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Neuroendocrine differentiation of prostate cancer

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Asian Journal of Andrology 2013年第3期15卷 328-332页

作者： Zhen Li Clark J Chen Jason K Wang Elaine Hsia Wei Li Jill Squires Yin Sun Jiaoti Huang Departments of Pathology and Urology Jonsson Comprehensive Cancer Center and Broad Center for Regenerative Medicine and Stem Cell Research David Geffen School of Medicine at UCLA Los Angeles CA 90095-1732. USA

Benign prostate and prostatic adeno- carcinoma contain rare quiescentneuroendocrine cells while small cell neu- roendocrine carcinoma （SCNC）, a variant form of prostate cancer, contains highly proliferative neuroendocrine tumor cells. We provide evidence that IL-8-CXCR2- P53 pathway keeps the NE cells in a quiescent state normally. P53 mutation inactivates this pathway, resulting in hyper-proliferation and aggressive beha- vior of the NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are different from those of adenocarci- noma, which explains SCNC＇s distinct bio- logy and the clinical observation that it does not respond to hormonal therapy.

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Proinflammatory cytokine TNFα promotes HPV-associated oral carcinogenesis by increasing cancer stemness

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International Journal of Oral Science 2020年第1期12卷 40-49页

作者： Hannah SHong Jonathan Akhavan Sung Hee Lee Reuben HKim Mo KKang No-Hee Park Ki-Hyuk Shin The Shapiro Family Laboratory of Viral Oncology and Aging Research UCLA School of DentistryLos AngelesCAUSA UCLA jonsson comprehensive Cancer Center Los AngelesCAUSA Department of medicine David Geffen School of Medicine at UCLALos AngelesCAUSA

High-risk human papillomaviruses(HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α(TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase(h TERT)-immortalized cells. TNFαtreatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as(1) calcium resistance,(2)anchorage independence, and(3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in h TERTimmortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated h TERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting micro RNAs mi R-203 and mi R-200 c. Overexpression of mi R-203 and mi R-200 c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.

关键词： carcinogenesis cytokine cancer

Chaperones in hepatitis C virus infection

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World Journal of Hepatology 2016年第1期8卷 9-35页

作者： Ronik Khachatoorian Samuel W French Department of Pathology and Laboratory medicine David Geffen School of Medicine at University of CaliforniaLos AngelesCA 90095United States jonsson comprehensive Cancer Center David Geffen School of Medicine at University of CaliforniaLos AngelesCA 90095United States UCLA AIDS Institute David Geffen School of Medicine at University of CaliforniaLos AngelesCA 90024United States

The hepatitis C virus(HCV) infects approximately 3% of the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 deaths occur worldwide due to HCV-associated diseases including cirrhosis and hepatocellular carcinoma. HCV is the most common indication for liver transplantation in patients with cirrhosis worldwide. HCV is an enveloped RNA virus classified in the genus Hepacivirus in the Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases:(1) binding and internalization;(2) cytoplasmic release and uncoating;(3) viral polyprotein translation and processing;(4) RNA genome replication;(5) encapsidation(packaging) and assembly; and(6) virus morphogenesis(maturation) and secretion. Many host factors are involved in the HCV life cycle. Chaperones are an important group of host cytoprotective molecules that coordinate numerous cellular processes including protein folding, multimeric protein assembly, protein trafficking, and protein degradation. All phases of the viral life cycle require chaperone activity and the interaction of viral proteins with chaperones. This review will present our current knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV infection will provide further insights into viral/host interactions and potential therapeutic targets for both HCV and other viruses.

关键词： Hepatitis C hepatitis C virus Chaperones Heat shock proteins viral life cycle

Establishment of xenografts of urological cancers on chicken chorioallantoic membrane(CAM)to study metastasis

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Precision Clinical medicine 2019年第3期2卷 140-151页

作者： Junhui Hu Moe Ishihara Arnold IChin Lily Wu Department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California at Los AngelesCA 90095USA Department of Urology David Geffen School of MedicineUniversity of California at Los AngelesCA 90095USA Department of Pediatrics David Geffen School of MedicineUniversity of California at Los AngelesCA 90095USA jonsson comprehensive Cancer Center David Geffen School of MedicineUniversity of California at Los AngelesCA 90095USA

Cancer of the urological system commonly occurs in the kidney,bladder,and prostate *** clear cell subtype of renal cell carcinoma(ccRCC)constitutes the great majority of kidney *** ccRCC portends a very poor outcome with no effective treatment *** cancer is the most common cancer in males in the *** recent advances in selective kinase inhibitors and immunotherapies,the rate of developing new treatment from bench to bedside is slow.A time-consuming step is at the animal drug testing stage,in which the mouse model is the gold *** the pursuit to streamline the in vivo cancer biology research and drug development,we explored the feasibility of the chicken chorioallantoic membrane(CAM)model to establish *** CAM model greatly shortens the time of tumor growth and lowers the cost comparing to immunocompromised *** generated CAM xenografts from ccRCC,bladder and prostate cancer,with established cancer cell lines and freshly isolated patient-derived tissues,either as primary tumor cells or small pieces of *** successful CAM engraftment rate from the different tumor sources is 70%or *** our previously established metastatic ccRCC mouse model,we showed that the CAM xenograft maintains the same tumor growth pattern and metastatic behavior as observed in *** together,CAM can serve as a valuable platform to establish new patient-derived xenografts(PDXs)to study tumor biology,thus accelerating the development of individualized treatment to halt the deadly metastatic stage of cancer.

关键词： chorioallantoic membrane prostate cancer bladder cancer kidney cancer animal mode

From bulk, single-cell to spatial RNA sequencing

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International Journal of Oral Science 2021年第4期13卷 339-344页

作者： Xinmin Li Cun-Yu Wang UCLA Technology Center for Genomics&Bioinformatics Department of Pathology and Laboratory MedicineDavid Geffen School of MedicineUCLALos AngelesCAUSA Laboratory of Molecular Signaling Division of Oral Biology and MedicineSchool of Dentistry and Jonsson Comprehensive Cancer CenterUCLALos AngelesCAUSA Department of Bioengineering Henry Samueli School of Engineering and Applied ScienceUCLALos AngelesCAUSA

RNA sequencing(RNAseq)can reveal gene fusions,splicing variants,mutations/indels in addition to differential gene expression,thus providing a more complete genetic picture than DNA *** most widely used technology in genomics tool box has evolved from classic bulk RNA sequencing(RNAseq),popular single cell RNA sequencing(scRNAseq)to newly emerged spatial RNA sequencing(spRNAseq).Bulk RNAseq studies average global gene expression,scRNAseq investigates single cell RNA biology up to 20,000 individual cells simultaneously,while spRNAseq has ability to dissect RNA activities spatially,representing next generation of RNA *** article highlights these technologies,characteristic features and suitable applications in precision oncology.

关键词： representing RNAseq spatially

The molecular basis for ethnic variation and histological subtype differences in prostate cancer

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Science China(Life Sciences) 2013年第9期56卷 780-787页

作者： ZONG Yang GOLDSTEIN Andrew S. HUANG JiaoTi Howard Hughes Medical Institute University of California Departments of Molecular and Medical Pharmacology University of California Urology University of California jonsson comprehensive Cancer Center David Geffen School of Medicine University of California Eli and Edythe Broad Center of Regenerative medicine and Stem Cell Research University of California Pathology and Laboratory medicine University of California

Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy.

关键词： prostate cancer castration resistance neuroendocrine differentiation small cell neuroendocrine carcinoma

Periodontitis-induced systemic inflammation exacerbates atherosclerosis partly via endothelial–mesenchymal transition in mice

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International Journal of Oral Science 2019年第3期11卷 201-212页

作者： Jin Sook Suh Sol Kim Kristina I.Bostrom Cun-Yu Wang Reuben H.Kim No-Hee Park The Shapiro Family Laboratory of Viral Oncology and Aging Research UCLA School of DentistryLos AngelesCAUSA Department of medicine David Geffen School of Medicine at UCLALos AngelesCAUSA Division of Oral Biology and medicine UCLA School of DentistryLos AngelesCAUSA UCLA jonsson comprehensive Cancer Center Los AngelesCAUSA Department of Bioengineering UCLA Samueli School of EngineeringLos AngelesCAUSA

Growing evidence suggests close associations between periodontitis and *** further understand the pathological relationships of these associations,we developed periodontitis with ligature placement around maxillary molars or ligature placement in conjunction with Porphyromonas gingivalis lipopolysaccharide injection at the ligature sites (ligature/***) in Apolipoprotein E knock out mice and studied the atherogenesis process in these *** mice were fed with high fat diet for 11 weeks and sacrificed for analyzing periodontitis,systemic inflammation,and *** did not develop periodontitis or systemic inflammation and had minimal lipid deposition in the aortas,but mice receiving ligature or ligature/*** showed severe periodontitis,systemic inflammation,and aortic plaque *** aortic plaque contained abundant macrophages and cells expressing both endothelial and mesenchymal cell *** severity of periodontitis was slightly higher in mice receiving ligature/*** than ligature alone,and the magnitude of systemic inflammation and aortic plaque formation were also notably greater in the mice with ligature/*** observations indicate that the development of atherosclerosis is due to systemic inflammation caused by severe *** vitro,*** enhanced the secretion of pro-inflammatory cytokines from macrophages and increased the adhesion of monocytes to endothelial cells by upregulating the expression of adhesion molecules from endothelial ***,secretory proteins,such as TNF-α,from macrophages induced endothelial–mesenchymal transitions of the endothelial *** together,systemic inflammation induced by severe periodontitis might exacerbate atherosclerosis via,in part,causing aberrant functions of vascular endothelial cells and the activation of macrophages in mice.

关键词： via aortic cells TNF-α did had but was

Association of an anaplastic lymphoma kinase pathway signature with cell de-differentiation, neoadjuvant chemotherapy response, and recurrence risk in breast cancer

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Cancer Communications 2020年第9期40卷 422-434页

作者： Dingxie Liu Yong Wu Bluewater Biotech LLC New ProvidenceMandaluyongNJ 07974USA Division of Cancer Research and Training Department of Internal MedicineCharles R.Drew University of Medicine and ScienceLos AngelesCA 90059USA david geffen UCLA school of medicine and UCLA Jonsson Comprehensive Cancer CenterLos AngelesCA 90059USA

Background:Aberrant activation of anaplastic lymphoma kinase(ALK)signaling has been found to be involved in the tumorigenesis of multiple types of *** aim of this study was to determine the role of this pathway in the pathogenesis of breast ***:An ALK pathway signature that we generated previously was used to compute the ALK pathway activity in 6381 breast cancer samples from 42 microarray datasets,and the associations between ALK pathway signature score and clinical variables were examined using logistic regression and survival ***:Our results indicated that high ALK pathway activity was a significant risk factor for hormone receptor-negative,high-grade breast cancer in the 42 *** pathway activity was positively associated with pathological complete response(pCR)in 15 datasets annotated with patient’s neoadjuvant chemotherapy response information(overall odds ratio=1.67,P50 years old,with positive lymph nodes,or with residual disease after neoadjuvant ***:ALK may be involved in breast cancer tumorigenesis,and ALK pathway signature score may serve as a prognostic biomarker for breast cancer.

关键词： Anaplastic Lymphoma Kinase Breast cancer Differentiation Disease free survival Gene signature Neoadjuvant chemotherapy response Prognosis prediction

Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma

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Signal Transduction and Targeted Therapy 2023年第5期8卷 2329-2344页

作者： Junhui Hu Ping Tan Moe Ishihara Nicholas ABayley Shiruyeh Schokrpur Jeremy GReynoso Yangjun Zhang Raymond JLim Camelia Dumitras Lu Yang Steven MDubinett Parmjit SJat Jacques Van Snick Jiaoti Huang Arnold IChin Robert MPrins Thomas GGraeber Hua Xu Lily Wu Department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA Department of Urology West China HospitalChengduChina Department of Hematology and Oncology University of California San DiegoSan DiegoCA92103USA Department of Neurosurgery David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA Department of Biological Repositories Department of UrologyZhongnan Hospital of Wuhan UniversityWuhanChina Department of medicine David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA jonsson comprehensive Cancer Center David Geffen School of Medicine at UCLAUniversity of California Los AngelesLos AngelesCA90095USA MRC Prion Unit at UCL Institute of Prion Diseases33 Cleveland StreetLondonW1W 7FFUK Ludwig Institute for Cancer Research Ltd BrusselsBelgium Department of Pathology Duke UniversityDurhamNCUSA Department of Urology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA Cancer Precision Diagnosis and Treatment and Translational medicine Hubei Engineering Research Center WuhanChina

Loss of function of the von Hippel-Lindau(VHL)tumor suppressor gene is a hallmark of clear cell renal cell carcinoma(ccRCC).The importance of heterogeneity in the loss of this tumor suppressor has been under *** study the impact of intratumoral VHL heterogeneity observed in human ccRCC,we engineered VHL gene deletion in four RCC models,including a new primary tumor cell line derived from an aggressive metastatic *** VHL gene-deleted(VHL-KO)cells underwent epithelial-to-mesenchymal transition(EMT)and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing(VHL+)*** tumors with either VHL+or VHL-KO cells alone exhibit minimal metastatic *** tumors displayed rampant lung metastases,highlighting a novel cooperative metastatic *** poorly proliferative VHL-KO cells stimulated the proliferation,EMT,and motility of neighboring VHL+***(POSTN),a soluble protein overexpressed and secreted by VHL non-expressing(VHL−)cells,promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular *** deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical *** work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

关键词： VHL metastasis motility