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Role of SKP1-CUL1-F-Box-Protein (SCF) E3 Ubiquitin Ligases in Skin Cancer

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Journal of Genetics and Genomics 2013年第3期40卷 97-106页

作者： Chuan-Ming Xie Wenyi Wei Yi Sun School of Biomedical Sciences The Chinese University of Hong Kong Shatin New Territories Department of pathology Beth Israel Deaconess Medical Center Harvard Medical School Division of Radiation and Cancer Biology Department of Radiation Oncology University of Michigan

Many biological processes such as cell proliferation, differentiation, and cell death depend precisely on the timely synthesis and degradation of key regulatory proteins. While protein synthesis can be regulated at multiple levels, protein degradation is mainly controlled by the ubiquitin-proteasome system （UPS）, which consists of two distinct steps：（1） ubiquitylation of targeted protein by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase, and （2） subsequent degradation by the 26S proteasome. Among all E3 ubiquitin ligases, the SCF （SKP1-CUL1-F-box protein） E3 ligases are the largest family and are responsible for the turnover of many key regulatory proteins. Aberrant regulation of SCF E3 ligases is associated with various human diseases, such as cancers, including skin cancer. In this review, we provide a comprehensive overview of all currently published data to define a promoting role of SCF E3 ligases in the development of skin cancer. The future directions in this area of research are also discussed with an ultimate goal to develop small molecule inhibitors of SCF E3 ligases as a novel approach for the treatment of human skin cancer. Furthermore, altered components or substrates of SCF E3 ligases may also be developed as the biomarkers for early diagnosis or predicting prognosis.

关键词： Carcinogenesis F-box proteins RING proteins SCF E3 ligases Skin Ubiquitin ligases

pathology of Alcoholic Liver Disease

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Journal of Clinical and Translational Hepatology 2014年第2期2卷 103-109页

作者： Romulo Celli Xuchen Zhang Department of pathology Yale University School of Medicine New Haven CT USA pathology and Laboratory Service VA Connecticut Health System and Department of Pathology Yale University School of Medicine West Haven CT USA

Alcohol-attributable burden on global health is increasing, and the relationship between population alcohol consumption and liver-related deaths is strong. Longstanding scientific and clinical work has led to a relatively thorough, if not complete, understanding of the effects of alcohol consumption on the liver. Pathologic features of alcoholic liver disease (ALD) are recognized by pathologists and used to assist clinicians in diagnosing and determining severity of disease in patients suspected of ALD. In this review, we discuss the pathologic manifestations of ALD and provide salient points on their pathophysiology. In addition, the benefits and indications of liver biopsy and important differential diagnoses, including features distinguishing these entities, are reviewed.

关键词： Alcoholic liver disease Steatosis Steatohepatitis pathology

Multi-layered control of PD-L1 expression in Epstein-Barr virus-associated gastric cancer

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 116-130页

作者： Christos N.Miliotis Frank J.Slack HMS Initiative for RNA Medicine Department of PathologyCancer CenterBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMA 02115USA

Gastric cancer(GC)is the fifth most common cancer *** approximately 10%of GC cases,cancer cells show ubiquitous and monoclonal Epstein-Barr virus(EBV)infection.A significant feature of EBV-associated GC(EBVaGC)is high lymphocytic infiltration and high expression of immune checkpoint proteins,including programmed death-ligand 1(PD-L1).This highlights EBVaGC as a strong candidate for immune checkpoint blockade ***,several recent studies have shown that EBV positivity in GC correlates with positive response to programmed cell death protein 1(PD-1)/PD-L1 blockade *** the mechanisms that control PD-L1 expression in EBVaGC can indicate new predictive biomarkers for immunotherapy,as well as therapeutic targets for combination *** mechanisms have been implicated in PD-L1 expression regulation,including structural variations,post-transcriptional control,oncogenic activation of intrinsic signaling pathways,and increased sensitivity to extrinsic *** review provides the most recent updates on the multilayered control of PD-L1 expression in EBVaGC.

关键词： Epstein-Barr virus gastric cancer immunotherapy programmed death-ligand 1

miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells

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Neural Regeneration Research 2025年第1期20卷 277-290页

作者： Meng Cong Jing-Jing Hu Yan Yu Xiao-Li Li Xiao-Ting Sun Li-Ting Wang Xia Wu Ling-Jie Zhu Xiao-Jia Yang Qian-Ru He Fei Ding Hai-Yan Shi School of Medicine Nantong UniversityNantongJiangsu ProvinceChina Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education and Coinnovation Center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina Department of Physiology Jiangsu Health Vocational CollegeNanjingJiangsu ProvinceChina Department of pathology Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina

Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve ***-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular ***,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain *** investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose *** mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest *** performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest ***,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded ***,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously *** findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in ***-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell *** helps to explain the mechanism of action of the secretome and e

关键词： axotomy cell-free therapy conditioned medium extracellular vesicles hypoxic preconditioning microRNA oxygen-glucose deprivation peripheral nerve injury Schwann cell precursors

Resistance to apoptosis should not be taken as a hallmark of cancer

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Chinese Journal of Cancer 2014年第2期33卷 47-50页

作者： Rui-An Wang Zeng-Shan Li Qing-Guo Yan Xiu-Wu Bian Yan-Qing Ding Xiang Du Bao-Cun Sun Yun-Tian Sun Xiang-Hong Zhang Department of pathology The Fourth Military Medical University Department of pathology The Third Military Medical University Department of pathology Nanfang Medical University Department of pathology Fudan University Department of pathology Tianjin Medical University Department of pathology Cancer Hospital of Chinese Academy for Medical Sciences Department of pathology Hebei Medical University

In the research community, resistance to apoptosis is often considered a hallmark of cancer. However, pathologists who diagnose cancer via microscope often see the opposite. Indeed, increased apoptosis and mitosis are usually observed simultaneously in cancerous lesions. Studies have shown that increased apoptosis is associated with cancer aggressiveness and poor clinical outcome. Furthermore, overexpression of Bcl-2, an antiapoptotic protein, is linked with better survival of cancer patients. Conversely, Bax, CD95, Caspase-3, and other apoptosis-inducing proteins have been found to promote carcinogenesis. This notion of the role of apoptosis in cancer is not new; cancer cells were found to be short-lived 88 years ago. Given these observations, resistance to apoptosis should not be considered a hallmark of cancer.

关键词：癌症患者抗凋亡蛋白 Caspase-3 抗细胞凋亡 Bcl-2蛋白 Bax蛋白有丝分裂过度表达

Ethnic difference of Helicobacter pylori gastritis: Korean and Japanese gastritis is characterized by male- and antrum-predominant acute foveolitis in comparison with American gastritis

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World Journal of Gastroenterology 2005年第1期11卷 94-98页

作者： Inchul Lee Hojung Lee Mijung Kim Manabu Fukumoto Shinji Sawada Shriram Jakate Victor E.Gould Department of pathology

AIM: To investigate the clinicopathological factors underlying the ethnic differences of Helicobacter pylori gastritis and ***: We analyzed clinicopathological parameters of gastric biopsies having H pylori infection that were randomly selected from different ethnic populations including 147 Americans, 149 Japanese, and 181 ***: Males were predominant in Japanese and Korean populations (77.9 and 67.4% respectively) in comparison with Americans (48.3%) (P＜0.001). H pylori gastritis in Koreans and Japanese was characterized by the predominant antral involvement. In the antrum,neutrophilic infiltration into the proliferative zone of pit, i,*** foveolitis, was more frequent in Koreans (82%) than in Japanese (71%) (P＜0.05) and Americans (61%) (P＜0.001).Interstitial neutrophilic infiltration, intestinal metaplasia and atrophy were also frequent in Koreans and Japanese. In the body, the prevalence of acute foveolitis was not significantly different among the populations while chronic interstitial inflammation and lymphoid follicles were more pronounced in the body of Americans than in the body of others (P＜0.01).CONCLUSION: The male-, and antrum-predominant Hpylori gastritis in Koreans and Japanese is compatible with the pattern of sex and topographical distribution of gastric cancer incidence. Our data suggest that persistent acute foveolitis at the proliferative zone is a crucial step in the gastric carcinogenesis.

关键词： Helicobacter pylori in fection Gastritis Ethnic groups

Proteolytic-antiproteolytic balance and its regulation in carcinogenesis

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World Journal of Gastroenterology 2005年第9期11卷 1251-1266页

作者： Elzbieta Skrzydlewska Mariola Sulkowska Mariusz Koda Stanislaw Sulkowski Department Department of pathology

Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g. cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.

关键词： Proteases Protease inhibitors Reactive oxygen species

pathology handling of pancreatoduodenectomy specimens:Approaches and controversies

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World Journal of Gastrointestinal Oncology 2014年第9期6卷 351-359页

作者： María del Carmen Gómez-Mateo Luis Sabater-Ortí Antonio Ferrández-Izquierdo Department of pathology Hospital Universitario Donostia Department of General and Gastroenterological Surgery Hospital Clínico ValenciaUniversity of Valencia Department of pathology Hospital Clínico ValenciaUniversity of Valencia

Pancreatic cancer,with a 5% 5-year survival rate,is the fourth leading cause of cancer death in Western ***,only 20% of all patients benefit from surgical *** need to prolong survival has prompted pathologists to develop improved protocols to evaluate pancreatic specimens and their surgical ***,the new protocols will provide clinicians with more powerful prognostic indicators and accurate information to guide their therapeutic *** the availability of several guidelines for the handling and pathology reporting of duodenopancreatectomy specimens and their continual updating by expert pathologists,there is no consensus on basic issues such as surgical margins or the definition of incomplete excision(R1) of pancreatic ductal *** article reviews the problems and controversies that dealing with duodenopancreatectomy specimens pose to pathologists,the various terms used to define resection margins or infiltration,and *** reviewing the literature,including previous guidelines and based on our own experience,we present our protocol for the pathology handling of duodenopancreatectomy specimens.

关键词： Pancreatic ductal adenocarcinoma Duodenopancreatectomy specimens Resection margins pathology protocols

The pathology of unusual subtypes of prostate cancer

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Chinese Journal of Cancer Research 2016年第1期28卷 130-143页

作者： Jing Li Zhe Wang State Key Laboratory of Cancer Biology Department of Pathology Xi Jing Hospital Fourth Military Medical University

There are some current literatures describing the morphologic change of prostate carcinoma variants. Some subtypes do not respond to hormone deprivation therapy, for example adenosquamous and squamous cell carcinoma （SQCC）, basaloid and adenoid cystic carcinoma （ACC）, small cell carcinoma （SmCC）, sarcomatoid carcinoma, urothelial carcinoma; some are defined in special Gleason grade, some develop different prognosis. So, it is very important to identify these rare subtypes to avoid misdiagnosis. In this review, we aim to describe the typical clinicopathological features of the rare variants of prostate cancer, including prostate acinar adenocarcinoma morphologic variants.

关键词： Prostate carcinoma subtype ductal neuroendocrine (NE) squamous mucinous foamy pseudo hyperplastic