Apolipoprotein E Promotes Invasion in Oral Squamous Cell Carcinoma
| Autor: | Michael B. Prystowsky, Olivier Loudig, Berrin Ustun, Thomas J. Belbin, Jeffrey E. Segall, Ryung S. Kim, Thomas M. Harris, Thomas J. Ow, Sangeeta K. Jayakar, Margaret Brandwein-Gensler, Geoffrey Childs |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Cell signaling Pathology medicine.medical_specialty Proto-Oncogene Proteins c-jun Biology Models Biological MMP7 Article Pathology and Forensic Medicine 03 medical and health sciences Apolipoproteins E Cell Line Tumor Gene Knockdown Techniques medicine Humans Neoplasm Invasiveness RNA Messenger Phosphorylation RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Gene knockdown Genome Human Kinase JNK Mitogen-Activated Protein Kinases Extracellular Matrix Gene Expression Regulation Neoplastic Transcription Factor AP-1 Cholesterol 030104 developmental biology Cell culture Matrix Metalloproteinase 7 Podosomes Invadopodia Carcinoma Squamous Cell Cancer research Mouth Neoplasms Transcriptome Signal Transduction |
| Zdroj: | The American Journal of Pathology. 187:2259-2272 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2017.06.016 |
| Popis: | Oral squamous cell carcinoma (OSCC) patients generally have a poor prognosis, because of the invasive nature of these tumors. In comparing transcription profiles between OSCC tumors with a more invasive (worst pattern of tumor invasion 5) versus a less invasive (worst pattern of tumor invasion 3) pattern of invasion, we identified a total of 97 genes that were overexpressed at least 1.5-fold in the more invasive tumor subtype. The most functionally relevant genes were assessed using in vitro invasion assays with an OSCC cell line (UM-SCC-1). Individual siRNA knockdown of 15 of these 45 genes resulted in significant reductions in tumor cell invasion compared to a nontargeting siRNA control. One gene whose knockdown had a strong effect on invasion corresponded to apolipoprotein E ( APOE ). Both matrix degradation and the number of mature invadopodia were significantly decreased with APOE knockdown. APOE knockdown also resulted in increased cellular cholesterol, consistent with APOE's role in regulating cholesterol efflux. APOE knockdown resulted in decreased levels of phospho–extracellular signal–regulated kinase 1/2, phospho–c-Jun N-terminal kinase, and phospho-cJun, as well as decreased activator protein 1 (AP-1) activity. Expression of matrix metalloproteinase 7 ( MMP7 ), an AP-1 target, was also significantly decreased. Our findings suggest that APOE protein plays a significant role in OSCC tumor invasion because of its effects on cellular cholesterol and subsequent effects on cell signaling and AP-1 activity, leading to changes in the expression of invasion-related proteins, including MMP7. |
| Databáze: | OpenAIRE |
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