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顺铂新辅助化疗通过MMP14介导的EMT激活上调GSDMD以增强口腔鳞状细胞癌转移

Neoadjuvant Chemotherapy With Cisplatin Up-Regulates GSDMD to Enhance Oral Squamous Cell Carcinoma Metastasis Through MMP14-Mediated EMT Activation.

作者信息

Huang Zixian, Jiang Qiming, Zhang Qianyu, Lu Nan, Rui Xi, Chen Rui, Wang Yan, Wang Yuepeng, Xu Xiaoding, Huang Zhiquan

机构信息

Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.

出版信息

Adv Sci (Weinh). 2025 Jul;12(25):e2501149. doi: 10.1002/advs.202501149. Epub 2025 Apr 3.

DOI:10.1002/advs.202501149
PMID:40178046
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12224931/
Abstract

Neoadjuvant chemotherapy has been widely used for the treatment of solid tumors. However, clinical observations have shown that patients with oral squamous cell carcinoma (OSCC) who are receiving neoadjuvant chemotherapy with cisplatin still face issues such as a poor lymph node response and even lymph node progression, but the underlying mechanisms remain unidentified. In this work, it is found that low-dose cisplatin promoted oral squamous cell carcinoma migration, invasion and lymph node metastasis, and gasdermin D (GSDMD) is identified as a potential regulator. GSDMD interacted with MMP14, promoting its expression and epithelial‒mesenchymal transition (EMT) activation without activating pyroptosis. Moreover, pH-responsive nanoparticles (NPs) for the systemic delivery of a GSDMD siRNA (siGSDMD) is developed and showed that this NP-delivered siGSDMD can effectively inhibit OSCC tumor growth and metastasis via the efficient silencing of GSDMD expression in vivo. This findings indicate that GSDMD can be a biomarker to predict the prognosis of OSCC patients receiving neoadjuvant chemotherapy and that NP-mediated GSDMD silencing can be a promising strategy for the treatment of patients with advanced OSCC receiving neoadjuvant chemotherapy with cisplatin.

摘要

新辅助化疗已广泛应用于实体瘤的治疗。然而，临床观察表明，接受顺铂新辅助化疗的口腔鳞状细胞癌（OSCC）患者仍面临淋巴结反应不佳甚至淋巴结进展等问题，但其潜在机制尚不清楚。在这项研究中，发现低剂量顺铂促进口腔鳞状细胞癌的迁移、侵袭和淋巴结转移，并确定gasdermin D（GSDMD）为潜在调节因子。GSDMD与MMP14相互作用，促进其表达并激活上皮-间质转化（EMT），而不激活细胞焦亡。此外，还开发了用于全身递送GSDMD siRNA（siGSDMD）的pH响应纳米颗粒（NPs），结果表明这种NP递送的siGSDMD可通过在体内有效沉默GSDMD表达来有效抑制OSCC肿瘤生长和转移。这些发现表明，GSDMD可作为预测接受新辅助化疗的OSCC患者预后的生物标志物，并且NP介导的GSDMD沉默可能是治疗接受顺铂新辅助化疗的晚期OSCC患者的一种有前景的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/08e3a718b56f/ADVS-12-2501149-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/bf1867e2b5ca/ADVS-12-2501149-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/e9a45a4930e2/ADVS-12-2501149-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/6a7f49b1fa86/ADVS-12-2501149-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/0f9c87145aa0/ADVS-12-2501149-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/680d1c5a6297/ADVS-12-2501149-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/e79017e6c273/ADVS-12-2501149-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/08e3a718b56f/ADVS-12-2501149-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/bf1867e2b5ca/ADVS-12-2501149-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/e9a45a4930e2/ADVS-12-2501149-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/6a7f49b1fa86/ADVS-12-2501149-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/0f9c87145aa0/ADVS-12-2501149-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/680d1c5a6297/ADVS-12-2501149-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/e79017e6c273/ADVS-12-2501149-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/769a/12224931/08e3a718b56f/ADVS-12-2501149-g006.jpg

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本文引用的文献

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Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial.卡瑞利珠单抗联合白蛋白结合型紫杉醇和顺铂用于可切除局部晚期头颈部鳞状细胞癌的新辅助化疗免疫治疗：一项II期试点试验
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Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer.
比较紫杉烷类药物联合铂类与紫杉烷类药物联合铂类和 5-FU 在局部可切除口腔癌新辅助化疗中的 3 期 RCT。
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Immunohistochemical Assessment of Microvessel Density in OSCC: Spatial Heterogeneity of Angiogenesis and Its Impact on Survival.口腔鳞状细胞癌微血管密度的免疫组织化学评估：血管生成的空间异质性及其对生存的影响
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