Abstract
Despite recent improvements in local control of head and neck cancers (HNC), distant metastasis remains a major cause of death. Hence, further understanding of HNC biology, and in particular, the genes/pathways driving metastasis is essential to improve outcome. Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and metadherin (MTDH) in HNC patient samples. Targets of miR-375 were confirmed using qRT-PCR, Western blot analysis, and luciferase assays. Phenotypic effects of miR-375 reexpression and MTDH knockdown were assessed using viability (MTS), clonogenic survival, cell migration/invasion, as well as in vivo tumor formation assays. The prognostic significance of miR-375 or MTDH in nasopharyngeal carcinoma (NPC) was determined by comparing low versus high expression groups. MiR-375 expression was significantly reduced (P = 0.01), and conversely, MTDH was significantly increased (P = 0.0001) in NPC samples. qRT-PCR, Western blots, and luciferase assays corroborated MTDH as a target of miR-375. Reexpression of miR-375 and siRNA knockdown of MTDH both decreased cell viability and clonogenic survival, cell migration/invasion, as well as in vivo tumor formation. NPC patients whose tumors expressed high levels of MTDH experienced significantly lower survival and, in particular, higher distant relapse rates (5-year distant relapse rates: 26% vs. 5%; P = 0.005). Dysregulation of miR-375 and MTDH may represent an important oncogenic pathway driving human HNC progression, particularly distant metastases, which is now emerging as a major cause of death for HNC patients. Hence, targeting this pathway could potentially be a novel therapeutic strategy by which HNC patient outcome could be improved.
Highlights
Head and neck squamous cell carcinomas (HNSCC) constitute the fifth most common malignancy worldwide [1]
Nasopharyngeal carcinoma (NPC) patients whose tumors expressed high levels of MTDH experienced significantly lower survival and, in particular, higher distant relapse rates (5-year distant relapse rates: 26% vs. 5%; P 1⁄4 0.005)
Dysregulation of miR-375 and MTDH may represent an important oncogenic pathway driving human head and neck cancers (HNC) progression, distant metastases, which is emerging as a major cause of death for HNC patients
Summary
Head and neck squamous cell carcinomas (HNSCC) constitute the fifth most common malignancy worldwide [1]. Patients with locally advanced HNSCC have 5-year overall survival (OS) rates hovering around 30% to 45%. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). (2), underscoring a considerable opportunity for improving outcome. Nasopharyngeal carcinoma (NPC) is another malignancy of the head and neck region; NPCs are distinct from other head and neck cancers (HNC) due to their unique etiologic, clinical/biological, and epidemiologic characteristics. Advanced NPC patients have a 5-year OS rate of approximately 70% [3], showing a need for improvement. It is imperative to acquire a deeper understanding of HNC biology to guide the development and evaluation of novel therapies, to improve patient outcome
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