Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches

Lo, Kwok Wai; Chung, Grace Tin‐Yun; To, Ka‐Fai

doi:10.1016/j.semcancer.2011.12.011

Cited by 191 publications

(162 citation statements)

References 73 publications

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“…A number of chromosomal abnormalities involving specific oncogenes and tumor suppressor genes, including amplification of NPC-associated oncogenes such as lymphotoxin b receptor (LTBR) and cyclin D1 (CCND1) 7 and deletion or inactivation of tumor suppressor genes such as p16, 8 cytochrome b5 reductase2 (CYB5R2) 9 and FEZ family zinc finger 2 (FEZF2), 10 have been detected in NPC cases. 5 This finding suggests that genomic instability might play an important role in NPC pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Li¹,

Liu²,

Lin

et al. 2014

Cancer Biology & Therapy

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These authors equally contributed to this work. Keywords: FGFR3-TACC3, fusion gene, NPC, proliferation, tumorigenesisAbbreviations: FGFR3, fibroblast growth factor receptor 3; TACC3, transforming acidic coiled-coil-containing protein 3; NPC, nasopharyngeal carcinoma; LTBR, lymphotoxin b receptor; CCND1, cyclin D1; RT-PCR, reverse transcription-PCR; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; SDS, sodium dodecyl sulfate; DTT, DL-dithiothreitol; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PI, propidium iodide.Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers.

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Section: Introductionmentioning

confidence: 99%

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Li¹,

Liu²,

Lin

et al. 2014

Cancer Biology & Therapy

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“…Nasopharyngeal carcinoma (NPC) is one of the most common cancers in southern China and Southeast Asia, with the highest incidence rate (40 per 100 000 persons per year) being among the Cantonese-speaking subpopulation in Guangdong province, China [22][23][24]. It is consistently associated with infection with Epstein-Barr virus, and occurs with striking geographical and ethnic differences in incidence [22].…”

Section: Introductionmentioning

confidence: 99%

Sp1 and c‐Myc regulate transcription of BMI1 in nasopharyngeal carcinoma

et al. 2013

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B-lymphoma mouse Moloney leukemia virus insertion region 1 (Bmi1), a member of the polycomb group, has elevated expression and is involved in the pathogenesis of various aggressive cancers, including nasopharyngeal carcinoma (NPC). To date, the mechanisms underlying the high expression of Bmi1 in NPC remain obscure. To gain new insights into the transcriptional regulation of BMI1, we cloned and characterized the promoter region of BMI1. Luciferase reporter assays demonstrated that the region from À783 to +375 showed significant promoter activity. With the use of a series of 5′-deletion and 3′-deletion promoter constructs in luciferase reporter assays, the +167/+232 and À536/À134 regions were found to be sufficient for full promoter activity. Transcriptional activity of the BMI1 promoter was dependent on the Sp1 binding site cluster (+181/ +214) as well as the E-box elements (À181), and was abolished after mutation of the two cis-elements. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays demonstrated that Sp1 bound to the region from +181 to +214 within the BMI1 promoter. In addition, gain-of-function and loss-of-function analyses revealed that Sp1 augmented Bmi1 expression. Further investigations using immunohistochemistry and quantitative RT-PCR disclosed a significant positive correlation between the expression of Sp1 and Bmi1 in normal nasopharyngeal epithelial cells, NPC cells, and NPC tissue specimens. In addition, Myc, the known transcription factor for BMI1 in neuroblastomas, also activated the transcription of BMI1 through binding to the E-box element (À181) within its promoter, and showed a positive correlation with the mRNA level of BMI1 in NPC. In conclusion, these findings provide valuable mechanistic insights into the role of Sp1 and c-Myc in BMI1 transcription in NPC, and suggest that targeting of Sp1 or c-Myc may be a potential therapeutic strategy for NPC.

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“…Ultimately, this leads to a late disease presentation as well as detection. The pathogenesis of NPC involves genetic and epigenetic changes in the nasopharyngeal epithelium (4). Previous studies have improved current understanding of the potential molecular targets and signaling pathways involved in NPC pathogenesis, which has assisted the development of targeted therapies for the treatment of NPC, including cetuximab (Erbitux ® ), bevacizumab (Avastin Potential therapeutic compounds are typically evaluated using two platforms: Two-dimensional (2D) cell culture models and in vivo animal models (10).…”

Section: Introductionmentioning

confidence: 99%

Modeling nasopharyngeal carcinoma in three dimensions

et al. 2017

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Abstract. Nasopharyngeal carcinoma (NPC) is a type of cancer endemic in Asia, including Malaysia, Southern China, Hong Kong and Taiwan. Treatment resistance, particularly in recurring cases, remains a challenge. Thus, studies to develop novel therapeutic agents are important. Potential therapeutic compounds may be effectively examined using two-dimensional (2D) cell culture models, three-dimensional (3D) spheroid models or in vivo animal models. The majority of drug assessments for cancers, including for NPC, are currently performed with 2D cell culture models. This model offers economical and high-throughput screening advantages. However, 2D cell culture models cannot recapitulate the architecture and the microenvironment of a tumor. In vivo models may recapitulate certain architectural and microenvironmental conditions of a tumor, however, these are not feasible for the screening of large numbers of compounds. By contrast, 3D spheroid models may be able to recapitulate a physiological microenvironment not observed in 2D cell culture models, in addition to avoiding the impediments of in vivo animal models. Thus, the 3D spheroid model offers a more representative model for the study of NPC growth, invasion and drug response, which may be cost-effective without forgoing quality. Contents1. Introduction 2. 2D cell culture models 3. In vivo animal models 4. 3D spheroid models 5. 3D spheroid models for high-throughput drug screening 6. NPC 3D spheroids 7. Conclusion IntroductionNasopharyngeal carcinoma (NPC) is a type of cancer that affects the nasopharynx, commonly at the posterior and superior region in the fossa of Rosenmüller (1). It is a geographically distinct cancer, which is prevalent in south-east Asia, southern China and southern Africa (2). Viral, dietary, hereditary and lifestyle factors have been identified as risk factors for NPC (2). Current NPC treatment consists of radiotherapy, chemotherapy or chemo-radiotherapy; treatment resistance, particularly in advanced and recurrent cases of NPC, remains a challenge (2). NPC is staged according to the TNM system, whereby T describes the primary tumor invasion to the tissue or organs near the nasopharynx, N describes the spread to the lymph nodes and M indicates the metastasis of the tumor. NPC is usually detected at a late stage (III or IV) (2). Early-stage NPC has unspecific and ambiguous clinical symptoms such as neck lumps, bloodstained sputum, mild hearing loss and a unilateral headache which may be ignored by its sufferer or misdiagnosed by a doctor (3). Ultimately, this leads to a late disease presentation as well as detection. The pathogenesis of NPC involves genetic and epigenetic changes in the nasopharyngeal epithelium (4). Previous studies have improved current understanding of the potential molecular targets and signaling pathways involved in NPC pathogenesis, which has assisted the development of targeted therapies for the treatment of NPC, including cetuximab (Erbitux

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Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches

Cited by 191 publications

References 73 publications

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Sp1 and c‐Myc regulate transcription of BMI1 in nasopharyngeal carcinoma

Modeling nasopharyngeal carcinoma in three dimensions

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