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Systematic screening for potential therapeutic targets in osteosarcoma through a kinome-wide CRISPR-Cas9 library

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Cancer Biology & Medicine 2020年第3期17卷 782-794页

作者： Yuanzhong Wu Liwen Zhou Zifeng Wang Xin Wang Ruhua Zhang Lisi Zheng Tiebang Kang Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China

Objective:Osteosarcoma is the most common primary malignant bone tumor.However,the survival of patients with osteosarcoma has remained unchanged during the past 30 years,owing to a lack of efficient therapeutic targets.Methods:We constructed a kinome-targeting CRISPR-Cas9 library containing 507 kinases and 100 nontargeting controls and screened the potential kinase targets in osteosarcoma.The CRISPR screening sequencing data were analyzed with the Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout(MAGeCK)Python package.The functional data were applied in the 143B cell line through lenti-CRISPR-mediated gene knockout.The clinical significance of kinases in the survival of patients with osteosarcoma was analyzed in the R2:Genomics Analysis and Visualization Platform.Results:We identified 53 potential kinase targets in osteosarcoma.Among these targets,we analyzed 3 kinases,TRRAP,PKMYT1,and TP53RK,to validate their oncogenic functions in osteosarcoma.PKMYT1 and TP53RK showed higher expression in osteosarcoma than in normal bone tissue,whereas TRRAP showed no significant difference.High expression of all 3 kinases was associated with relatively poor prognosis in patients with osteosarcoma.Conclusions:Our results not only offer potential therapeutic kinase targets in osteosarcoma but also provide a paradigm for functional genetic screening by using a CRISPR-Cas9 library,including target design,library construction,screening workflow,data analysis,and functional validation.This method may also be useful in potentially accelerating drug discovery for other cancer types.

关键词： Osteosarcoma kinase CRISPR-Cas9 library TRRAP PKMYT1 TP53RK

Snail部分通过下调TEL2促进鼻咽癌转移

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癌症 2019年第5期38卷 232-242页

作者： Yi Sang Chun Cheng Yi-Xin Zeng Tiebang Kang 华南肿瘤学国家重点实验室肿瘤医学协同创新中心中山大学肿瘤防治中心广东广州510060 中山大学附属第八医院中心实验室广东深圳518033 江西省肿瘤转移与精准治疗重点实验室南昌大学第三附属医院江西南昌330008

背景与目的转移是鼻咽癌(nasopharyngeal carcinoma,NPC)患者治疗失败的主要原因。我们之前报道,SERPINE1的负调节因子TEL2可以抑制鼻咽癌转移到淋巴结。方法我们进行了一系列体内和体外实验来阐明Snail和TEL2之间的调控关系,分别在3株S... 详细信息

背景与目的转移是鼻咽癌(nasopharyngeal carcinoma,NPC)患者治疗失败的主要原因。我们之前报道,SERPINE1的负调节因子TEL2可以抑制鼻咽癌转移到淋巴结。方法我们进行了一系列体内和体外实验来阐明Snail和TEL2之间的调控关系,分别在3株Snail低表达的鼻咽癌细胞系(S26、6?10B、HK1)与2株Snail高表达的鼻咽癌细胞系(S18、5?8F)中检测了TEL2的表达水平。我们采用荧光素酶和染色质免疫沉淀方法分析Snail和TEL2的相互作用,采用侵袭实验检测Snail/TEL2途径在细胞迁移和鼻咽癌细胞侵袭中的作用,采用裸鼠尾静脉注射鼻咽癌细胞来检测肺转移情况。结果 Snail异位表达下调了TEL2的mRNA和蛋白水平,shRNA敲低Snail则可上调TEL2的表达水平。荧光素酶和染色质免疫沉淀实验表明Snail可与TEL2的启动子直接结合。Snail异位表达增强了NPC细胞的迁移和侵袭,并且TEL2过表达削弱了这种作用。TEL2过表达也减弱了缺氧诱导的细胞迁移和侵袭并且增加了转移性肺结节的数量。Snail过表达减少了转移性肺结节的数量。结论 TEL2是Snail的新靶点,可抑制Snail诱导的鼻咽癌的迁移、侵袭和转移。

关键词： TEL2 Snail 转移鼻咽癌

Low expression of centrosomal protein 78(CEP78)is associated with poor prognosis of colorectal cancer patients

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Chinese Journal of Cancer 2016年第10期35卷 509-517页

作者： Meifang Zhang Tingmei Duan Li Wang Jianjun Tang Rongzhen Luo Ruhua Zhang Tiebang Kang State Key Laboratory of Oncology in South China Collaborative Innova-tion Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China. Department of Pathology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China. Research Department Sun Yat-sen University Cancer CenterGuang-zhou 510060GuangdongP.R.China.

Background: Centrosomal protein 78(CEP78) has been characterized as a component of the centrosome required for the regulation of centrosome-related events during the cell cycle, but its role in human cancers remains unclear. This study aimed to investigate the role and the clinical value of CEP78 in colorectal cancer(CRC).Methods: Quantitative real-time polymerase chain reaction(q RT-PCR) and immunohistochemistry were performed to examine CEP78 expression in CRC tissues and adjacent noncancerous tissues. The association between CEP78 expression and clinical outcomes of CRC patients was determined. The effect of CEP78 on cell growth was examined in vitro by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT) assay, colony formation, and flow cytometry assays and in vivo using a nude mouse model.Results: The expression level of CEP78 was significantly lower in tumor tissues than in the adjacent normal tissues(P < 0.01). Low CEP78 expression was significantly associated with poor differentiation(P etastasis(P = 0.003), large tumor size(P = 0.017), lymphatic mtient= 0.034), distant metastasis(P s with low CEP78 expression h= 0.029), and advanced stage(P Meier analysis indicated that paad shorter survival than those wit= 0.011). Kaplan–h high CEP78 expression(P < 0.01). Overexpression of CEP78 in CRC cells significantly reduced cell viability and colony formation in vitro and halted tumor growth in vivo. Further study showed that CEP78 reintroduction in CRC cells resulted in G2/M phase arrest rather than cell apoptosis.Conclusions: CEP78 might function as a tumor suppressor and serve as a novel prognostic marker in CRC.

关键词：中心体蛋白结直肠癌预后患者细胞周期聚合酶链反应 RT-PCR 实验检测

RMI2 plays crucial roles in growth and metastasis of lung cancer

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Signal Transduction and Targeted Therapy 2020年第1期5卷 907-909页

作者： Weixiang Zhan Yina Liu Ying Gao Run Gong Wen Wang Ruhua Zhang Yuanzhong Wu Tiebang Kang Denghui Wei State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer Center510060 GuangzhouChina The Sixth Affiliated Hospital Sun Yat-sen University510000 GuangzhouChina Department of Abdominal Oncology The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University519000 ZhuhaiGuangdongChina

Dear Editor,Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death in the world,but its therapeutic targets are still being explored.Genome instability as a key hallmark of cancer not only contributes to cancer initiation and progression,1 but also creates vulnerabilities that are relatively specific to cancer cells,which may be potential therapeutic targets for cancer patients.During DNA Double-Strand Breaks(DSBs)repair,BTR(BLM-Topo IIIα-RMI1/RMI2)complex promotes the dissolution of double Holliday junctions to form non-crossover products and is often considered as a tumor suppressor.2 However,the function of each individual component of this BTR complex in cancer remains largely unknown.

关键词： cancer metastasis Lung

SUMOylation stabilizes hSSB1 and enhances the recruitment of NBS1 to DNA damage sites

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1516-1527页

作者： Liwen Zhou Lisi Zheng Kaishun Hu Xin Wang Ruhua Zhang Yezi Zou Li Zhong Shang Wang Yuanzhong Wu Tiebang Kang Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research CenterSun Yat-sen Memorial HospitalSun Yat‐sen UniversityGuangzhouChina

Human single-stranded DNA-binding protein 1(hSSB1)is required for the efficient recruitment of the MRN complex to DNA doublestrand breaks and is essential for the maintenance of genome integrity.However,the mechanism by which hSSB1 recruits NBS1 remains elusive.Here,we determined that hSSB1 undergoes SUMOylation at both K79 and K94 under normal conditions and that this modification is dramatically enhanced in response to DNA damage.SUMOylation of hSSB1,which is specifically fine-tuned by PIAS2α,and SENP2,not only stabilizes the protein but also enhances the recruitment of NBS1 to DNA damage sites.Cells with defective hSSB1 SUMOylation are sensitive to ionizing radiation,and global inhibition of SUMOylation by either knocking out UBC9 or adding SUMOylation inhibitors significantly enhances the sensitivity of cancer cells to etoposide.Our findings reveal that SUMOylation,as a novel posttranslational modification of hSSB1,is critical for the functions of this protein,indicating that the use of SUMOylation inhibitors(e.g.,2-D08 and ML-792)may be a new strategy that would benefit cancer patients being treated with chemo-or radiotherapy.

关键词： SSB1 damage NBS1

Snail promotes metastasis of nasopharyngeal carcinoma partly by down-regulating TEL2

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Cancer Communications 2018年第1期38卷 622-631页

作者： Yi Sang Chun Cheng Yi-Xin Zeng Tiebang Kang State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterNo.651 Dongfeng East RoadGuangzhou 510060People’s Republic of China Department of Center Laboratory The Eighth Affiliated Hospital of Sun Yat-Sen UniversityNo.3025 Shennan Middle RoadShenzhen 518033People’s Republic of China Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment The Third Affiliated Hospital of Nanchang UniversityNo.128 Xianshan North RoadNanchang 330008People’s Republic of China

Background:Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma(NPC).We previously reported that TEL2,a negative regulator of SERPINE1,could inhibit NPC metastasis to lymph nodes.Method:A series of in vivo and in vitro assays were performed to elucidate the regulation between Snail and TEL2.TEL2 expression was analyzed in three representative NPC cell lines expressing low levels of Snail(S26,6-10B,HK1)and two cell lines expressing high levels of Snail(S18,5-8F).Luciferase and chromatin immunoprecipitation assays were used to analyze the interaction between Snail and TEL2.The roles of the Snail/TEL2 pathway in cell migration and invasion of NPC cells were examined using transwell assays.Metastasis to the lungs was examined using nude mouse receiving NPC cells injection through the tail vein.Results:Ectopic Snail expression down-regulated TEL2 at the mRNA and protein levels,whereas knockdown of Snail using short hairpin RNA up-regulated TEL2.Luciferase and chromatin immunoprecipitation assays indicated that Snail binds directly to the TEL2 promoter.Ectopic Snail expression enhanced migration and invasion of NPC cells,and such effects were mitigated by TEL2 overexpression.TEL2 overexpression also attenuated hypoxia-induced cell migration and invasion,and increased the number of metastatic pulmonary nodules.Snail overexpression reduced the number of metastatic pulmonary nodules.Conclusions:TEL2 is a novel target of Snail and suppresses Snail-induced migration,invasion and metastasis in NPC.

关键词： TEL2 Snail Metastasis Nasopharyngeal carcinoma

Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes

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Signal Transduction and Targeted Therapy 2021年第3期6卷 909-924页

作者： Li Zhong Dan Liao Jingjing Li Wenqiang Liu Jingxuan Wang Cuiling Zeng Xin Wang Zhiliang Cao Ruhua Zhang Miao Li Kuntai Jiang Yi-Xin Zeng Jianhua Sui Tiebang Kang State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouChina Department of Oncology The Fifth Affiliated Hospital of Sun Yat-Sen UniversityZhuhaiGuangdongChina National Institute of Biological Sciences BeijingChina Sun Yat-sen University School of Medicine ShenzhenChina Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhouChina

It remains unknown for decades how some of the therapeutic fusion proteins positive in a small percentage of cancer cells account for patient outcome.Here,we report that osteosarcoma Rab22a-NeoF1 fusion protein,together with its binding partner PYK2,is sorted into exosomes by HSP90 via its KFERQ-like motif(RVLFLN^(142)).The exosomal Rab22a-NeoF1 fusion protein facilitates the pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages.The exosomal PYK2 activates RhoA in its negative recipient osteosarcoma cells and induces signal transducer and activator of transcription 3 activation in its recipient macrophages to increase M2 phenotype.Consequently,lung metastases of its recipient osteosarcoma cells are promoted by this exosomal Rab22a-NeoF1 fusion protein,and this event can be targeted by disrupting its interaction with PYK2 using a designed internalizing RGD peptide.

关键词： osteosarcoma lung metastasis

MFN2 suppresses clear cell renal cell carcinoma progression by modulating mitochondria-dependent dephosphorylation of EGFR

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Cancer Communications 2023年第7期43卷 808-833页

作者： Li Luo Denghui Wei Yihui Pan Qiu-Xia Wang Jian-Xiong Feng Bing Yu Tiebang Kang Junhang Luo Jiefeng Yang Song Gao State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouGuangdongP.R.China Department of Urology The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdongP.R.China Department of Urology The Third Affiliated Hospital of Soochow UniversityChangzhouJiangsuP.R.China

Background:Clear cell renal cell carcinoma(ccRCC)is the most lethal renal cancer.An overwhelming increase of patients experience tumor progression and unfavorable prognosis.However,the molecular events underlying ccRCC tumorigenesis and metastasis remain unclear.Therefore,uncovering the underlying mechanisms will pave the way for developing novel therapeutic targets for ccRCC.In this study,we sought to investigate the role of mitofusin-2(MFN2)in supressing ccRCC tumorigenesis and metastasis.Methods:The expression pattern and clinical significance of MFN2 in ccRCC were analyzed by using the Cancer Genome Atlas datasets and samples from our independent ccRCC cohort.Both in vitro and in vivo experiments,including cell proliferation,xenograft mouse models and transgenic mouse model,were used to determine the role of MFN2 in regulating the malignant behaviors of ccRCC.RNA-sequencing,mass spectrum analysis,co-immunoprecipitation,bio-layer interferometry and immunofluorescence were employed to elucidate the molecular mechanisms for the tumor-supressing role of MFN2.Results:we reported a tumor-suppressing pathway in ccRCC,characterized by mitochondria-dependent inactivation of epidermal growth factor receptor(EGFR)signaling.This process was mediated by the outer mitochondrial membrane(OMM)protein MFN2.MFN2 was down-regulated in ccRCC and associated with favorable prognosis of ccRCC patients.in vivo and in vitro assays demonstrated thatMFN2 inhibited ccRCC tumor growth and metastasis by suppressing the EGFR signaling pathway.In a kidney-specific knockout mouse model,loss of MFN2 led to EGFR pathway activation and malignant lesions in kidney.Mechanistically,MFN2 preferably binded small GTPaseRab21 in its GTPloading form,which was colocalized with endocytosed EGFR in ccRCC cells.Through this EGFR-Rab21-MFN2 interaction,endocytosed EGFR was docked to mitochondria and subsequently dephosphorylated by the OMM-residing tyrosine-protein phosphatase receptor type J(PTPRJ).Conclusions:Our findings uncover an important non-canonica

关键词： ccRCC EGFR signaling pathway MFN2 PTPRJ Rab21

Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1657-1669页

作者： Xinxin Xiong Siyu Chen Jianfei Shen Hua You Han Yang Chao Yan Ziqian Fang Jianeng Zhang Xiuyu Cai Xingjun Dong Tiebang Kang Wende Li Penghui Zhou State Key Laboratory of Oncology in Southern China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China Guangdong Provincial People’s Hospital Guangdong Academy of Medical SciencesGuangzhou 510515China Guangdong Laboratory Animals Monitoring Institute Guangdong Key Laboratory of Laboratory AnimalsGuangzhou 510663China Department of Thoracic Surgery Taizhou Hospital of Zhejiang ProvinceWenzhou Medical UniversityLinhai 317000China Affiliated Cancer Hospital&Institute of Guangzhou Medical University Guangzhou 510095China Department of Thoracic Surgery Sun Yat-sen University Cancer CenterGuangzhou 510060China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

The combination of immune checkpoint blockade(ICB)with chemotherapy significantly improves clinical benefit of cancer treatment.Since chemotherapy is often associated with adverse events,concomitant treatment with drugs managing side effects of chemotherapy is frequently used in the combination therapy.However,whether these ancillary drugs could impede immunotherapy remains unknown.Here,we showed that∆9-tetrahydrocannabinol(THC),the key ingredient of drugs approved for the treatment of chemotherapy-caused nausea,reduced the therapeutic effect of PD-1 blockade.The endogenous cannabinoid anandamide(AEA)also impeded antitumor immunity,indicating an immunosuppressive role of the endogenous cannabinoid system(ECS).

关键词： JAK/STAT drugs chemotherapy treatment