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LATS1 Promotes B-ALL tumorigenesis by Regulating YAP1 Phosphorylation and Subcellular Localization

Current Medical Science 2024年第1期44卷 81-92页

作者： Feng ZHANG Mohammed Awal Issah Hai-ying FU Hua-rong ZHOU Ting-bo LIU Jian-zhen SHEN fujian provincial key laboratory on Hematology Fujian Medical Center of HematologyFujian Institute of HematologyClinical Research Center for Hematological Malignancies of Fujian ProvinceFujian Medical University Union HospitalFuzhou 350001China Tamale Technical University Faculty of Allied Health and Pharmaceutical SciencesDepartment of Medical Laboratory TechnologyTamale NS-011-2000Ghana department of Hematology The Third Affiliated People's Hospital of Fujian University of Traditional Chinese MedicineThe Third People's Hospital of Fujian ProvinceFuzhou 350122China

Objective YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors;differentiating between these roles may depend on the YAP1 phosphorylation *** specific function of YAP1 in B cell acute lymphoblastic leukemia(B-ALL),however,is currently ***,in the present study,the role of YAP1 in B-ALL was investigated using relevant cell lines and patient *** The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting,quantitative real-time polymerase chain reaction,flow cytometry,immunostaining,and nude mouse subcutaneous tumorigenesis *** expression levels of Hippo pathway-related molecules before and after verteporfin(VP)treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 *** Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation ***1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells;YAP1 was distributed in the nuclei in NALM6 *** of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 *** and after VP treatment,the expression of the upstream gene LATS1 was upregulated;its overexpression promoted YAP1-Ser127 ***,YAP1 was distributed in the *** LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function;thus,VP,which targets this axis,may serve as a new therapeutic method for improving the outcomes for B-ALL patients.

关键词： acute lymphoblastic leukemia large tumor suppressor kinase 1 phosphorylation RNA-Seq Yesl-associated protein

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Role of mitophagy in head and neck squamous cell carcinoma:Prognosis and immune insights

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Radiation Medicine and Protection 2024年第2期5卷 100-112页

作者： Qin Ding Wei Liu Junping Pan Lihua Wang Wenquan Hong Sunqin Cai Xin Chen Duanyu Lin Sufang Qiu department of Radiation Oncology Clinical Oncology School of Fujian Medical UniversityFujian Cancer Hospital(Fujian Branch of Fudan University Shanghai Cancer Center)Fuzhou 350014China fujian provincial key laboratory of Translational Cancer Medicine Fuzhou 350014China department of Nuclear Medicine Clinical Oncology School of Fujian Medical UniversityFujian Cancer Hospital(Fujian Branch of Fudan University Shanghai Cancer Center)Fuzhou 350014China

Objective:To explore the correlation between mitophagy and the tumor microenvironment(TME)in patients with head and neck squamous cell carcinoma(HNSCC),with an aim to enhance therapeutic efficacy for ***:A machine learning-based multigene prognostic signature was developed based on mitophagy-related differentially expressed genes(MRGs)identified in The Cancer Genome Atlas *** signature was correlated with the TME using gene set enrichment *** association between this prognostic signature and various immunological features of the TME was explored,including status of tumor-infiltrating immune cells,expression of immune checkpoint molecules,and the *** validated the expression of hub gene CSNK2A2 and assessed its relationship with immunomarker *** PCR validated CSNK2A2 knockdown in HNSCC cell *** experiments including Transwell assays to determine cell migration and invasion,Cell Counting Kit 8 assay,and 5-ethynyl-2-deoxyuridine assay were performed to confirm the role of CSNK2A2 in ***,a subcutaneous xenograft model was generated in C3H mice to validate our ***:The MRG-based prognostic signature showed excellent predictive ***-risk patients had significantly shorter progression-free and overall survival(Ptumor growth and smaller tumor ***:We established a potential prognostic signature that could impr

关键词： Head and neck squamous cell carcinoma Mitophagy tumor microenvironment CSNK2A2 Prognostic model

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WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

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International Journal of Oral Science 2024年第1期16卷 85-96页

作者： Qingling Huang Yi Xiao Ting Lan Youguang Lu Li Huang Dali Zheng department of Biochemistry and Molecular Biology School of Basic Medical SciencesFujian Medical UniversityFuzhouChina fujian key laboratory of Oral Diseases School and Hospital of StomatologyFujian Medical UniversityFuzhouChina department of Preventive Dentistry School and Hospital of StomatologyFujian Medical UniversityFuzhouChina department of Dentistry The First Affiliated Hospital of Fujian Medical UniversityFuzhouChina

Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor *** findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.

关键词： WNT squamous tumorigenesis

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Pan-cancer immunogenic death analysis identifies key roles of CXCR3 and CCL18 in hepatocellular carcinoma

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Genes & Diseases 2024年第2期11卷 568-570页

作者： Jia Guo Xin Sun Guowei Pan Ce Li Xin He Xiaofang Che Zan Teng Xiujuan Qu Yunpeng Liu Bowen Yang department of Medical Oncology Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning ProvinceLiaoning Provincial Clinical Research Center for CancerClinical Cancer Research Center of ShenyangThe First Hospital of China Medical UniversityShenyangLiaoning 110001China Research Center for Universal Health School of Public HealthChina Medical UniversityShenyangLiaoning 110122China

Immunogenic death is a form of programmed cell death that is common in the development and progression of ***,its impact on tumor progression differs depending on the location of the ***,it also plays an important role in antitumor immunity because the process of immunogenic death can release substances that activate immunity.1 Therefore,in this study,the key mechanism of mediating immunogenic death in hepatocellular carcinoma(HCC)was found from the excavation of the immunogenic death characteristics of pan-cancer and the in-depth investigation of its effects on different tumor types(Fig.1A).

关键词： death CXCR3 immunity

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Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1204-1221页

作者： Xiaohui Chen Meichun Gao Yongzhen Xia Xin Wang Jingbo Qin Hongying He Weirong Liu Xiaowei Zhang Shuangzhou Peng Zhiping Zeng Ying Su Xiaokun Zhang School of Pharmaceutical Science Fujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamen 361002China NucMito Pharmaceuticals Co. Ltd.Xiamen 361000China department of Clinical laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor *** pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to *** Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer ***,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 *** vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent *** studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related ***,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 ***,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

关键词： XS561 Nur77 Bcl-2 Apoptosis Mitochondria Phase separation TNBC TAMR

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Pien Tze Huang Inhibits Proliferation of Colorectal Cancer Cells through Suppressing PNO1 Expression and Activating p53/p21 Signaling Pathway

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Chinese Journal of Integrative Medicine 2024年第6期30卷 515-524页

作者： CAO Liu-jing LIU Li-ya CHEN You-qin HAN Yu-ying WEI Li-hui YAO Meng-ying FANG Yi WU Mei-zhu CHENG Ying Thomas J.Sferra LIU Hui-xin LI Li PENG Jun SHEN A-ling Clinical Research Institute the Second Affiliated Hospital&Academy of Integrative MedicineFujian University of Traditional Chinese MedicineFuzhou350122China fujian key laboratory of Integrative Medicine in Geriatrics Fujian University of Traditional Chinese MedicineFuzhou350122China department of Pediatrics Case Western Reserve University School of MedicineUH Rainbow Babies and Children’s HospitalClevelandOH44106USA Innovation and Transformation Center Fujian University of Traditional Chinese MedicineFuzhou350122China department of Health Management Fujian Provincial HospitalShengli Clinical College of Fujian Medical UniversityFuzhou000000China

ObjectiveTo explore the regulatory effect of Pien Tze Huang (PZH) on targeting partner of NOB1 (PNO1) and it’s down-stream mediators in colorectal cancer (CRC) *** polymerase chain reaction was performed to determine mRNA levels of PNO1, TP53, and CDKN1A. Western blotting was performed to determine protein levels of PNO1, p53, and p21. HCT-8 cells were transduced with a lentivirus over-expressing PNO1. Colony formation assay was used to detect cell survival in PNO1 overexpression of HCT-8 cells after PZH treatment. Cell-cycle distribution, cell viability and cell apoptosis were performed to identify the effect of PNO1 overexpression on cell proliferation and apoptosis of HCT-8 cells after PZH treatment. Xenograft BALB/c nude mice bearing HCT116 cells transduced with sh-PNO1 or sh-Ctrl lentivirus were evaluated. Western blot assay was performed to detect PNO1, p53, p21 and PCNA expression in tumor sections. Terminal deoxynucleotidyl transferase dUTP nick end labling (TUNEL) assay was used to determine the apoptotic cells in *** treatment decreased cell viability, down-regulated PNO1 expression, and up-regulated p53 and p21 expressions in HCT-8 cells (Ptumor growth, inhibiting cell proliferation inhibition and apoptosis induction in vivo (P<0.05). Similarly, PNO1 knockdown attenuated the effects of PZH treatment on the down-regulation of PNO1 and up-regulation of p53 and p21 in vivo (P<0.05).ConclusionThe mechanism by which PZH induces its CRC anti-proliferative effect is at least in part by regulating the expression of PNO1 and its downstream targets p53 and p21.

关键词： colorectal cancer Pien Tze Huang Chinese medicine partner of NOB1 proliferation p53/p21 pathway

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Triterpenoids-templated self-assembly nanosystem for biomimetic delivery of CRISPR/Cas9 based on the synergy of TLR-2 and ICB to enhance HCC immunotherapy

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3205-3217页

作者： Bing-Chen Zhang Chun-Mei Lai Bang-Yue Luo Jing-Wei Shao fujian provincial key laboratory of Cancer Metastasis Chemoprevention and Chemotherapy College of ChemistryFuzhou UniversityFuzhou 350116China department of laboratory Medicine Dongguan Institute of Clinical Cancer Researchthe Tenth Affiliated Hospital of Southern Medical University(Dongguan People’s Hospital)Dongguan 523058China College of Materials and Chemical Engineering MinjiangUniversityFuzhou350108China

Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade(ICB)***,combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted ***,based on a universal triterpene template and the anticancer active agent ursolic acid(UA),a cytomembrane-coated biomimetic delivery nanoplatform(UR@M)prepared by the selfassembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma(HCC)***@M showed enhanced tumor accumulation in vivo with homologous tumor targeting,and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target *** activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway,which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of *** strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor ***,the UA-templated strategy“killed three birds with one stone”by establishing a self-assembly nanosystem,inducing tumor cell death,and promoting synergistic immunostimulation for HCC treatment.

关键词： Ursolic acid Self-assembly Biomimetic nanoplatform Hepatocellular carcinoma CRISPR/Cas9 Immune checkpoint blockade Gene therapy Immunotherapy

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Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC(CTONG1804):a multicenter open-label phase II study

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Signal Transduction and Targeted Therapy 2024年第1期9卷 249-258页

作者： Si-Yang Liu Song Dong Xue-Ning Yang Ri-Qiang Liao Ben-Yuan Jiang Qun Wang Xiao-Song Ben Gui-Bin Qiao Jun-Tao Lin Hong-Hong Yan Li-Xu Yan Qiang Nie Hai-Yan Tu Bin-Chao Wang Jin-Ji Yang Qing Zhou Hong-Rui Li Ke Liu Wendy Wu Si-Yang Maggie Liu Wen-Zhao Zhong Yi-Long Wu Guangdong Lung Cancer Institute Guangdong Provincial Key Laboratory of Translational Medicine in Lung CancerGuangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina department of Thoracic Surgery Zhongshan HospitalFudan UniversityShanghaiChina department of Thoracic Surgery Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina department of Pathology Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina fujian key laboratory of Advanced Technology for Cancer Screening and Early Diagnosis FuzhouChina Berry Oncology Corporation FuzhouChina Chinese Thoracic Oncology Group(CTONG) GuangzhouChina department of Hematology The First Affiliated HospitalJinan UniversityGuangzhouChina

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 *** patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK *** received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 *** primary endpoint was the major pathological response(MPR).key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and ***-two patients were enrolled,with 46 undergoing *** MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,***(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant *** with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–***+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).

关键词： chemotherapy NSCLC treatment

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Pien Tze Huang Inhibits Migration and Invasion of Hepatocellular Carcinoma Cells by Repressing PDGFRB/YAP/CCN2 Axis Activity

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Chinese Journal of Integrative Medicine 2024年第2期30卷 115-124页

作者： LUO Zhi-yi TIAN Qi CHENG Niang-mei LIU Wen-han YANG Ye CHEN Wei ZHANG Xiang-zhi ZHENG Xiao-yuan CHEN Ming-sheng ZHUANG Qiu-yu ZHAO Bi-xing LIU Cong-sheng LIU Xiao-long LI Qin WANG Ying-chao The United Innovation of Mengchao Hepatobiliary Technology key laboratory of fujian Province Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China fujian Pien Tze Huang Enterprise key laboratory of Natural Medicine Research and Development Zhangzhou Pien Tze Huang Pharmaceutical Co.Ltd.ZhangzhouFujian Province(363099)China College of Biological Science and Engineering and Mengchao Med-X Center Fuzhou UniversityFuzhou(350116)China department of Internal Medicine Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China

Objective:To investigate the effects of Pien Tze Huang(PZH) on the migration and invasion of HCC cells and underlying molecular ***:Cell counting kit-8(CCK-8) was applied to evaluate the cell viabilities of SMMC-7721,SK-Hep-1,C3A and HL-7702(6 × 10^(3)cells/well) co-incubated with different concentrations of PZH(0,0.2,0.4,0.6,0.8 mg/mL) for 24 ***,wound healing assay,CCK-8and Annexin V-FITC/PI staining were conducted to investigate the effects of PZH on the migration,invasion,proliferation and apoptosis of SK-Hep-1 and SMMC-7721 cells(650 μg/mL for SK-Hep-1 cells and 330 μg/mL for SMMC-7721 cells),*** vivo,lung metastasis mouse model constructed by tail vein injection of HCC cells was used for evaluating the anti-metastasis function of ***-Hep-1 cells(10^(6)cells/200 μL per mice) were injected into B-NDG mice via tail *** 8 mice were randomly divided into PZH and control groups,4 mice in each *** 2-d inoculation,mice in the PZH group were administered with PZH(250 mg/kg,daily) and mice in the control group received only vehicle(PBS) from the 2nd day after xenograft to day *** analysis based on RNA-seq was subsequently used for deciphering anti-tumor mechanism of *** real-time polymerase chain reaction(qRT-PCR) and Western blot were applied to verify RNA-seq *** reporter assay was performed to examine the transcriptional activity of yes-associated protein(YAP).Results:PZH treatment significantly inhibited the migration,invasion,proliferation and promoted the apoptosis of HCC cells in vitro and in vivo(P<0.01).Transcriptome analysis indicated that Hippo signaling pathway was associated with anti-metastasis function of *** study showed PZH significantly inhibited the expressions of platelet derived growth factor receptor beta(PDGFRB),YAP,connective tissue growth factor(CCN2),N-cadherin,vimentin and matrix metallopeptidase 2(MMP2,P<0.01).Meanwhile,the phosphorylatio

关键词： PienTzeHuang hepatocellular carcinoma RNA-seq Hippo yes-associated protein

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Consideration on immunotherapy of liver metastases of malignant tumors

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World Journal of Gastrointestinal Surgery 2024年第8期16卷 2374-2381页

作者： Chuang Jiang Zhi-Hong Zhang Jia-Xin Li Division of Liver Surgery Department of General Surgery and Laboratory of Liver Surgeryand State Key Laboratory of Biotherapy and Collaborative Innovation Center of BiotherapyWest China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina department of General Surgery Dafang County People's HospitalBijie 551600Guizhou ProvinceChina

In this editorial,we comment on the article“Analysis of the impact of immuno-therapy efficacy and safety in patients with gastric cancer and liver metastasis”by Liu et al that was published in the recent issue of the World Journal of Gastroin-testinal *** has prompted us to think and summarize some thoughts on immunotherapy for malignant tumor liver *** plays a crucial role in the treatment of malignant tumors;however,the presence of liver metastases in advanced tumors may impact its *** patients with liver metastases can still benefit from immunotherapy,multiple clinical studies have indicated that,compared to other sites of metastasis,liver metastases may diminish the effectiveness of *** efficacy of immune checkpoint inhibitors in patients with liver metastases often fails to reach the ideal level,primarily due to the liver metastases exploiting the host's peripheral immune to-lerance mechanisms to promote systemic CD8(+)T cell exhaustion,resulting in a systemic immune-tolerant *** article aims to summarize the reasons for the decreased efficacy of immunotherapy following liver metastasis in various malignant tumors and propose potential clinical strategies for manage-ment.

关键词： Liver metastasis Immunotherapy Immune tolerance Cancer Treatment

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