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Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress

International Journal of oral Science 2021年第1期13卷 108-116页

作者： Wen Chen Chenzhou Wu Yafei Chen Yuhao Guo Ling Qiu Zhe Liu Haibin Sun Siyu Chen Zijian An Zhuoyuan Zhang Yi Li Longjiang Li State Key Laboratory of oral Diseases&National Clinical Research Center for oral Diseases&department of head and neck oncology West China Hospital of StomatologySichuan UniversityChengduChina Department of Oral and Maxillofacial-Head and Neck Oncology Capital Medical University School of StomatologyBeijingChina

C18 ceramide plays an important role in the occurrence and development of oral squamous cell carcinoma.However,the function of ceramide synthase 1,a key enzyme in C18 ceramide synthesis,in oral squamous cell carcinoma is still unclear.The aim of our study was to investigate the relationship between ceramide synthase 1 and oral cancer.In this study,we found that the expression of ceramide synthase 1 was downregulated in oral cancer tissues and cell lines.In a mouse oral squamous cell carcinoma model induced by 4-nitroquinolin-1-oxide,ceramide synthase 1 knockout was associated with the severity of oral malignant transformation.Immunohistochemical studies showed significant upregulation of PCNA,MMP2,MMP9,and BCL2 expression and downregulation of BAX expression in the pathological hyperplastic area.In addition,ceramide synthase 1 knockdown promoted cell proliferation,migration,and invasion in vitro.Overexpression of CERS1 obtained the opposite effect.Ceramide synthase 1 knockdown caused endoplasmic reticulum stress and induced the VEGFA upregulation.Activating transcription factor 4 is responsible for ceramide synthase 1 knockdown caused VEGFA transcriptional upregulation.In addition,mild endoplasmic reticulum stress caused by ceramide synthase 1 knockdown could induce cisplatin resistance.Taken together,our study suggests that ceramide synthase 1 is downregulated in oral cancer and promotes the aggressiveness of oral squamous cell carcinoma and chemotherapeutic drug resistance.

关键词： endoplasmic cancer reticulum

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Electrochemical flow aziridination of unactivated alkenes

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National Science Review 2023年第10期10卷 86-95页

作者：王盛淳王鹏杰李树劲陈宜鸿孙志军雷爱文 Institute for Advanced Studies (IAS) College of Chemistry and Molecular SciencesWuhan University State Key Laboratory of oral & maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School & Hospital of Stomatology Wuhan University department of oral maxillofacial-head neck oncology School and Hospital of Stomatology Wuhan University

Aziridines derived from bioactive molecules may have unique pharmacological activities,making them useful in pharmacology(e.***.mitomycin C).Furthermore,the substitution of the epoxide moiety in epothilone B with aziridine,an analog of epoxides,yielded a pronounced enhancement in its anticancer efficacy.Thus,there is interest in developing novel synthetic technologies to produce aziridines from bioactive molecules.However,known methods usually require metal catalysts,stoichiometric oxidants and/or pre-functionalized amination reagents,causing difficulty in application.A practical approach without a metal catalyst and extra-oxidant for the aziridination of bioactive molecules is in demand,yet challenging.Herein,we report an ele ctro-oxidative flow protocol that accomplishes an oxidant-free aziridination of natural products.This process is achieved by an oxidative sulfonamide/alkene cross-coupling,in which sulfonamide and alkene undergo simultaneous oxidation or alkene is oxidized preferentially.Further anticancer treatments in cell lines have demonstrated the pharmacological activities of these aziridines,supporting the potential of this method for drug discovery.

关键词： alkene aziridination electro-oxidative cross-coupling flow chemistry N -centered radical alkene radical cation

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Recurrence and cancerization of ameloblastoma: multivariate analysis of 87 recurrent craniofacial ameloblastoma to assess risk factors associated with early recurrence and secondary ameloblastic carcinoma

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Chinese Journal of Cancer Research 2017年第3期29卷 189-195页

作者： Rong Yang Zheqi Liu Sandhya Gokavarapu Canbang Peng Wei Cao Tong Ji Department of Oral and Maxillofacial-Head and Neck Oncology Shanghai Stomatology Key LaboratoryShanghai Ninth People's HospitalShanghai Jiao Tong University School of Medicine head&neck oncology Reconstructive Surgery Department of Surgical OncologyKrishna Institute of Medical Science

Objective: The recurrence and progression of ameloblastoma are unpredictable. Therefore, we examined the influence of clinical factors on recurrence time and analyzed the clinical factors associated with early recurrence and cancerization. We then developed a staging system to predict early recurrence and cancerization. Methods: All of the primary craniofacial ameloblastoma patients treated in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine were recorded. There were 87 recurrent cases used to create a staging system and tested in a Cox regression analysis for risk factors associated with early recurrence or cancerization following surgery. Results: There were 890 craniofacial ameloblastoma patients, and 72 cases had recurrence. There were also 15 cases with cancerous recurrence. The overall recurrence rate was 9.78%, and the cancer rate was 1.69%. The primary cases were classified into the following 3 stages based on clinicopathological features: stage I, the maximum tumor diameter 6 cm or tumor invasion to the maxilla sinus/orbital floor/soft tissue; and stage III, tumor invasion of the skull base or metastasis into regional lymph nodes. When the method of surgery was controlled by partial correlation, the staging had significance with recurrence time (P=0.004). The Cox analysis showed the tumor stage was correlated with recurrence time (P=0.027) and cancerization time (P=0.002). However, the surgical method did not influence the recurrence time when adjusted for cofounding variables. Conclusions: Tumor larger than 6 cm and invasion to soft tissues or adjacent anatomical structures are associated with early recurrence. This staging system can be used to predict the risk factors of early recurrence and cancerization in ameloblastoma patients.

关键词： Recurrence ameloblastoma stage ameloblastic carcinoma cancerization

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Sustained delivery of vascular endothelial growth factor mediated by bioactive methacrylic anhydride hydrogel accelerates peripheral nerve regeneration after crush injury

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Neural Regeneration Research 2022年第9期17卷 2064-2071页

作者： Wanlin Xu Yifan Wu Hao Lu Yun Zhu Jinhai Ye Wenjun Yang Department of Oral and Maxillofacial-Head and Neck Oncology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghaiChina Jiangsu Key Laboratory of oral Diseases Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina

Neurotrophic factors,currently administered orally or by intravenous drip or intramuscular injection,are the main method for the treatment of peripheral nerve crush injury.However,the low effective drug concentration arriving at the injury site results in unsatisfactory outcomes.Therefore,there is an urgent need for a treatment method that can increase the effective drug concentration in the injured area.In this study,we first fabricated a gelatin modified by methacrylic anhydride hydrogel and loaded it with vascular endothelial growth factor that allowed the controlled release of the neurotrophic factor.This modified gelatin exhibited good physical and chemical properties,biocompatibility and supported the adhesion and proliferation of RSC96 cells and human umbilical vein endothelial cells.When injected into the epineurium of crushed nerves,the composite hydrogel in the rat sciatic nerve crush injury model promoted nerve regeneration,functional recovery and vascularization.The results showed that the modified gelatin gave sustained delivery of vascular endothelial growth factors and accelerated the repair of crushed peripheral nerves.

关键词： bioactive material controlled release crush injury hydrogel muscle function nerve regeneration peripheral nerve sciatic function index vascular endothelial growth factor vascularization

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Patient-derived xenograft platform of OSCC： a renewable human bio-bank for preclinical cancer research and a new co-clinical model for treatment optimization

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Frontiers of Medicine 2016年第1期10卷 104-110页

作者： Shuyang Sun Zhiyuan Zhang department of oral and maxillofacial-head neck oncology Ninth People's Hospital Shanghai Jiao Tong University School of Medicine'Shanghai Key Laboratory of Stomatology Shanghai 200011 China

Advances in next-generation sequencing and bioinformatics have begun to reveal the complex genetic landscape in human cancer genomes, including oral squamous cell carcinoma （OSCC）. Sophisticated preclinical models that fully represent intra- and inter-tumoral heterogeneity are required to understand the molecular diversity of cancer and achieve the goal of personalized therapies. Patient-derived xenograft （PDX） models generated from human tumor samples that can retain the histological and genetic features of their donor tumors have been shown to be the preferred preclinical tool in translational cancer research compared with other conventional preclinical models. Specifically, genetically well-defined PDX models can be applied to accelerate targeted antitumor drug development and biomarker discovery. Recently, we have successfully established and characterized an OSCC PDX panel as part of our tumor bio-bank for translational cancer research. In this paper, we discuss the establishment, characterization, and preclinical applications of the PDX models. In particular, we focus on the classification and applications of the PDX models based on validated annotations, including clinicopathological features, genomic profiles, and pharmacological testing information. We also explore the translational value of this well-annotated PDX panel in the development of co-clinical trials for patient stratification and treatment optimization in the near future. Although various limitations still exist, this preclinical approach should be further tested and improved.

关键词： patient-derived xenograft models personalized medicine co-clinical trial patient stratification oral squamous cellcarcinoma

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Methods for monitoring cancer cell pyroptosis

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Cancer Biology & Medicine 2022年第4期19卷 398-414页

作者： Shuo Wang Yuantong Liu Lu Zhang Zhijun Sun The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory of oral Biomedicine Ministry of EducationSchool and Hospital of StomatologyWuhan UniversityWuhan 430079China department of oral maxillofacial-head neck oncology School and Hospital of StomatologyWuhan UniversityWuhan 430079China

Pyroptosis is a form of proinflammatory cell death that depends on the gasdermin family of proteins.The main features of pyroptosis are altered membrane permeability,cell swelling,membrane rupture,and the ability to mobilize a strong immune response.The relationship between pyroptosis and cancer has become a popular topic in immunological research.Multiple strategies for inducing pyroptosis in cancer cells have been developed for cancer therapy,including chemotherapy,small molecule drugs,and nanomedicines.In this review,we systematically discuss recent advances in research on the mechanisms of pyroptosis,and compare pyroptosis with apoptosis and necroptosis from several aspects.The development of various experimental systems has accompanied rapid progress in this field,but little consensus on monitoring pyroptosis is currently available.We focus on techniques commonly used to monitor pyroptosis,and describe future techniques that may be used to increase our knowledge in this field.Overall,the advancement of pyroptosis detection methods will help researchers to better investigate the relationships between pyroptosis and various cancers,and should provide insights into the use of these promising tools for cancer treatments.

关键词： Pyroptosis gasdermin caspase cancer immunotherapy cell death

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Expert consensus on the clinical application of recombinant adenovirus human p53 for head and neck cancers

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International Journal of oral Science 2021年第4期13卷 333-338页

作者： Yi Li Wei Guo Xiuqin Li Jianguo Zhang Moyi Sun Zhangui Tang Wei Ran Kai Yang Guilin Huang Longjiang Li State Key Laboratory of oral Diseases&National Clinical Research Center for oral Diseases&department of head and neck oncology West China Hospital of StomatologySichuan UniversityChengduChina department of Oromaxillofacial head and neck oncology Shanghai Ninth People’s HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghaiChina department of Obstetrics and Gynecology Shengjing Hospital China Medical UniversityShenyangChina department of oral and maxillofacial Surgery School and Hospital of StomatologyPeking UniversityBeijingChina department of oral and maxillofacial Surgery The Third Affiliated HospitalAir Force Medical UniversityXi’anChina department of oral and maxillofacial Surgery Xiangya School of StomatologyCentral South UniversityChangshaChina department of oral and maxillofacial Surgery First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina department of oral and maxillofacial Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina department of oral and maxillofacial Surgery Stomatological HospitalZunyi Medical UniversityZunyiChina

The first gene therapy product,recombinant adenovirus human p53(rAd-p53),has been approved by CFDA since 2013.During these years,most of the clinical trials and the relevant basic research were carried out by Chinese oncologists.Gendicine was proved to be a safe and promising gene therapy drug for patients who suffered from head and neck squamous cell carcinoma(HNSCC).The basic therapeutic theories of gene therapy were totally different from the traditional ones,such as surgeries or radioand chemotherapy,and the evaluation of treatment outcomes should also be changed simultaneously.However,there still existed a lot of misunderstandings about gene therapy,which resulted in improper administration,insufficient dosage calculation,and treatment cycles,and the treatment outcomes were unsatisfactory,especially for inexperienced oncologists or hospitals.Therefore,we will provide some practical guidance here on the gene therapy of rAd-p53 based on our previous research and experience,which focused on the basic theories and clinical issues,to answer the questions arising during the clinical of gene therapy and to accelerate the development of gene therapy for the benefit of patients bearing malignant tumors.

关键词： clinical dosage totally

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Eliciting pyroptosis to fuel cancer immunotherapy: mechanisms and strategies

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Cancer Biology & Medicine 2022年第7期19卷 948-964页

作者： Wuyin Wang Lu Zhang Zhijun Sun The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory of oral Biomedicine Ministry of Education School&Hospital of StomatologyWuhan UniversityWuhan 430079China department of oral maxillofacial-head neck oncology School&Hospital of StomatologyWuhan UniversityWuhan 430079China

Immune checkpoint blockade(ICB)therapy has recently shown promise in treating several malignancies.However,only a limited number of patients respond to this treatment,partially because of the“immune cold”condition of the tumor immune microenvironment.Pyroptosis is a type of gasdermin-mediated programmed cell death that often leads to inflammation and immune responses.Many studies on the mechanism and function of pyroptosis have led to increasing recognition of the role of pyroptosis in malignant progression and immune therapy.Pyroptosis has the potential to alter the tumor immune microenvironment by releasing tumor-associated antigens,damage-associated molecular patterns,and proinflammatory cytokines,thus leading to intratumoral inflammatory responses,stimulation of tumor-specific cytotoxic T cell infiltration,conversion of“cold”to“hot”tumors,and ultimately improving the efficacy of ICB therapy.Some cancer treatments have been shown to restore anticancer immunosurveillance through the induction of pyroptosis.Therapy promoting pyroptosis and ICB therapy may have synergistic effects in cancer treatment.This review summarizes the mechanisms and roles of pyroptosis in the tumor microenvironment and combination treatment strategies.An improved understanding of the roles of pyroptosis in tumorigenesis,immune evasion,and treatment would aid in the development of therapeutic strategies for malignancies.

关键词： Pyroptosis immune checkpoint blockade immunogenic cell death tumor immunotherapy

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Cancer cells corrupt normal epithelial cells through miR-let-7c-rich small extracellular vesicle-mediated downregulation of p53/PTEN

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International Journal of oral Science 2022年第4期14卷 470-478页

作者： Weilian Liang Yang Chen Hanzhe Liu Hui Zhao Tingting Luo Hokeung Tang Xiaocheng Zhou Erhui Jiang Zhe Shao Ke Liu Zhengjun Shang The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory for oral Biomedicine Ministry of Education School and Hospital of StomatologyWuhan UniversityWuhanChina Shenzhen PKU-HKUST Medical Center(Peking University Shenzhen Hospital) ShenzhenChina department of oral and maxillofacial Surgery School and Hospital of StomatologyWuhan UniversityWuhanChina Department of Oral and Maxillofacial-Head and Neck Oncology School&Hospital of StomatologyWuhan UniversityWuhanChina

Tumor volume increases continuously in the advanced stage, and aside from the self-renewal of tumor cells, whether the oncogenic transformation of surrounding normal cells is involved in this process is currently unclear. Here, we show that oral squamous cell carcinoma(OSCC)-derived small extracellular vesicles(s EVs) promote the proliferation, migration, invasion, and epithelial-mesenchymal transition(EMT) of normal epithelial cells but delay their apoptosis. In addition, nuclear-cytoplasmic invaginations and multiple nucleoli are observed in s EV-treated normal cells, both of which are typical characteristics of premalignant lesions of OSCC. Mechanistically, mi Rlet-7c in OSCC-derived s EVs is transferred to normal epithelial cells, leading to the transcriptional inhibition of p53 and inactivation of the p53/PTEN pathway. In summary, we demonstrate that OSCC-derived s EVs promote the precancerous transformation of normal epithelial cells, in which the mi R-let-7c/p53/PTEN pathway plays an important role. Our findings reveal that cancer cells can corrupt normal epithelial cells through s EVs, which provides new insight into the progression of OSCC.

关键词： cor invasion transferred

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Papillary cystadenoma of the parotid gland: A case report

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World Journal of Clinical Cases 2019年第3期7卷 366-372页

作者： Li Wang Shi-Kun Zhang Ying Ma Patrick K Ha Zhi-Ming Wang department of oral and maxillofacial Surgery Shengjing Hospital of China Medical University department of Pathology Shengjing Hospital of China Medical University Division of head and neck Oncologic and Endocrine Surgery Department of Otolaryngology-Head and Neck Surgery University of California-San Francisco

BACKGROUND Papillary cystadenoma is a rare benign epithelial tumor of the salivary gland,which is characterized by papillary structures and oncocytic cells with rich eosinophilic cytoplasm. We found only one case of papillary cystadenoma in nearly 700 cases of salivary gland tumors. Our case was initially mistaken for a tumor of the right temporomandibular joint(TMJ) capsule rather than of parotid gland origin. Preoperative magnetic resonance imaging(MRI) and computed tomography(CT) should be carefully studied, which allows for appropriate preoperative counseling and operative planning.CASE SUMMARY Here, we report an unusual case of a 54-year-old woman with a parotid gland papillary cystadenoma(PGPC) that was misdiagnosed as a tumor of the right TMJ capsule. She was initially admitted to our hospital due to a mass anterior to her right ear inadvertently found 5 d ago. Preoperative CT and MRI revealed a well circumscribed tumor that was attached to the right TMJ capsule. The patient underwent a resection through an incision for TMJ, but evaluation of an intraoperative frozen section revealed a benign tumor of the parotid gland. Then we removed part of the parotid gland above the temporal facial trunk. The facial nerve was preserved. Postoperative histopathological findings revealed that the tumor was PGPC. No additional treatment was performed. There was no recurrence during a 20-mo follow-up period.CONCLUSION The integrity of the interstitial space around the condyle in MRI or CT should be carefully evaluated for parotid gland or TMJ tumors.

关键词： Papillary cystadenoma Parotid gland Temporomandibular joint Case report

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