探究頭頸癌生長、轉移的機轉
第一部分: Drp1 的敲低表現經由抑制FOXM1和MMP12 的表達, 有助於抑制頭頸癌的生長和轉移
Drp1的異常表達已在多種人類癌症中被發現，並可預測不良預後。Drp1在頭頸癌(HNC)發展中的病理特徵及機制尚不完全清楚。在本研究中，我們證明了頭頸癌組織中Drp1的表現顯著上升及其表現與頭頸癌患者較差的生存相關。在體外和體內模型中，Drp1的減少抑制了腫瘤的生長和轉移。此外，我們還探索了miR-575可以靶向Drp1 mRNA的3’UTR，並減弱Drp1蛋白的表達。機制研究表明，Drp1通過增加轉錄因子FOXM1與MMP12啓動子區域的特異性結合，在轉錄水平上調控MMP12。臨床結果顯示，Drp1的表達與FOXM1和MMP12在頭頸癌腫瘤組織中的表達呈正相關，提示其與頭頸癌發生過程中病理的相關性。總的來說，我們的研究為Drp1的作用提供了新的觀點，並強調了靶向miR-575/Drp1/FOXM1/MMP12軸作為中斷頭頸癌進展的新療法。
II. 探究鼻咽癌病人放射治療後慢性副作用
第二部分: 鼻咽癌病人接受放射治療後對頸動脈壁內膜厚度的長期影響
血管異常是鼻咽癌病人接受放射治療後顯著的組織學變化。本篇研究是檢測放射治療後的時間長短是否與頸動脈壁厚度(IMT)的進展有關，同時研究其與發炎指標的相關性。收錄經放射治療後超過一年以上的一佰零五位鼻咽癌病人及二十五位健康的成人，利用B-mode超音波測量總頸動脈外壁(CCA)的頸動脈壁厚度。結果發現在所有鼻咽癌病人，總頸動脈外壁的頸動脈壁厚度的增加與放射治療後的時間長短是呈現正相關。總結來說: 因為放射治療的慢性副作用，放射治療引起的血管病變是一個動態且持續進展的過程。在年齡大於五十歲及放射治療後四十個月的鼻咽癌病人，顱外彩色都普勒超音波可以是正規追蹤檢查的一部份。
第三部分: 放射治療後的鼻咽癌病人, 頸部放射治療對於心血管自主功能的長期影響
壓力反射是鼻咽癌病人頸部放射治療後的慢性後遺症。本篇研究是檢測鼻咽癌病人放射治療後的心血管自主功能，以便檢測其相關結果與預測因子。收錄經放射治療後超過六個月以上的八十九位的鼻咽癌病人，與四十八位健康成人相比較其心血管自主功能，同時評估發炎因子與頸動脈壁厚度(IMT)。
本篇研究顯示在鼻咽癌病人，心跳速率對於經深呼吸及瓦爾賽薩爾瓦(Valsalva)比率的反應，其自主功能的參數是顯著降低。心血管自主功能不足，普遍與心血管迷走神經傳輸相對不足有相關。此外，本篇研究也顯示放射治療後的時間及C-反應蛋白質的數值與心血管自主功能異常有顯著相關。總結來說: 放射治療引起的心血管自主功能的降低是放射治療後一個動態且持續進展的過程。慢性發炎反應在這過程扮演一個非常重要的角色。

My dissertation includes three parts. The first part is focused on Drp1 knockdown contributes to the suppression of head and neck cancer growth and metastasis by inhibiting FOXM1 and MMP12 expression. The second part is focused on the long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma. The third part is focused on the long-term effects of neck irradiation on cardiovascular autonomic function: a study in patients with NPC after radiotherapy.

I. Dissecting the growth and metastasis mechanism of head and neck cancer (HNC)
Section I: Drp1 knockdown contributes to the suppression of head and neck cancer growth and metastasis by inhibiting FOXM1 and MMP12 expression
Abnormal Drp1 expression is usually disclosed in various human cancers and correlated to a poor prognosis. At the present, the clinical-pathological characteristics and underlying mechanism of Drp1 in the development of head and neck cancer (HNC) are not fully understood. Therefore, we demonstrated a significant overexpression of Drp1 in HNC tissues. Moreover, its overexpression correlated with poor survival in the patients with HNC. Silenced Drp1 suppressed tumor growth and metastasis in vitro and in vivo. In addition, we found that miR-575 could target the 3’UTR of Drp1 messenger ribonucleic acid (mRNA) and reduce Drp1 protein expression. By increasing the specific binding of the transcription factor FOXM1 to the MMP12 promoter region, MMP12 was upregulated by Drp1 at a transcriptional level in the mechanistic research. Clinical pathologic tissues stains demonstrated that Drp1 expression positively related to FOXM1 and MMP12 expression in HNC tumor tissues, suggesting its pathological results in the connection of HNC development. In conclusion, our research offers mechanistic perception into the role of Drp1 and demonstrates the potential of targeting the miR-575/Drp1/FOXM1/MMP12 axis as a novel therapy for the discontinuation of HNC progression.
II. Exploring the chronic side-effects after radiotherapy in patients with nasopharyngeal cancer
Section II: Long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma
Vasculopathy is the most noticeable histologic change associated with nasopharyngeal carcinoma (NPC) after radiotherapy. In the present study, we demonstrated that the duration after radiotherapy correlates with the progression of carotid intima-media thickness (IMT) and explored its relationship with inflammatory markers. We
examined one hundred and five patients with NPC after radiotherapy for over a year and 25 healthy control subjects were examined by B-mode ultrasound for IMT measurement at the far wall of the common carotid artery (CCA). We found that increased IMT was associated with the duration after radiotherapy in a linear manner. In conclusion, radiation-induced vasculopathy is a dynamic and progressive process caused by late radiation effects. Extracranial color-coded duplex sonography should be arranged to the part of routine follow-up in patients with NPC aged ≥50 years at 40 months post-radiotherapy.
Section III: Long-term effects of neck irradiation on cardiovascular autonomic function: a study in patients with NPC after radiotherapy
Baroreflex was explored as a late sequela of neck radiotherapy in patients with NPC.
In the present study, we demonstrated the cardiovascular autonomic function in patients with NPC after radiotherapy to examine the predictive factors associated with the outcome. We evaluated 89 patients with NPC more than six months after radiotherapy for cardiovascular autonomic function and compared with 48 control healthy subjects. Inflammatory markers and carotid IMT were also evaluated.
The studies showed that the autonomic parameters including heart rate response to deep breathing and the Valsalva ratio were significantly lower in the patient group compared to the control group. Cardiovascular autonomic impairment was generally mild with relative sparing of the efferent cardiovagal pathway. We also found that the time after radiotherapy and C-reactive protein level were significantly associated with the degree of cardiovascular autonomic dysfunction. Collectively, our study demonstrated that radiation-induced cardiovascular autonomic impairment is a dynamic and progressive process that occurs in patients with NPC long after radiotherapy. Chronic inflammation also plays a predominant role in this course.

Section I: Drp1 knockdown contributes to the suppression of head and neck cancer growth and metastasis by inhibiting FOXM1 and MMP12 expression
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Section II: Long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma
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