣的是，研究中也發現放射線會降低細胞miR-148a-3p的釋放量，促進未照射放射線癌細胞增殖、遷移等能力（bystander effect）。相反的提高培養基中miR-148a-3p含量，則可以抑制此現象。這些結果顯示了癌細胞可以藉由miR-148a-3p表現量調控頭頸癌的放射線抗性，並透過釋放miR-148a-3p改變腫瘤微環境（tumor microenvironment）。

摘要(英)

Radiotherapy is a common type of cancer treatment used for treating head and neck cancer (HNSCC), and rectal cancer (RC). Unfortunately, the local recurrence or metastasis leads to treatment failure. Today, there are no effective methods for evaluating the risk of cancer recurrence. MicroRNAs (miRNA) are involved in post-transcriptional gene regulation. In addition, miRNAs are packed into extracellular vesicles and released into the body fluids that have played a role in cell communication. Hence, the miRNA expression in the body fluids is considered a potential target of liquid biopsy. To date, no research has suggested that the miRNA expression in the blood could regulate cancer radiosensitivity or play the role of message transport. Therefore, we have discovered miRNA as a blood biomarker by investigating the miRNA expression level in the plasma samples. Also, the candidate miRNA expression in plasma could be considered an important indicator for promoting radioresistant.
In this research, the high-throughput method was used to select the 22 miRNAs as the candidates for radiation response. Nine miRNAs’ expressions showed a significant change after radiotherapy. Furthermore, the expression level of three miRNAs and the four miRNA ratios significantly changes in the poor responsive group. The public data also showed the expression of miR-519d-3p in the tissue of HNSCC is associated with a 5-year survival period. Finally, two prediction models were established for predicting the response of radiotherapy after six months of treatment by multiple logistic regression.
DNA breaks are the majorly caused by radiotherapy. This occurrence induces cell apoptosis and cell-cycle arrest by the DNA damage response. In chapter three, the activities of three miRNAs, including miR-342-5p, miR-148a-3p, and miR-323a-3p, involved in the radioresistance or regulation of the genes by DNA damage response remain unclear. We delved into the radiation effect of miR-148a-3p in HNSCC. The result showed that the expression level of miR-148a-3p was significantly decreased by radiation in the HNSCC cell line. Moreover, overexpression of the miR-148a-3p increased the radiation effect by the tests of cell viability, migration, and colony formation ability. Furthermore, immunofluorescence staining showed that miR-148a-3p also increased the DNA damage level further causing genome instability. MiR-148a-3p may regulate integrin alpha 5 (ITGA5), Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), 14-3-3, and increase the effect of radiation. Interestingly, miR-148a-3p are released into the conditioned media (CM). Radiation suppresses the release of miR-148a-3p in CM and further induces the cell viability and migration ability of non-radiated bystander cells. Moreover, a high expression level of miR-148a-3p in CM inhibits these effects.
Taken together, the in vivo study shows that miR-148a-3p may not only play an important role in the radiation effect but may change the signaling of miR-148a-3p in tumor microenvironments.

關鍵字(中)

★ 微型核糖核酸
★ 癌症
★ 放射線治療
★ 生物標記
★ 治療預後
★ 旁觀者效應

關鍵字(英)

★ microRNA
★ Cancer
★ Radiotherapy
★ Biomarker
★ Prognosis
★ Bystander effect

論文目次

中文摘要 VI
ABSTRACT VIII
LIST OF FIGURES XIV
LIST OF TABLES XVI
LIST OF ABBREVIATIONS (ALPHABETICAL ORDER) XVII
CHAPTER 1: LITERATURE REVIEW 1
1.1. Introduction to radiotherapy 1
1.1.1. Radiotherapy for cancer 1
1.1.2. Radioresistance of cancer 2
1.1.3. Radiotherapy induced bystander effect 3
1.1.4. DNA damage and repair in radiotherapy 4
1.2. Introduction to HNSCC 5
1.2.1. Signs and symptoms of HNSCC 5
1.2.2. The radiotherapy for HNSCC 6
1.3. Introduction to RC 6
1.3.1. Signs and symptoms of RC 6
1.3.2. The radiotherapy for RC 7
1.4. Introduction to microRNA (miRNA) 7
1.4.1. Biogenesis and mechanism of miRNA 8
1.4.2. miRNA dysregulation in disease 8
1.4.3. The miRNA in extracellular vesicles 9
1.5. Significances and purpose 9
CHAPTER 2: MATERIALS AND METHODS 22
2.1. Patient recruitments 22
2.2. Ethics approval and informed consent 22
2.3. Plasma preparation and miRNA isolation and quantification by RT-PCR 22
2.4. Cells Culturing and maintaining 23
2.5. Radiation treatment on culture cells 23
2.6. miRNA mimic transfection 24
2.7. Colony formation assay 24
2.8. Cell proliferation assay 25
2.9. Wound healing assay 25
2.10. microRNA target prediction 25
2.11. Western blotting 26
2.12. Immunofluorescence and micronucleus staining 26
2.13. Conditioned medium (CM) transfer 27
2.14. Overall survival curve and statistical analysis 27
CHAPTER 3: THE MIRNA CLASSIFIERS AS THE ANCILLARY PROGNOSTIC SIGNATURE FOR RADIOTHERAPY 29
3.1. Introduction 29
3.2. Results 30
3.2.1. Identification of candidate miRNAs in plasma to differentially expressed between poor response and response groups of radiotherapy. 30
3.2.2. Changes in miRNA expression levels upon radiotherapy 31
3.2.3. miRNAs expression levels linked to radiotherapy responses 31
3.2.4. Ratio analysis for candidate miRNAs in plasma 32
3.2.5. Two classifiers for predicting the response of radiotherapy 33
3.3. Discussion 34
CHAPTER 4: MIR-148A-3P: POTENTIAL TARGETS FOR THE DEVELOPMENT OF A RADIOSENSITIZER 52
4.1. Introduction 52
4.2. Results 53
4.2.1. Candidate miRNAs induce radiosensitivity by cell viability assay in HNSCC 53
4.2.2. Association of miR-148a-3p expression and radiation response 54
4.2.3. miR-148a-3p enhances the radiosensitivity by wound healing assay upon radiation 55
4.2.4. miR-148a-3p induces DNA damage and decreases the genome stability upon radiation 56
4.2.5. 14-3-3, ITGA5, and ROCK1 are the potential targets of miR-148a-3p 57
4.2.6. Low expression of miR-148a-3p is observed in radiated conditional media, which could cause a bystander effect 57
4.2.7. Expression of miR-148a-3p in non-radiated cells regulate the bystander effect 58
4.3. Discussion 60
CHAPTER 5: CONCLUDING REMARKS AND FUTURE DIRECTION 86
5.1. Conclusion remarks 86
5.2. Future direction 88
5.2.1. To investigate the mechanisms of miR-148a-3p involved in radiosensitivity. 88
5.2.2. To investigate whether the miR-148a-3p are packed in the EVs, further causing bystander effect 91
5.2.3. To know the upstream regulator of miR-148a-3p 93
CHAPTER 6: REFERENCES 100
CHAPTER 7: APPENDIX 114
7.1. Publication list 114
7.2. Patient list 115
7.2.1. 中華民國 115
7.2.2. 美國 115

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指導教授

馬念涵(Nianhan Ma)

審核日期

2022-2-11

推文