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The transcription factor ZEB1 promotes chemoresistance in prostate cancer cell lines

Asian Journal of Andrology 2019年第5期21卷 460-467页

作者： Octavio Orellana-Serradell Daniela Herrera Enrique A Castellon Hector R Contreras Department of Basic and Clinical Oncology Faculty of MedicineUniversity of ChileIndependenciaSantiago 8380453Chile

One of the factors promoting tumoral progress is the abnormal activation of the epithelial-mesenchymal transition(EMT)program which has been associated with chemoresistance in tumoral cells.The transcription factor zinc finger E-box-binding homeobox 1(ZEB1),a key EMT activator,has recently been related to docetaxel resistance,the main chemotherapeutic used in advanced prostate cancer treatment.The mechanisms involved in this protective effect are still unclear.In a previous work,we demonstrated that ZEB1 expression induced an EMT-like phenotype in prostate cancer cell lines.In this work,we used prostate cancer cell lines 22Rvl and DU145 to study the effect of ZEB1 modulation on docetaxel resistance and its possible mechanisms.The results showed that ZEB1 overexpression conferred to 22Rvl cell resistance to docetaxel while its silencing made DU145 cells more sensitive to it.Analysis of resistance markers showed no presenee of ATP-binding cassette subfamily B member 1(MDR1)and no changes in breast cancer resistance protein(BCRP)or ATP-binding cassette subfamily C member 10(MRP7).However,a correlation between ZEB1,multidrug resistance-associated protein 1(MRP1),and ATP-binding cassette subfamily C member 4(MRP4)expression was observed.MRP4 inhibition,using MK571,resensitized cells with ZEB1 overexpression to docetaxel treatment.In addition,modulation of ZEB1 and subsequent change in MRP4 expression correlated with a lower apoptotic response to docetaxel,characterized by lower B-cell lymphoma 2(Bcl2),high BCL2-associated X protein(Bax),and high active caspase 3 expression.The response to docetaxel in our model seems to be mediated mainly by activation of the apoptotic death program.Our results showed that modulation of MRP4 could be a mediator of ZEBl-related resistance to docetaxel in prostate cancer,making it a possible marker for chemotherapy response in patients who do not express MDR1.

关键词： chemoresistance prostate cancer ZEB1

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The transcription factor ZEB1 promotes an aggressive phenotype in prostate cancer cell lines

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Asian Journal of Andrology 2018年第3期20卷 294-299页

作者： Octavio Orellana-Serradell Daniela Herrera Enrique A Castellon Hector R Contreras Department of Basic and Clinical Oncology Faculty of Medicine University of Chile Independencia Santiago 8380453 Chile.

It has been reported that one of the factors that promotes tumoral progression is the abnormal activation of the epithelial-mesenchymal transition program. This process is associated with tumoral cells acquiring invasive and malignant properties and has the transcription factor zinc finger E-box-binding homeobox 1 （ZEB1） as one of its main activators. However, the role of ZEB1 in promoting malignancy in prostate cancer （PC, a） is still unclear. Here, we report that ZEB1 expression correlates with Gleason score in PCa samples and that expression of ZEB1 regulates epithelial-mesenchymal transition and malignant characteristics in PCa cell lines. The results showed that ZEB1 expression is higher in samples of higher malignancy and that overexpression of ZEB1 was able to induce epithelial-mesenchymal transition by upregulating the mesenchymal marker Vimentin and downregulating the epithelial marker E-Cadherin. On the contrary, ZEB 1 silencing repressed Vimentin expression and upregulated E-Cadherin. ZEB1 expression conferred enhanced motility and invasiveness and a higher colony formation capacity to 22Rvl cells whereas DU145 cells with ZEB1 silencing showed a decrease in those same properties. The results showed that ZEB1 could be a key promoter of tumoral progression toward advanced stages of PC, a.

关键词： epithelial-mesenchymal transition prostate cancer transcriptional repression ZEB1

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In-vivo optical imaging in head and neck oncology: basic principles, clinical applications and future directions

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International Journal of Oral Science 2018年第1期10卷 14-26页

作者： Chenzhou Wu John Gleysteen Nutte Tarn Teraphongphom Yi Li Eben Rosenthal State Key Laboratory of Oral Diseases & National clinical Research Center for Oral Diseases & department of Head and Neck oncology West China Hospital of StomatologySichuan University department of Otolaryngology University of Tennessee Health Science Center department of Otolaryngology and Radiology Stanford University

Head and neck cancers become a severe threat to human’s health nowadays and represent the sixth most common cancer worldwide. Surgery remains the first-line choice for head and neck cancer patients. Limited resectable tissue mass and complicated anatomy structures in the head and neck region put the surgeons in a dilemma between the extensive resection and a better quality of life for the patients. Early diagnosis and treatment of the pre-malignancies, as well as real-time in vivo detection of surgical margins during en bloc resection, could be leveraged to minimize the resection of normal tissues. With the understanding of the head and neck oncology, recent advances in optical hardware and reagents have provided unique opportunities for real-time pre-malignancies and cancer imaging in the clinic or operating room. Optical imaging in the head and neck has been reported using autofluorescence imaging, targeted fluorescence imaging, high-resolution microendoscopy, narrow band imaging and the Raman spectroscopy. In this study, we reviewed the basic theories and clinical applications of optical imaging for the diagnosis and treatment in the field of head and neck oncology with the goal of identifying limitations and facilitating future advancements in the field.

关键词：中国牙科口腔医学

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Liquid biopsy to detect resistance mutations against anti-epidermal growth factor receptor therapy in metastatic colorectal cancer

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World Journal of Gastrointestinal oncology 2022年第9期14卷 1654-1664页

作者： Guillermo Valenzuela Mauricio Burotto Katherine Marcelain Jaime Gonzalez-Montero Department of Basic and Clinical Oncology University of ChileSantiago 8380453Chile department of Internal Medicine Hospital del SalvadorSantiago 7500922Chile department of oncology Bradford-Hill Clinical Research CenterSantiago 8420383Chile

Colorectal cancer(CRC) is a major cause of mortality worldwide, associated with a steadily growing prevalence. Notably, the identification of KRAS, NRAS, and BRAF mutations has markedly improved targeted CRC therapy by affording treatments directed against the epidermal growth factor receptor(EGFR) and other anti-angiogenic therapies. However, the survival benefit conferred by these therapies remains variable and difficult to predict, owing to the high level of molecular heterogeneity among patients with CRC. Although classification into consensus molecular subtypes could optimize response prediction to targeted therapies, the acquisition of resistance mutations to targeted therapy is, in part, responsible for the lack of response in some patients. However, the acquisition of such mutations can induce challenges in clinical practice. The utility of liquid biopsy to detect resistance mutations against anti-EGFR therapy has recently been described. This approach may constitute a new standard in the decision algorithm for targeted CRC therapy.

关键词： Colorectal neoplasms Precision medicine Liquid biopsy Cetuximab Panitumumab

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New era:prospects for managing cancer of unknown primary

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癌症生物学与医学:英文版 2023年第8期20卷 562-567页

作者： Yize Li Yinmiao Bai Hongchen Ji Zhihui Liu Hongmei Zhang department of clinical oncology Xijing HospitalThe Fourth Military Medical UniversityXi’an 710032China

Cancer of unknown primary(CUP)is a highly heterogeneous tumor type that is confirmed to be metastatic through pathological examination;however,its primary lesion cannot be determined on the basis of detailed clinical information and diagnostic methods.The current guidelines have not changed the basic definition of CUP.Some studies have reported a decline in the incidence of CUP,to approximately 2%1,with the development of diagnostic techniques such as radiology,histopathology,and genetic testing.

关键词： Cancer clinical cancer

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The genetic and epigenetic alterations in human hepatocellular carcinoma： a recent update

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Protein & Cell 2014年第9期5卷 673-691页

作者： Ming Liu Lingxi Jiang Xin-Yuan Guan department of clinical oncology University of Hong Kong Hong Kong China

Hepatocellular carcinoma （HCC） is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally accepted that the progression of HCC is a long-term process with accumulation of multiple genetic and epigenetic alterations, which further lead to the activation of critical oncogenes or inactivation of tumor suppressor genes. HCC is characterized with multiple cancer hallmarks including their ability to proliferate, anti-poptosis, invade, metastasis, as well as the emerging features such as stem cell properties and energy metabolic switch. The irreversible alterations at genetic level could be detected as early as in the pre-neoplastic stages and accumulate during cancer progression. Thus, they might account for the cancer initiating steps and further malignant transformation. In addition to genetic alterations, epigenetic alterations can affect the cancer transcriptome more extensively. Alterations in DNA methylation, histone modification, miRNAs, RNA editing, and IncRNAs might result in disrupted gene regulation networks and substantially contribute to HCC progression. In this review, the genetic and epigenetic alterations which significantly contribute to the malignant capabilities of HCC will be updated and summarized in detail. Further characterization of those critical molecular events might better elucidate the pathogenesis of HCC and provide novel therapeutic targets for treatment of this deadly disease.

关键词： hepatocellular carcinoma （HCC） cancerhallmarks genetic regulation epigenetic regulation,therapeutic targets HCC progression

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Consensus molecular subtypes of colorectal cancer in clinical practice:A translational approach

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World Journal of clinical oncology 2021年第11期12卷 1000-1008页

作者： Guillermo Valenzuela Joaquín Canepa Carolina Simonetti Loreto Solo de Zaldívar Katherine Marcelain Jaime González-Montero basic and clinical oncology department University of ChileSantiago 8380453Chile

The identification of several genetic mutations in colorectal cancer(CRC)has allowed a better comprehension of the prognosis and response to different antineoplastic treatments.Recently,through a systematic process,consensus molecular subtypes(CMS)have been described to characterize genetic and molecular mutations in CRC patients.Through CMS,CRC patients can be categorized into four molecular subtypes of CRC by wide transcriptional genome analysis.CMS1 has microsatellite instability and mutations in CIMP and BRAF pathways.CMS2,distinguished by mutations in specific pathways linked to cellular metabolism,also has a better prognosis.CMS3 has a KRAS mutation as a hallmark.CMS4 presents mutations in fibrogenesis pathways and mesenchymalepithelial transition,associated with a worse prognosis.CMS classification can be a meaningful step in providing possible answers to important issues in CRC,such as the use of adjuvant chemotherapy in stage II,personalized first-line chemotherapy for metastasic CRC,and possible new target treatments that address specific pathways in each molecular subtype.Understanding CMS is a crucial step in personalized medicine,although prospective clinical trials selecting patients by CMS are required to pass proof-of-concept before becoming a routine clinical tool in oncology routine care.

关键词： Colorectal neoplasms Precision medicine Microsatellite instability Nextgeneration sequencing

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Long non-coding RNAs in hepatocellular carcinoma: Potential roles and clinical implications

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World Journal of Gastroenterology 2017年第32期23卷 5860-5874页

作者： Zhao-Shan Niu Xiao-Jun Niu Wen-Hong Wang Laboratory of Micromorphology School of Basic MedicineMedical Department of Qingdao University oncology Specialty Medical Department of Qingdao University department of Pathology School of Basic MedicineMedical Department of Qingdao University

Long non-coding RNAs(lnc RNAs) are a subgroup of non-coding RNA transcripts greater than 200 nucleotides in length with little or no protein-coding potential. Emerging evidence indicates that lnc RNAs may play important regulatory roles in the pathogenesis and progression of human cancers, including hepatocellular carcinoma(HCC). Certain lnc RNAs may be used as diagnostic or prognostic markers for HCC, a serious malignancy with increasing morbidity and high mortality rates worldwide. Therefore, elucidating the functional roles of lnc RNAs in tumors can contribute to a better understanding of the molecular mechanisms of HCC and may help in developing novel therapeutic targets. In this review, we summarize the recent progress regarding the functional roles of lnc RNAs in HCC and explore their clinical implications as diagnostic or prognostic biomarkers and molecular therapeutic targets for HCC.

关键词： Hepatocellular carcinoma Long non-coding RNAs Function Biomarker Therapeutic target

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The commensal consortium of the gut microbiome is associated with favorable responses to anti-programmed death protein 1 (PD-1) therapy in thoracic neoplasms

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Cancer Biology & Medicine 2021年第4期18卷 1040-1052页

作者： Huihui Yin Lu Yang Gongxin Peng Ke Yang Yuling Mi Xingsheng Hu Xuezhi Hao Yuchen Jiao Xiaobing Wang Yan Wang State Key Laboratory of Molecular oncology department of Medical oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Center for Bioinformatics Institute of Basic Medical SciencesChinese Academy of Medical Sciences&School of Basic MedicinePeking Union Medical CollegeBeijing 100021China department of Medical oncology Cancer Hospital of Huanxing Chaoyang District BeijingBeijing 100122China department of Medical oncology Chaoyang Sanhuan Cancer HospitalBeijing 100021China

Objective:Immune checkpoint inhibitors have revolutionized cancer therapy for multiple types of solid tumors,but as expected,a large percentage of patients do not show durable responses.Biomarkers that can predict clinical responses to immunotherapies at diagnosis are therefore urgently needed.Herein,we determined the associations between baseline gut commensal microbes and the clinical treatment efficiencies of patients with thoracic neoplasms during anti-programmed death protein 1(PD-1)therapy.Methods:Forty-two patients with advanced thoracic carcinoma who received anti-PD-1 treatment were enrolled in the study.Baseline and time-serial stool samples were analyzed using 16S ribosomal RNA gene sequencing.Tumor responses,patient progression-free survival,and overall survival were used to measure clinical outcomes.Results:The diversities of the baseline gut microbiota were similar between responders(n=23)and nonresponders(n=19).The relative abundances of the Akkermansiaceae,Enterococcaceae,Enterobacteriaceae,Carnobacteriaceae and Clostridiales Family XI bacterial families were significantly higher in the responder group.These 5 bacterial families acted as a commensal consortium and better stratified patients according to clinical responses(P=0.014).Patients with a higher abundance of commensal microbes had prolonged PFS(P=0.00016).Using multivariable analysis,the abundance of the commensal consortium was identified as an independent predictor of anti-PD-1 immunotherapy in thoracic neoplasms(hazard ratio:0.17;95%confidence interval:0.05–0.55;P=0.003).Conclusions:Baseline gut microbiota may have a critical impact on anti-PD-1 treatment in thoracic neoplasms.The abundance of gut commensal microbes at diagnosis might be useful for the early prediction of anti-PD-1 immunotherapy responses.

关键词： Gut microbiota commensal microbes anti-PD-1 immunotherapy thoracic neoplasms

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Classification of patients with metastatic colorectal cancer into consensus molecular subtypes into real-world: A pilot study

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World Journal of clinical oncology 2023年第10期14卷 409-419页

作者： Jaime González-Montero Mauricio Burotto Guillermo Valenzuela Debora Mateluna Florencia Buen-Abad Jessica Toro Olga Barajas Katherine Marcelain Bradford Hill clinical Research Center Santiago 8420383Chile basic and clinical oncology department University of ChileSantiago 8380453Chile

BACKGROUND Colorectal cancer is a complex disease with high mortality rates.Over time,the treatment of metastatic colorectal cancer(mCRC)has gradually improved due to the development of modern chemotherapy and targeted therapy regimens.However,due to the inherent heterogeneity of this condition,identifying reliable predictive biomarkers for targeted therapies remains challenging.A recent promising classification system—the consensus molecular subtype(CMS)system—offers the potential to categorize mCRC patients based on their unique biological and molecular characteristics.Four distinct CMS categories have been defined:immune(CMS1),canonical(CMS2),metabolic(CMS3),and mesenchymal(CMS4).Nevertheless,there is currently no standardized protocol for accurately classifying patients into CMS categories.To address this challenge,reverse transcription polymerase chain reaction(RT-qPCR)and next-generation genomic sequencing(NGS)techniques may hold promise for precisely classifying mCRC patients into their CMSs.AIM To investigate if mCRC patients can be classified into CMS categories using a standardized molecular biology workflow.METHODS This observational study was conducted at the University of Chile clinical Hospital and included patients with unresectable mCRC who were undergoing systemic treatment with chemotherapy and/or targeted therapy.Molecular biology techniques were employed to analyse primary tumour samples from these patients.RT-qPCR was utilized to assess the expression of genes associated with fibrosis(TGF-βandβ-catenin)and cell growth pathways(c-MYC).NGS using a 25-gene panel(TumorSec)was performed to identify specific genomic mutations.The patients were then classified into one of the four CMS categories according to the clinical consensus of a Tumour Board.Informed consent was obtained from all the patients prior to their participation in this study.All techniques were conducted at University of Chile.RESULTS Twenty-six patients were studied with the techniques and then evaluated by the Tumour Board to dete

关键词： Metastatic colorectal cancer Targeted therapy Consensus molecular subtypes Personalized medicine

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