1 材料与方法

1.1 数据来源

1.2 芯片数据的预处理

1.3 差异表达基因的筛选

1.4 NPC与OSCC共享风险基因网络的构建

1.5 识别NPC与OSCC共享风险功能模块

1.6 网络拓扑属性分析与核心基因的识别

1.7 KEGG通路富集分析

2 结果与分析

2.1 芯片数据的预处理

图1

2.2 差异表达基因的筛选

2.3 NPC与OSCC共享风险基因网络的构建

图2

2.4 疾病网络模块与核心基因的识别

2.5 模块的功能富集分析

图3

3 讨论

The authors have declared that no competing interests exist.

作者已声明无竞争性利益关系。

参考文献 View Option 原文顺序
文献年度倒序
文中引用次数倒序
被引期刊影响因子

[1] Chua MLK, Wee JTS, Hui EP, Chan ATC . Nasopharyngeal carcinoma
Lancet, 2016,387(10022):1012-1024. [DOI]
[本文引用: 1]

[2] Jiang S, Dong Y . Human papillomavirus and oral squamous cell carcinoma: A review of HPV-positive oral squamous cell carcinoma and possible strategies for future
Curr Probl Cancer, 2017,41(5):323-327. [DOI]
URLPMID:28416242 [本文引用: 1]
Abstract Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Besides tobacco use and alcohol consumption, human papillomavirus (HPV) infection has also been identified as a risk factor for OSCC recently. The OSCC incidence has increased in recent years, especially among younger women. The purpose of this article is to review clinical and epidemiological studies on the association between HPV infection and OSCCs, and the efficacy of HPV vaccine, so as to provide possible policy implications for preventing HPV-positive OSCC. It is necessary to review the present related body of knowledge to determine whether the association between HPV infection and OSCC has been thoroughly studied. The study was based on literature review. Studies were identified using electronic databases including MEDLINE, PubMed, EMBASE, etc. The inclusion and exclusion criteria were based on consultation from a panel of experts in this area and carefully designed. Based on a systematic review of literatures, HPV infection is a possible cause for the incidence of HPV-positive OSCCs. The prevalence of HPV infection possibly contributed to the increasing trends of HPV-positive OSCCs. Oral HPV infection is a form of HPV transmission. Oral sex behaviors and open-mouthed kissing are probably reasons for oral HPV infection. We also have some epidemiological evidences proving that HPV vaccine provides a possible solution for preventing oral HPV infection. Increased awareness of HPV-positive OSCCs is essential due to the severity of this problem. Biological and epidemiological data regarding the link between sexual behavior and HPV-associated cancers indicate a probable connection, although definitive data are needed. Future studies are needed to investigate the mechanisms of how HPV infection causes HPV-positive OSCCs, whether HPV vaccine provides a prevention for OSCCs, and other important issues. Copyright 2017 Elsevier Inc. All rights reserved.

[3] Stearns FW . One hundred years of pleiotropy: a retrospective
Genetics, 2010,186(3):767-773. [DOI]
URLPMID:21062962 [本文引用: 1]
No abstract available.

[4] Lee YR, Chen M, Pandolfi PP . The functions and regulation of the PTEN tumour suppressor: new modes and prospects
Nat Rev Mol Cell Biol, 2018,19(9):547-562. [DOI]
URL [本文引用: 1]

[5] Newman ME . Modularity and community structure in networks
Proc Natl Acad Sci USA, 2006,103(23):8577-8582. [DOI]
[本文引用: 1]

[6] Clauset A, Newman ME, Moore C . Finding community structure in very large networks
Phys Rev E Stat Nonlin Soft Matter Phys, 2004,70(6 pt 2):66111. [DOI]
URLPMID:15697438 [本文引用: 1]
The discovery and analysis of community structure in networks is a topic of considerable recent interest within the physics community, but most methods proposed so far are unsuitable for very large networks because of their computational cost. Here we present a hierarchical agglomeration algorithm for detecting community structure which is faster than many competing algorithms: its running time on a network with n vertices and m edges is O (md log n) where d is the depth of the dendrogram describing the community structure. Many real-world networks are sparse and hierarchical, with m approximately n and d approximately log n, in which case our algorithm runs in essentially linear time, O (n log(2) n). As an example of the application of this algorithm we use it to analyze a network of items for sale on the web site of a large on-line retailer, items in the network being linked if they are frequently purchased by the same buyer. The network has more than 400 000 vertices and 2 x 10(6) edges. We show that our algorithm can extract meaningful communities from this network, revealing large-scale patterns present in the purchasing habits of customers.

[7] Zhao XL, Zuo XY, Qin JH, Liang Y, Zhang NZ, Luan YZ, Rao SQ . A novel biological pathway expansion method based on the knowledge of protein-protein interactions
Hereditas (Beijing) , 2014,36(04):387-394.
[本文引用: 1]

赵小蕾, 左晓宇, 覃继恒, 梁岩, 张乃尊, 栾奕昭, 饶绍奇 . 基于蛋白质互作知识的生物学通路扩充新方法
遗传, 2014,36(4):387-394. [DOI]
[本文引用: 1]

[8] Travers J, Milgram S . An experimental study of the small world problem
Sociometry, 1969,32(4):425-443. [DOI]
URL [本文引用: 1]
Arbitrarily selected individuals (N=296) in Nebraska and Boston are asked to generate acquaintance chains to a target person in Massachusetts, employing "the small world method" (Milgram, 1967). Sixty-four chains reach the target person. Within this group the mean number of intermediaries between starters and targets is 5.2. Boston starting chains reach the target person with fewer intermediaries than those starting in Nebraska; subpopulations in the Nebraska group do not differ among themselves. The funneling of chains through sociometric "stars" is noted, with 48 per cent of the chains passing through three persons before reaching the target. Applications of the method to studies of large scale social structure are discussed.

[9] Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller JW . Pleiotropy in complex traits: challenges and strategies
Nat Rev Genet, 2013,14(7):483-495. [DOI]
URLPMID:4104202 [本文引用: 1]
Abstract Genome-wide association studies have identified many variants that each affects multiple traits, particularly across autoimmune diseases, cancers and neuropsychiatric disorders, suggesting that pleiotropic effects on human complex traits may be widespread. However, systematic detection of such effects is challenging and requires new methodologies and frameworks for interpreting cross-phenotype results. In this Review, we discuss the evidence for pleiotropy in contemporary genetic mapping studies, new and established analytical approaches to identifying pleiotropic effects, sources of spurious cross-phenotype effects and study design considerations. We also outline the molecular and clinical implications of such findings and discuss future directions of research.

[10] Wang J, Mei F, Gao X, Wang S . Identification of genes involved in Epstein-Barr virus-associated nasopharyngeal carcinoma
Oncol Lett, 2016,12(4):2375-2380. [DOI]
URLPMID:27698802 [本文引用: 1]
Nasopharyngeal carcinoma (NPC) is the most common cancer originating from the nasopharynx, and can be induced by infection with Epstein-Barr virus (EBV). To study the mechanisms of EBV-associated NPC, a microarray of the GSE12452 dataset was analyzed. GSE12452 was downloaded from Gene Expression Omnibus and consisted of 31 NPC samples and 10 normal healthy nasopharyngeal tissue samples. The differentially-expressed genes (DEGs) were screened using the linear models for microarray data package in R. Using Database for Annotation, Visualization and Integrated Discovery software, potential functions of the DEGs were predicted by Gene Ontology and pathway enrichment analyses. With the information from the Search Tool for the Retrieval of Interacting Genes/Proteins database, the protein-protein interaction (PPI) network was visualized by Cytoscape. Furthermore, modules of the PPI network were searched using ClusterONE in Cytoscape. A total of 951 DEGs were screened in the NPC samples compared with the normal healthy nasopharyngeal tissue samples. Function enrichment indicated that the upregulated genes were associated with the cell cycle, cytoskeleton organization and DNA metabolism. Meanwhile, the downregulated genes were mainly associated with cell differentiation, hormone metabolism, inflammatory response and immune response. PPI networks for the DEGs suggested that upregulated mitotic arrest deficient 2-like 1 (MAD2L1; degree=133), proliferating cell nuclear antigen (PCNA; degree=125) and cyclin B1 (CCNB1; degree=115), and downregulated member A1 of aldehyde dehydrogenase 1 (ALDH1A1; degree=15) may be of great importance as they exhibited higher degrees on interaction. Mucin 1 (MUC1) was a key node of module 4. Overall, the study indicated thatMAD2L1,CCNB1,PCNA,ALDH1A1andMUC1may have a correlation with EBV-associated NPC.

[11] Kato K, Kawashiri S, Yoshizawa K, Kitahara H, Okamune A, Sugiura S, Noguchi N, Yamamoto E . Expression form of p53 and PCNA at the invasive front in oral squamous cell carcinoma: correlation with clinicopathological features and prognosis
J Oral Pathol Med, 2011,40(9):693-698. [DOI]
URLPMID:21501231Magsci [本文引用: 1]
J Oral Pathol Med (2011) 40: 693-698Background: Abnormalities in cell-cycle-controlling genes are important in the malignant transformation and proliferation of tumors. Among these genes, the tumor suppressor gene p53 is the most notable, and its mutations provide an indicator of tumor progression and prognosis. Proliferating cell nuclear antigen (PCNA) is a highly conserved nuclear protein that is expressed during cell replication and DNA repair. This study examined the expression of p53 and PCNA at the invasive front of oral squamous cell carcinomas (OSCC) by immunohistochemical staining, and investigated the relationship of these proteins to clinicopathological findings and prognosis.Methods: Fifty-nine biopsy cases of OSCC were examined by immunohistochemical staining. Clinicopathological data were gathered and patient survival was analyzed.Results: The p53 labeling index (p53-LI) and PCNA labeling index (PCNA-LI) were examined at the invasive front of the tumors. A high p53-LI (p53+) was observed in 17 of the 59 cases (28.8%) and a high PCNA-LI (PCNA+) was observed in 28 of the 59 cases (47.5%). Among the modes of cancer invasion, many of the p53+/PCNA+ cases could be confirmed as highly invasive cancer (P < 0.05). In addition, the p53+/PCNA+ cases showed a high risk of tumor recurrence compared with the other expression forms, and patients with p53+/PCNA+ had a worse prognosis than those with the other expression forms. High labeling indices of p53 and PCNA are associated with poor prognosis in patients with OSCC.Conclusion: We suggest that it is important to investigate the expression of p53 and PCNA at the invasive front of OSCC.

[12] Poosarla C, Ramesh M, Ramesh K, Gudiseva S, Bala S, Sundar M. Proliferating cell nuclear antigen in premalignancy and oral squamous cell carcinoma
J Clin Diagn Res, 2015, 9(6): ZC39-C41. [DOI]
URLPMID:26266215 [本文引用: 1]
Abstract INTRODUCTION: Cancer has multifactorial aetiology and is a multistep process involving initiation, promotion and tumour progression. Cellular proliferation is one of the important indicators for the biologic aggressiveness of a malignant lesion. The dysregulated proliferation may be a significant change to determine the potential prognosis of various malignant tumours. AIM: The aim of this study was to evaluate the expression of proliferating cell nuclear antigen (PCNA) as an indicator for clinical aggressiveness in oral premalignancy and squamous cell carcinoma. MATERIALS AND METHODS: A total of 50 blocks were taken from the Department of Oral Pathology which was diagnosed previously histopathologically. It comprised of normal oral mucosa (10), dysplasia (10) and grades of oral squamous cell carcinoma (30) of patients between the age group of 40-60 years. From each block, sections of 4 micro metre thicknesses were prepared and placed on poly- L lysine coated slides. These sections were immunohistochemically stained with monoclonal proliferating cell antibody (PC10). The stained slides were evaluated by a single examiner for cell count. RESULTS: A comparison between study groups and controls showed a probability value (p-value) < 0.05. Significant increase in the proliferative index from the normal to oral squamous cell carcinoma was noticed. Poorly differentiated squamous cell carcinoma showed maximum proliferative index followed by moderately differentiated, well differentiated squamous cell carcinoma, dysplasia and normal mucosa. CONCLUSION: Present study concluded that PCNA index can be used to assess the proliferation and aggressiveness in dysplasia and different grades oral squamous cell carcinoma.

[13] Madan M, Chandra S, Raj V, Madan R . Evaluation of cell proliferation in malignant and potentially malignant oral lesions
J Oral Maxillofac Pathol, 2015,19(3):297-305. [DOI]
URLPMID:4774281 [本文引用: 1]
To evaluate the cell proliferation rate by the expression of proliferating cell nuclear antigen (PCNA) and argyrophilic nucleolar organizing region (AgNOR) counts and to assess its usefulness as a marker for malignant potential in oral epithelial lesions. The study group included 30 cases of leukoplakia, 15 nondysplastic (NDL), 15 dysplastic (DL), 15 cases of oral squamous cell carcinoma (OSCC) and 5 cases of normal oral mucosa. Formalin fixed paraffin embedded tissues were subjected to immunohistochemical staining for PCNA and AgNOR technique. The PCNA labeling index (LI) and the AgNOR dots were evaluated for the entire sample. ANOVA, Tukey honestly significant difference, Pearson's correlation. In this study, the AgNOR count of OSCC was lower than the DL lesions moreover the AgNOR counts were found to be higher in normal mucosa as compared to the DL and the NDL epithelium. The study results also showed that the mean AgNOR count failed to distinguish between DL and NDL lesions. Overall we observed increased PCNA expression from normal epithelium to NDL to DL lesion. Based on the findings of the present study on oral epithelial precancerous and cancerous lesions we conclude that mean AgNOR count alone cannot be a valuable parameter to distinguish between the normal, NDL, DL epithelium and OSCC but, on the other hand, we found out that PCNA can be a useful biomarker for delineating normal epithelium from DL epithelium and OSCC.

[14] Zhai X, Yang Y, Wan J, Zhu R, Wu Y . Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells
Oncol Rep, 2013,30(6):2983-2991. [DOI]
URLPMID:24064966Magsci [本文引用: 1]
An elevated rate of glucose consumption and the dependency on aerobic glycolysis for ATP generation have long been observed in cancer cells, a phenomenon known as the Warburg effect. The altered energy metabolism in cancer cells provides an attractive opportunity for developing novel cancer therapeutic strategies. Lactate dehydrogenase (LDH), which catalyzes the transformation of pyruvate to lactate, plays a vital role in the process of glycolysis. It has been reported that the level of LDH-A expression is increased both in head and neck cancer cells and in the blood serum of nasopharyngeal carcinoma (NPC) patients, and is associated with poor prognosis. However, the effect of LDH-A inhibition on NPC cells remains unknown. Here, in the present study, we found that oxamate, a classical inhibitor of LDH-A, suppressed cell proliferation in a dose- and time-dependent manner both in CNE-1 and CNE-2 cells, two NPC cancer cell lines. LDH inhibition by oxamate induced G(2)/M cell cycle arrest via downregulation of the CDK1/cyclin B1 pathway and promoted apoptosis through enhancement of mitochondrial ROS generation. N-acetylcysteine, a specific scavenger of ROS, significantly blocked the growth inhibition effect induced by oxamate. We also identified that oxamate increased sensitivity to ionizing radiation in the two NPC cancer cell lines. Furthermore, we verified similar results in tumor xenograft models. Collectively, these results suggest that LDH-A may serve as a promising therapeutic target for NPC treatment.

[15] Chen X, Zhang FH, Chen QE, Wang YY, Wang YL, He JC, Zhou J . The clinical significance of CDK1 expression in oral squamous cell carcinoma
Med Oral Patol Oral Cir Bucal, 2015,20(1):e7-e12. [DOI]
URLPMID:25129248 [本文引用: 1]
To evaluate the clinical significance of cyclin-dependent kinase 1 (CDK1) in 77 oral squamous cell carcinomas (OSCC) using immunohistochemical methods.Immunohistochemical expression of CDK1 was compared with various clinicopathological features in 77 OSCC and 60 controlled epithelia adjacent to the tumours. In addition, correlation of CDK1 expression and prognostic and the 5-year accumulative survival rate of OSCC were investigated.The CDK1 protein was expressed in 52 cases of 77 tumor tissues (67.5%), compared with 21 cases of 60 controlled (35.0%). The expression of CDK1 was significantly correlated with the histological grade of OSCC (P<0.05). The CDK1 protein was over-expressed in recurrent tumors or in those with lymph node metastasis. Statistical analysis showed a significant reduction in the 5-year accumulative survival rate in CDK1 positive cases compared with CDK1 negative cases (P<0.05). Namely, the CDK1 positive patients had poor prognosis.The expression of CDK1 might serve as malignant degree and prognostic markers for the survival of OSCC.

[16] Zhang Y, Liu Z . STAT1 in cancer: friend or foe?
Discov Med, 2017,24(130):19-29. [DOI]
URLPMID:28950072 [本文引用: 1]
Abstract The first STAT family member, STAT1, is an essential component of interferon (IFN)-signaling, which mediates several cellular functions in response to stimulation by cytokines, growth factors, and hormones, such as the IFNs and IL-6. The role and significance of STAT1 in cancer biology have been studied for a decade. The majority of evidence shows that activating STAT1 plays a tumor suppressor role in cancer cells. Nevertheless, results from some experiments and clinical studies suggest that STAT1 also exerts tumor promoter effects under specific conditions. In some malignant phenotypes, STAT1 can function either as an oncoprotein or tumor suppressor in the same cell type, depending on the specific genetic background. Thus, the function of STAT1 in cancer biology remains a mystery. In this review, we discuss both the "friend" and "foe" features of STAT1 by summarizing its tumor suppressor or oncogenic functions and mechanisms. To explain how STAT1 may mediate its tumor suppressor effects, we discuss several possible mechanisms, one of which is linked to the role of STAT1, an isoform of STAT1.

[17] Qu S, Guo Y, Huang ST, Zhu XD . Inhibition of STAT1 sensitizes radioresistant nasopharyngeal carcinoma cell line CNE-2R to radiotherapy
Oncotarget, 2018,9(9):8303-8310. [DOI]
URL [本文引用: 1]
Radioresistance remains a major obstacle for clinicians in the treatment of nasopharyngeal carcinoma (NPC). Others and we have reported that signal transducer and activator of transcription 1 (STAT1) may be as an important gene for resistance to radiation. However, the relationship between STAT1 and radioresistance is still elusive. In this study, by constitutive silencing STAT1 in human radioresistant nasopharyngeal carcinoma CNE-2R cell line, we showed that inhibition of STAT1 enhanced radiosensitivity of CNE-2R. Furthermore, knockdown of STAT1 led to growth suppression and apoptosis promotionin vitroandin vivo. Moreover, cells with low STAT1 expression increased G2/M phase and decreased S phase at 2Gy. These result revealed that knockdown of stat1 expression could sensitizes the CNE-2R to radiotherapy, But the exact mechanism needs to be further clarified.

[18] Laimer K, Spizzo G, Obrist P, Gastl G, Brunhuber T, Schafer G, Norer B, Rasse M, Haffner MC, Doppler W . STAT1 activation in squamous cell cancer of the oral cavity: a potential predictive marker of response to adjuvant chemotherapy
Cancer, 2007,110(2):326-333. [DOI]
[本文引用: 1]

[19] Urata S, Izumi K, Hiratsuka K, Maolake A, Natsagdorj A, Shigehara K, Iwamoto H, Kadomoto S, Makino T, Naito R, Kadono Y, Lin WJ, Wufuer G, Narimoto K, Mizokami A . C-C motif ligand 5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment
Cancer Sci, 2018,109(3):724-731. [DOI]
URL [本文引用: 1]
Chemokines and their receptors have key roles in cancer progression. The present study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration ofLNCaP cells significantly increased when co‐cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identifiedCCL5 as a concentration‐dependent promoter ofLNCaP cell migration. The migration ofLNCaP cells was suppressed when C‐C motif ligand 5 (CCL5) neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interferingRNAincreased the migration ofLNCaP cells compared with control cells, andCCL5 did not promote the migration of androgen receptor knockdownLNCaP. ElevatedCCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent withCCL5 activity upstream of androgen receptor signaling.

[20] Kan JY, Wu DC, Yu FJ, Wu CY, Ho YW, Chiu YJ, Jian SF, Hung JY, Wang JY, Kuo PL . Chemokine (C-C motif) ligand 5 is involved in tumor-associated dendritic cell- mediated colon cancer progression through non-coding RNA MALAT-1
J Cell Physiol, 2015,230(8):1883-1894. [DOI]
URLPMID:25546229 [本文引用: 1]
Tumor micro-environment is a critical factor in the development of cancer. The aim of this study was to investigate the inflammatory cytokines secreted by tumor-associated dendritic cells (TADCs) that contribute to enhanced migration, invasion, and epithelial-to-mesenchymal transition (EMT) in colon cancer. The administration of recombinant human chemokine (C-C motif) ligand 5 (CCL5), which is largely expressed by colon cancer surrounding TADCs, mimicked the stimulation of TADC-conditioned medium on migration, invasion, and EMT in colon cancer cells. Blocking CCL5 by neutralizing antibodies or siRNA transfection diminished the promotion of cancer progression by TADCs. Tumor-infiltrating CD11c(+) DCs in human colon cancer specimens were shown to produce CCL5. The stimulation of colon cancer progression by TADC-derived CCL5 was associated with the up-regulation of non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), which subsequently increased the expression of Snail. Blocking MALAT-1 significantly decreased the TADC-conditioned medium and CCL5-mediated migration and invasion by decreasing the enhancement of Snail, suggesting that the MALAT-1/Snail pathway plays a critical role in TADC-mediated cancer progression. In conclusion, the inhibition of CCL5 or CCL5-related signaling may be an attractive therapeutic target in colon cancer patients.

[21] Huang CY, Fong YC, Lee CY, Chen MY, Tsai HC, Hsu HC, Tang CH . CCL5 increases lung cancer migration via PI3K, Akt and NF-kappaB pathways
Biochem Pharmacol, 2009,77(5):794-803. [DOI]
URLPMID:19073147Magsci [本文引用: 1]
CCL5 (previously called RANTES) is in the CC-chemokine family and plays a crucial role in the migration and metastasis of human cancer cells. Besides, integrins are the major adhesive molecules in mammalian cells. Here we found CCL5 increased the migration and cell surface expression of αvβ3 integrin in human lung cancer cells (A549 cells). CCL5 stimulation increased phosphorylation of the p85α subunit of phosphatidylinositol 3-kinase (PI3K) and serine 473 of Akt. Also, we found that PI3K inhibitor (Ly294002) or Akt inhibitor suppressed CCL5-induced migration activities and integrin expression of A549 cells. Transfection of cells with p85 or Akt mutant also reduced CCL5-mediated cancer migration. In addition, treatment of A549 cells with CCL5 induced IκB kinase α/β (IKK α/β) phosphorylation, IκB phosphorylation, p65 Ser phosphorylation, and κB-luciferase activity. Furthermore, the CCL5-mediated increases in p65 Ser phosphorylation were inhibited by Ly294002 and Akt inhibitor. Taken together, our results suggest that CCL5 acts through PI3K/Akt, which in turn activates IKKα/β and NF-κB, resulting in the activation of αvβ3 integrin and contributing to the migration of human lung cancer cells.

[22] Khalid A, Wolfram J, Ferrari I, Mu C, Mai J, Yang Z, Zhao Y, Ferrari M, Ma X, Shen H . Recent advances in discovering the role of CCL5 in metastatic breast cancer
Mini Rev Med Chem, 2015,15(13):1063-1072. [DOI]
URLPMID:4968951 [本文引用: 1]
A variety of therapeutic strategies are currently under investigation to inhibit factors that promote tumor invasion, as metastasis is the most common cause of mortality for cancer patients. Notably, considerable emphasis has been placed on studying metastasis as a dynamic process that is highly dependent on the tumor microenvironment. In regards to breast cancer, chemokine C-C motif ligand 5 (CCL5), which is produced by tumor-associated stromal cells, has been established as an important contributor to metastatic disease. This review summarizes recent discoveries uncovering the role of this chemokine in breast cancer metastasis, including conditions that increase the generation of CCL5 and effects induced by this signaling pathway. In particular, CCL-5-mediated cancer cell migration and invasion are discussed in the context of intertwined feedback loops between breast cancer cells and stromal cells. Moreover, the potential use of CCL5 and its receptor chemokine C-C motif receptor 5 (CCR5) as targets for preventing breast cancer metastasis is also reviewed.

[23] Ma W, Feng L, Zhang S, Zhang H, Zhang X, Qi X, Zhang Y, Feng Q, Xiang T, Zeng YX . Induction of chemokine (C-C motif) ligand 5 by Epstein-Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma
Cancer Sci, 2018,109(5):1710-1722. [DOI]
URL [本文引用: 1]
Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein–Barr virus (EBV) infection and is known to be highly vascularized. Previous studies have suggested thatEBVoncoproteins contribute toNPCangiogenesis. However, the regulatory network ofEBVin angiogenesis still remains elusive. Herein, we reveal a novel mechanism ofEBV‐induced angiogenesis inNPC. First, we showed thatEBV‐infectedNPCcell lines generated larger tumors with more microvessels in mouse xenograft models. Subsequent proteomic analysis revealed thatEBVinfection increased the expression of a series of angiogenic factors, including chemokine (C‐C motif) ligand 5 (CCL5). We then proved thatCCL5 was a target ofEBVin inducing tumor angiogenesis and growth. Further investigation through transcriptome analysis indicated that the pro‐angiogenic function ofCCL5 might be mediated by thePI3K/AKTpathway. Furthermore, we confirmed that activation of thePI3K/AKTand hypoxia‐inducible factor‐1α pathways was essential forCCL5‐promoted angiogenesis. Finally, the immunohistochemical analysis of humanNPCspecimens also showed thatCCL5 was correlated with angiogenesis. Taken together, our study identifiesCCL5 as a keyEBV‐regulated molecular driver that promotesNPCangiogenesis, suggesting it as a potential therapeutic target.

[24] Rao SK, Pavicevic Z, Du Z, Kim JG, Fan M, Jiao Y, Rosebush M, Samant S, Gu W, Pfeffer LM, Nosrat C A . Pro-inflammatory genes as biomarkers and therapeutic targets in oral squamous cell carcinoma
J Biol Chem, 2010,285(42):32512-32521. [DOI]
URLPMID:20702412 [本文引用: 1]
Oral squamous cell carcinoma (OSCC) is a major health problem worldwide, and patients have a particularly poor 5-year survival rate. Thus, identification of the molecular targets in OSCC and subsequent innovative therapies are greatly needed. Prolonged exposure to alcohol, tobacco, and pathogenic agents are known risk factors and have suggested that chronic inflammation may represent a potential common denominator in the development of OSCC. Microarray analysis of gene expression in OSCC cell lines with high basal NF-B activity and OSCC patient samples identified dysregulation of many genes involved in inflammation, wound healing, angiogenesis, and growth regulation. In particular , , , and gene expression was up-regulated in OSCC. Moreover, IL-8 protein levels were significantly higher in OSCC cell lines as compared with normal human oral keratinocytes. Targeting IL-8 expression by siRNA significantly reduced the survival of OSCC cells, indicating that it plays an important role in OSCC development and/or progression. Inhibiting the inflammatory pathway by aspirin and the proteasome/NF-B pathway by bortezomib resulted in marked reduction in cell viability in OSCC lines. Taken together our studies indicate a strong link between inflammation and OSCC development and reveal IL-8 as a potential mediator. Treatment based on prevention of general inflammation and/or the NF-B pathway shows promise in OSCCs.

[25] Chuang JY, Yang WH, Chen HT, Huang CY, Tan TW, Lin YT, Hsu CJ, Fong YC, Tang CH . CCL5/CCR5 axis promotes the motility of human oral cancer cells
J Cell Physiol, 2009,220(2):418-426. [DOI]
URLPMID:19334035 [本文引用: 1]
CCL5 (previously called RANTES) is in the CC-chemokine family and plays a crucial role in the migration and metastasis of human cancer cells. On the other hand, the effect of CCL5 is mediated via CCR receptor. RT-PCR and flow cytometry studies demonstrated CCR5 but not CCR1 and CCR3 mRNA in oral cancer cell lines, especially higher in those with high invasiveness (SCC4) as compared with lower levels in HSC3 cells and SCC9 cells. Stimulation of oral cancer cells with CCL5 directly increased the migration and metalloproteinase-9 (MMP-9) production. MMP-9 small interfering RNA inhibited the CCL5-induced MMP-9 expression and thereby significantly inhibited the CCL5-induced cell migration. Activations of phospholipase C (PLC), protein kinase C (PKC), and NF-B pathways after CCL5 treatment was demonstrated, and CCL5-induced expression of MMP-9 and migration activity was inhibited by the specific inhibitor of PLC, PKC, and NF-B cascades. In addition, migration-prone sublines demonstrate that cells with increasing migration ability had more expression of MMP-9, CCL5, and CCR5. Taken together, these results indicate that CCL5/CCR5 axis enhanced migration of oral cancer cells through the increase of MMP-9 production. J. Cell. Physiol. 220: 418-426, 2009. 2009 Wiley-Liss, Inc.

[26] Xia H, Kong SN, Chen J, Shi M, Sekar K, Seshachalam VP, Rajasekaran M, Goh B, Ooi LL, Hui KM . MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence
Cancer Lett, 2016,383(1):85-93. [DOI]
URLPMID:27693640 [本文引用: 2]
61MELK is overexpressed in HCC and correlates with early recurrence and survival.61Silencing MELK inhibits growth, invasion, stemness and tumorigenicity of HCC cells.61MELK regulates cell cycle progression and mitosis-related genes through targeting FOXM1.

[27] Kiseljak-Vassiliades K, Zhang Y, Kar A, Razzaghi R, Xu M, Gowan K, Raeburn CD, Albuja-Cruz M, Jones KL, Somerset H, Fishbein L, Leong S, Wierman ME . Elucidating the role of the maternal embryonic leucine zipper kinase in adrenocortical carcinoma
Endocrinology, 2018,159(7):2532-2544. [DOI]
URL [本文引用: 1]
Abstract Adrenocortical carcinoma (ACC) is an aggressive cancer with a five-year survival less than 35%. Mortality remains high due to lack of targeted therapies. Using bioinformatic analyses, we identified Maternal Embryonic Leucine Zipper Kinase (MELK) as 4.1-fold overexpressed in ACC compared to normal adrenal samples. High MELK expression in human tumors correlated with shorter survival and with increased expression of genes involved in cell division and growth. We investigated the functional effects of MELK inhibition using newly developed ACC cell lines with variable MELK expression, CU-ACC1 and CU-ACC2, compared with H295R cells. In vitro treatment with the MELK inhibitor, OTSSP167, resulted in a dose dependent decrease in rates of cell proliferation, colony formation and cell survival, with relative sensitivity of each ACC cell line based upon the level of MELK overexpression. To confirm a MELK specific anti-tumorigenic effect, MELK was inhibited in H295R cells via multiple shRNAs. MELK silencing resulted in 1.9-fold decrease in proliferation, and 3 to 10-fold decrease in colony formation in soft agar and clonogenicity assays, respectively. In addition, while MELK silencing had no effect on survival in normoxia, exposure to a hypoxia resulted in a 6- and 8-fold increase in apoptosis as assessed by caspase-3 activation and TUNEL, respectively. Together these data suggest that MELK is a modulator of tumor cell growth and survival in a hypoxic microenvironment in adrenal cancer cells, and support future investigation of its role as a novel therapeutic kinase target in patients with adrenocortical carcinoma.

[28] Speers C, Zhao SG, Kothari V, Santola A, Liu M, Wilder-Romans K, Evans J, Batra N, Bartelink H, Hayes DF, Lawrence TS, Brown PH, Pierce LJ, Feng FY . Maternal embryonic leucine zipper kinase (MELK) as a novel mediator and biomarker of radioresistance in human breast cancer
Clin Cancer Res, 2016,22(23):5864-5875. [DOI]
URLPMID:27225691 [本文引用: 1]
Abstract PURPOSE: While effective targeted therapies exist for estrogen receptor-positive and HER2-positive breast cancer, no such effective therapies exist for triple-negative breast cancer (TNBC), thus it is clear that additional targets for radiosensitization and treatment are critically needed. EXPERIMENTAL DESIGN: Expression microarrays, qRT-PCR, and western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition. The effect of MELK knockdown on DNA damage repair kinetics was determined using H2AX staining. The in vivo effect of MELK knockdown on radiosensitivity was performed using mouse xenograft models. Kaplan-Meier analysis was used to estimate local control and survival information and a Cox proportional hazards model was constructed to identify potential factors impacting local recurrence-free survival. RESULTS: MELK expression is significantly elevated in breast cancer tissues compared to normal tissue as well as in TNBC compared to non-TNBC. MELK RNA and protein expression is significantly correlated with radioresistance in breast cancer cell lines. Inhibition of MELK (genetically and pharmacologically) induces radiation sensitivity in vitro and significantly delayed tumor growth in vivo in multiple models. Kaplan-Meier survival and multivariable analyses identify increasing MELK expression as being the strongest predictor of radioresistance and increased local recurrence in multiple independent datasets. CONCLUSIONS: Here, we identify MELK as a potential biomarker of radioresistance and target for radiosensitization in TNBC. Our results support the rationale for developing clinical strategies to inhibit MELK as a novel target in TNBC. Copyright 2016, American Association for Cancer Research.

[29] Li S, Li Z, Guo T, Xing XF, Cheng X, Du H, Wen XZ, Ji JF . Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer
Oncotarget, 2016,7(5):6266-6280. [DOI]
URLPMID:26701722 [本文引用: 1]
Maternal embryonic leucine zipper kinase (MELK) is upregulated in a variety of human tumors, and is considered an attractive molecular target for cancer treatment. We characterized the expression of MELK in gastric cancer (GC) and measured the effects of reducing MELK mRNA levels and protein activity on GC growth. MELK was frequently overexpressed in primary GCs, and higher MELK levels correlated with worse clinical outcomes. Reducing MELK expression or inhibiting kinase activity resulted in growth inhibition, G2/M arrest, apoptosis and suppression of invasive capability of GC cellsin vitroandin vivo. MELK knockdown led to alteration of epithelial mesenchymal transition (EMT)-associated proteins. Furthermore, targeting treatment with OTSSP167 in GC patient-derived xenograft (PDX) models had anticancer effects. Thus, MELK promotes cell growth and invasiveness by inhibiting apoptosis and promoting G2/M transition and EMT in GC. These results suggest that MELK may be a promising target for GC treatment.

[30] Liu H, Sun Q, Sun Y, Zhang J, Yuan H, Pang S, Qi X, Wang H, Zhang M, Zhang H, Yu C, Gu C . MELK and EZH2 cooperate to regulate medulloblastoma cancer stem- like cell proliferation and differentiation
Mol Cancer Res, 2017,15(9):1275-1286. [DOI]
URLPMID:28536141 [本文引用: 1]
Abstract Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported that more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog (SHH)-subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK- or EZH2-positive staining status could be considered as the potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2 and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stem-like cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients. IMPLICATIONS: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness; thus, representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma. Copyright 2017, American Association for Cancer Research.

[31] Puts GS, Leonard MK, Pamidimukkala NV, Snyder DE, Kaetzel DM . Nuclear functions of NME proteins
Lab Invest, 2018,98(2):211-218. [DOI]
URL [本文引用: 1]
Nuclear functions of NME proteinsLaboratory Investigation, Published online: 23 October 2017; doi:10.1038/labinvest.2017.109

[32] Wang C, Wang W, Liu Y, Yong M, Yang Y, Zhou H . Rac GTPase activating protein 1 promotes oncogenic progression of epithelial ovarian cancer
Cancer Sci, 2018,109(1):84-93. [DOI]
URLPMID:29095547 [本文引用: 1]
Rac GTPase activating protein 1 (RacGAP1) can regulate cytokinesis and cell differentiation. The oncogenic role of RacGAP1 has been partially studied in gastric cancer, colorectal cancer, and breast cancer. In the present study, we endeavor to evaluate its expression and functions in epithelial ovarian cancer (EOC). We retrospectively collected the clinicopathological information of 117 patients who underwent curative surgery for EOC. Expression of RacGAP1 protein in primary tumor tissues was evaluated by immunohistochemistry, which was significantly associated with tumor pathological grade, tumor stage, and lymph node metastasis. Patients with lower RacGAP1 level had a longer survival time and lower recurrence risk. Multivariate results identified the independent prognostic role of RacGAP1 for both recurrence and survival in EOC patients. Cellular studies showed that RacGAP1 can positively regulate the activation of RhoA and Erk proteins. In addition, wound healing assay and Transwell assay found that RacGAP1 can up egulate the migration and invasion process of EOC cells, respectively. In all, our results not only confirmed the prognostic role of RacGAP1 for recurrence and survival in EOC patients, but also highlighted its possible potency for drug development.

[33] Imaoka H, Toiyama Y, Saigusa S, Kawamura M, Kawamoto A, Okugawa Y, Hiro J, Tanaka K, Inoue Y, Mohri Y, Kusunoki M . RacGAP1 expression, increasing tumor malignant potential, as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer
Carcinogenesis, 2015,36(3):346-354. [DOI]
URLPMID:25568185 [本文引用: 1]
Rac GTPase-activating protein (RacGAP) 1 plays a key role in controlling various cellular phenomena including cytokinesis, transformation, invasive migration and metastasis. This study investigated the function and clinical significance of RacGAP1 expression in colorectal cancer (CRC). The intrinsic functions of RacGAP1 in CRC cells were analyzed using small interfering RNA (siRNA). We analyzed RacGAP1 mRNA expression in surgical specimens from 193 CRC patients (Cohort 1) by real-time PCR. Finally, we validated RacGAP1 protein expression using formalin-fixed paraffin-embedded samples from 298 CRC patients (Cohort 2) by immunohistochemistry. Reduced RacGAP1 expression by siRNA in CRC cell lines showed significantly decreased cellular proliferation, migration and invasion. In Cohort 1, RacGAP1 expression in CRC was significantly higher than in adjacent normal mucosa and increased according to tumor node metastasis stage progression. High RacGAP1 expression in tumors was significantly associated with progression and prognosis. In Cohort 2, RacGAP1 protein was overexpressed mainly in the nuclei of CRC cells; however, its expression was scarcely observed in normal colorectal mucosa. RacGAP1 protein expression was significantly higher in CRC patients with higher T stage, vessel invasion and lymph node and distant metastasis. Increased expression of RacGAP1 protein was significantly associated with poor disease-free and overall survival. Multivariate analyses revealed that high RacGAP1 expression was an independent predictive marker for lymph node metastasis, recurrence and poor prognosis in CRC. Our data provide novel evidence for the biological and clinical significance of RacGAP1 as a potential biomarker for identifying patients with lymph node metastasis and poor prognosis in CRC.

[34] Seder C W, Hartojo W, Lin L, Silvers A L, Wang Z, Thomas D G, Giordano T J, Chen G, Chang AC, Orringer MB, Beer DG . INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma
J Thorac Oncol, 2009,4(4):455-462. [DOI]
URLPMID:19240652 [本文引用: 1]
The expression, mechanisms of regulation, and functional impact of activin (INHBA) in esophageal adenocarcinoma (EAC) have not been fully defined. INHBAexpression was examined in 46 esophageal samples (nine Barrett's metaplasia (BM); seven BM/low-grade dysplasia; eight low-grade dysplasia; seven high-grade dysplasia; 15 EAC) using oligonucleotide microarrays and real-time reverse transcription-polymerase chain reaction (RT-PCR) and in 90 tissue samples (79 EAC; 8 dysplastic; 3 BM) using immunohistochemistry (IHC). The proliferation of EAC cell lines FLO and OE-33 was examined after treatment with exogenous activin. The proliferation of OE-33 was also examined after treatment with the activin inhibitor follistatin andINHBA-targeting siRNA. OE-33 and FLO cells were treated with 5-aza-2 eoxycytidine (5-AZA) and trichostatin A to investigate the role of epigenetic regulation inINHBAexpression. Primary EACs expressed 5.7-times moreINHBAmRNA than BM samples on oligonucleotide microarray. Transcript overexpression in EAC relative to BM was confirmed on real-time RT-PCR. IHC suggested higherINHBAprotein expression in EAC (69.6%) than in the dysplastic (37.5%) and BM samples (33.3%). FLO and OE-33 treated with activin demonstrated increased proliferation, and OE-33 cells treated with follistatin andINHBA-targeting siRNA demonstrated reduced proliferation, relative to untreated controls. Treatment of FLO cells with trichostatin A and 5-AZA up-regulatedINHBAmRNA and protein production by real time RT-PCR and IHC. INHBAis overexpressed in EAC relative to dysplastic and BM tissue.INHBAoverexpression may promote cell proliferation and may be affected by promoter demethylation and histone acetylation in EAC cell lines.

[35] Lyu S, Jiang C, Xu R, Huang Y, Yan S . INHBA upregulation correlates with poorer prognosis in patients with esophageal squamous cell carcinoma
Cancer Manag Res, 2018,10:1585-1596. [DOI]
URL [本文引用: 1]
Although extranodal NK/T cell lymphoma (ENKTCL) is consistently associated with Epstein-Barr virus (EBV) infection, the manifestation and prognostic value of serum EBV antibodies still remain unknown. One hundred and forty-one patients with ENKTCL were evaluated for serum EBV EA-IgA and VCA-IgA antibodies levels in the past 24 years in our institution. Their correlation with... [Show full abstract]

[36] Hansen NU, Genovese F, Leeming DJ, Karsdal MA . The importance of extracellular matrix for cell function and
in vivo likeness. Exp Mol Pathol, 2015,98(2):286-294. [DOI]
[本文引用: 1]

[37] Wu C . Focal adhesion: a focal point in current cell biology and molecular medicine
Cell Adh Migr, 2007,1(1):13-18. [DOI]
URLPMID:19262093 [本文引用: 1]
Abstract Cell-extracellular matrix (ECM) is an important property of virtually all cells in multi-cellular organisms. Cell-ECM adhesion research, therefore, has broad impact on biology and medicine. Studies over the past three decades have resulted in tremendous advance in our understanding of the molecular basis and functions of cell-ECM adhesion. Here, I focus on some of the general lessons that we have learned from recent studies on cell-ECM adhesion. In addition, I highlight several topics in this rapidly advancing research area. These topics, which include assembly, disassembly and regulation of cell-ECM adhesion structures, the molecular mechanisms of bi-directional signaling through cell-ECM adhesions, and the tissue and organ pathobiology of cell-ECM adhesion, are pertinent to our understanding of cell-ECM adhesion and signaling.

[38] He Y, Shao FY, Pi WD, Shi C, Chen YJ, Gong DP, Wang BJ, Cao ZW, Tang KL . Largescale transcriptomics analysis suggests over-expression of BGH3, MMP9 and PDIA3 in oral squamous cell carcinoma
PLoS One, 2016,11(1):e146530. [DOI]
URLPMID:4706424 [本文引用: 1]
Oral squamous cell carcinoma (OSCC) has been reported as the most prevalent cancer of the head and neck region, while early diagnosis remains challenging. Here we took a comprehensive bioinformatics study on microarray data of 326 OSCC clinical samples with control of 165 normal tissues. The cell interaction pathways of ECM-receptor interaction and focal adhesion were found to be significantly regulated in OSCC samples. Further analysis of the topological properties and expression consistency identified that three hub genes in the gene interaction network, MMP9, PDIA3 and BGH3, were consistently up-expressed in OSCC samples. When being validated on additional microarray datasets of 41 OSCC samples, the validation rate of over-expressed BGH3, MMP9, and PDIA3 reached 90%, 90% and 84% respectively. At last, immuno-histochemical assays were done to test the protein expression of the three genes on newly collected clinical samples of 35 OSCC, 20 samples of pre-OSCC stage, and 12 normal oral mucosa specimens. Their protein expression levels were also found to progressively increase from normal mucosa to pre-OSCC stage and further to OSCC (ANOVA p = 0.000), suggesting their key roles in OSCC pathogenesis. Based on above solid validation, we propose BGH3, MMP9 and PDIA3 might be further explored as potential biomarkers to aid OSCC diagnosis.

[39] Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP . Awakening guardian angels: drugging the p53 pathway
Nat Rev Cancer, 2009,9(12):862-873. [DOI]
[本文引用: 1]

[40] Gong Z, Yang Q, Zeng Z, Zhang W, Li X, Zu X, Deng H, Chen P, Liao Q, Xiang B, Zhou M, Li X, Li Y, Xiong W, Li G . An integrative transcriptomic analysis reveals p53 regulated miRNA, mRNA, and lncRNA networks in nasopharyngeal carcinoma
Tumour Biol, 2016,37(3):3683-3695. [DOI]
URLPMID:26462838 [本文引用: 1]
It has been reported that p53 dysfunction is closely related to the carcinogenesis of nasopharyngeal carcinoma (NPC). Recently, an increasing body of evidence has indicated that microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) participate in p53-associated signaling pathways and, in addition to mRNAs, form a complex regulation network to promote tumor occurrence and progression. The aim of this study was to elucidate the p53-regulated miRNAs, mRNAs, and lncRNAs and their regulating networks in NPC. Firstly, we overexpressed p53 in the NPC cell line HNE2 and performed transcriptomic gene expression profiling (GEP) analysis, which included miRNAs, mRNAs, and lncRNAs, using microarray technology at 0, 12, 24, and 48 h after transfection. There were 38 miRNAs (33 upregulated and 5 downregulated), 2107 mRNAs (296 upregulated and 1811 downregulated), and 1190 lncRNAs (133 upregulated and 1057 downregulated) that were significantly dysregulated by p53. Some of the dysregulated molecules were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Then, we integrated previously published miRNAs, mRNAs, and lncRNAs GEP datasets from NPC biopsies to investigate the expression of these p53 regulated molecules and found that 7 miRNAs, 218 mRNAs, and 101 lncRNAs regulated by p53 were also differentially expressed in NPC tissues. Finally, p53-regulated miRNA, mRNA, and lncRNA networks were constructed using bioinformatics methods. These miRNAs, mRNAs, and lncRNAs may participate in p53 downstream signaling pathways and play important roles in the carcinogenesis of NPC. Thorough investigations of their biological functions and regulating relationships will provide a novel view of the p53 signaling pathway, and the restoration of p53 functioning or its downstream gene regulating network is potentially of great value in treating NPC patients.