Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress.
Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress.
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作者：
Hai B;Zhao Q;Deveau MA;Liu F
基本原理：不可逆的唾液腺功能减退或口干症在接受放射治疗的头颈部癌症幸存者中很常见，即使应用各种新技术以最小化辐射（IR）损伤。这种情况严重损害了患者的生活质量，只能通过目前的治疗暂时缓解。近年来，我们发现胰岛素抵抗（IR）后唾液腺中的Sonic Hedgehog（Shh）的瞬时表达可以恢复唾液腺的功能，但其机制尚不完全清楚。研究方法：建立IR诱导的小鼠少涎模型，IR后3d，将携带Shh或对照GFP基因的腺病毒载体通过逆行导管滴注法导入下颌下腺（SMG），通过衰老相关β-半乳糖苷酶测定和衰老标志物表达来评价细胞衰老。通过qRT-PCR、Western blot和免疫荧光染色检测DNA损伤、氧化应激和相关基因的表达来探讨其机制。结果如下：Shh基因转移通过促进DNA修复和降低氧化应激来抑制IR诱导的细胞衰老，这是通过上调与DNA修复相关的基因（如survivin和miR-21）的表达以及抑制可能位于miR-21下游的促衰老基因Gdf 15的表达来介导的。结论：抑制细胞衰老有助于通过Hh信号的瞬时激活来拯救IR诱导的唾液过少，这与SMG中增强的DNA修复和降低的氧化应激有关。
Rationale: Irreversible hypofunction of salivary glands or xerostomia is common in head and neck cancer survivors treated with radiotherapy even when various new techniques are applied to minimize the irradiation (IR) damage. This condition severely impairs the quality of life of patients and can only be temporarily relieved with current treatments. We found recently that transient expression of Sonic Hedgehog (Shh) in salivary glands after IR rescued salivary function, but the underlying mechanisms are not totally clear. Methods: We generated a mouse model of IR-induced hyposalivation, and delivered adenoviral vectors carrying Shh or control GFP gene into submandibular glands (SMGs) via retrograde ductal instillation 3 days after IR. The cellular senescence was evaluated by senescence-associated beta-galactosidase assay and the expression of senescence markers. The underlying mechanisms were explored by examining DNA damage, oxidative stress, and the expression of related genes by qRT-PCR, Western blot and immunofluorescent staining. Results: Shh gene transfer repressed IR-induced cellular senescence by promoting DNA repair and decreasing oxidative stress, which is mediated through upregulating expression of genes related to DNA repair such as survivin and miR-21 and repressing expression of pro-senescence gene Gdf15 likely downstream of miR-21. Conclusion: Repressing cellular senescence contributes to the rescue of IR-induced hyposalivation by transient activation of Hh signaling, which is related to enhanced DNA repair and decreased oxidative stress in SMGs.
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影响因子：
11.8
作者：
Chou, Ruey-Hwang;Wang, Ying-Nai;Hsieh, Yi-Hsien;Li, Long-Yuan;Xia, Weiya;Chang, Wei-Chao;Chang, Ling-Chu;Cheng, Chien-Chia;Lai, Chien-Chen;Hsu, Jennifer L.;Chang, Wei-Jung;Chiang, Shu-Ya;Lee, Hong-Jen;Liao, Hsin-Wei;Chuang, Pei-Huan;Chen, Hui-Yu;Wang, Hung-Ling;Kuo, Sheng-Chu;Chen, Chung-Hsuan;Yu, Yung-Luen;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
--
作者：
Li YL;Chang JT;Lee LY;Fan KH;Lu YC;Li YC;Chiang CH;You GR;Chen HY;Cheng AJ
通讯作者：
Cheng AJ
影响因子：
4
作者：
Hai, Bo;Yang, Zhenhua;Liu, Fei
通讯作者：
Liu, Fei
DOI：
10.1016/j.ijrobp.2004.12.051
发表时间：
2005-07-15
影响因子：
7
作者：
Konings, AWT;Coppes, RP;Vissink, A
通讯作者：
Vissink, A
影响因子：
4.6
作者：
Chen KY;Chiu CH;Wang LC
通讯作者：
Wang LC